Cancer of the Larynx:

Current Concepts in the

Treatment of the Neck

Editors
A. Ferlito, Udine, Italy
W. Arnold, München, Germany

10 figures, 7 tables, 2000

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 Vol. 62, No. 4, 2000

Contents

177 Preface
Ferlito, A. (Udine); Arnold, W. (München)

178 The Biology of Tumor Invasion, Angiogenesis and Lymph Node Metastasis
Petruzzelli, G.J. (Maywood, Ill.)

186 The New Imaging-Based Classification for Describing the Location of

Lymph Nodes in the Neck with Particular Regard to Cervical Lymph Nodes
in Relation to Cancer of the Larynx
Som, P.M. (New York, N.Y.); Curtin, H.D. (Boston, Mass.); Mancuso, A.A.
(Gainsville, Fla.)

199 Diagnostic Procedures for Detection of Lymph Node Metastases in Cancer

of the Larynx
Kau, R.J. (Krefeld); Alexiou, C.; Stimmer, H.; Arnold, W. (Munich)

204 The Pathology of Neck Dissection in Cancer of the Larynx

Devaney, S.L. (Ann Arbor, Mich.); Ferlito, A.; Rinaldo, A. (Udine); Devaney, K.O.
(Ann Arbor, Mich.)

212 Classification and Terminology of Neck Dissections

Ferlito, A. (Udine); Som, P.M. (New York, N.Y.); Rinaldo, A.; Mondin, V. (Udine)

217 Surgical Treatment of the Neck in Cancer of the Larynx

Ferlito, A. (Udine); Silver, C.E. (Bronx, N.Y.); Rinaldo, A. (Udine); Smith, R.V.
(Bronx, N.Y.)

226 Nonsurgical Treatment of Advanced Metastatic Cervical Disease in Cancer

of the Larynx
Petruzzelli, G.J.; Emami, B. (Maywood, Ill.)

234 Author and Subject Index

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 ORL 2000;62:177

Preface

It is a pleasure to present a special issue devoted to ‘Cancer of the larynx:

Current concepts in the treatment of the neck’, as this highly-specialized topic
is of growing interest.
Cervical metastasis has been identified in the literature as the most adverse
independent prognostic factor in cancer of the larynx and the status of the
neck often determines the choice of treatment for the primary lesion. In the
last decade, many advances have been made in our understanding of the
mechanisms of the biology of tumor invasion, lymph node metastasis, the pat-
tern of spread of laryngeal cancer, clinical and pathological diagnostic proce-
dures for detecting cervical metastases, and the use of different surgical and
nonsurgical modalities for the management of the neck.
The authors have been selected for their high stature in their respective
subspecialist fields. It has been a pleasure to cooperate with these distin-
guished authorities and there has been a fruitful, continuous exchange of opin-
ions and information during the preparation of this special issue.
In the first article, Dr. G.J. Petruzzelli discusses the biology of tumor inva-
sion, angiogenesis, and lymph node metastasis in laryngeal cancer. This is fol-
lowed by a very interesting article dealing with the new imaging-based classifi-
cation for describing the location of lymph nodes in the neck, with particular
regard to cervical lymph nodes in relation to cancer of the larynx, written by
Drs. P.M. Som, H.D. Curtin and A.A. Mancuso. The diagnostic procedures
for detecting lymph node metastases in cancer of the larynx are presented by
Drs. R.J. Kau, Ch. Alexiou, H. Stimmer and W. Arnold. The fourth article,
written by Drs. S.L. Devaney, A. Ferlito, A. Rinaldo and K.O. Devaney, is
devoted to the pathology of neck dissection in cancer of the larynx. The subse-
quent article, written by Drs. A. Ferlito, P.M. Som, A. Rinaldo and V. Mon-
din, concerns the classification and terminology of neck dissection. It is hoped
that this approach will eliminate many often confusing and nondescriptive
terms and thereby facilitate better inter-physician and inter-institutional com-
munication. The sixth article considers surgical treatment of the neck in can-
cer of the larynx and is written by Drs. A. Ferlito, C.E. Silver, A. Rinaldo and
R.V. Smith. Finally, Drs. G.J. Petruzzelli and B. Emami devote the last article
to the nonsurgical treatment of advanced metastatic cervical disease in cancer
of the larynx.
The editors and authors hope that the reader will find this special issue
useful, informative and interesting.
Our grateful thanks go to Linda Haas for her continuous help and constant
support in organizing the manuscripts.
A. Ferlito, MD, W. Arnold, MD

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 ORL 2000;62:178–185
The Biology of Tumor Invasion,
Angiogenesis and Lymph Node
Metastasis
Guy J. Petruzzelli
Departments of Otolaryngology, Head and Neck Surgery and General Surgery, and Head and Neck Oncology
Program, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Ill., USA
Key Words
Cancer invasion W Angiogenesis W Lymph node
metastasis
Abstract
It is now well established that the development of cervi-
cal metastases, in particular those with extranodal exten-
sion of tumor, negatively impacts both regional control
and survival of patients with laryngeal carcinoma. This
chapter will begin with an introduction of the important
molecular events associated with the transition of the
squamous epithelium of the upper aerodigestive tract to
metastatic squamous cell carcinoma. We will then re-
view the critical cellular events identified as the tumor
progresses from an in situ to invasive and finally a meta-
static head and neck squamous cell carcinoma. Finally
we will review data from our own and other laboratories
which are studying the process of new blood vessel
growth (angiogenesis) induced by tumor-derived growth
factors. As we develop a better understanding of the cel-
lular and molecular mechanisms of metastasis in head
and neck squamous cell carcinoma, new therapies effec-
tive at preventing the development of secondary tumors
can be realized ultimately increasing the patient’s sur-
vival.
Copyright © 2000 S. Karger AG, Basel
© 2000 S. Karger AG, Basel
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Improved understanding of the patterns of intraorgan
spread of laryngeal cancer has led to the increased use of
oncologically sound larynx-preserving surgical proce-
dures. Adjuvant radiation therapy has been shown to
reduce the incidence of regional failure and chemoradia-
tion may eventually lead to increased survival by decreas-
ing the development of pulmonary and other distant
metastases. Despite these advances, patients with carci-
noma of the larynx, although controlled at the primary
site, continue to fail in the neck and distantly. It is now
well established that the development of cervical metas-
tases, in particular those with extranodal extension of
tumor, negatively impacts both regional control and sur-
vival of patients with laryngeal carcinoma [1]. A better
understanding of the cellular and molecular mechanisms
of metastasis in head and neck squamous cell carcinoma
(HNSCC) may lead to the genesis of new therapies effec-
tive at preventing the development of secondary tumors
and increasing the patient’s survival. This chapter will
begin with an introduction of the important molecular
events associated with the transition of the squamous epi-
thelium of the upper aerodigestive tract (UADT) to meta-
static squamous cell carcinoma. We will then review the
critical cellular events identified as the tumor progresses
from an in situ to invasive and finally a metastatic
HNSCC.
Guy J. Petruzzelli, MD, PhD, FACS
Head and Neck Oncology Program, Cardinal Bernardin Cancer Center
2160 S. First Ave, Bldg 112, Rm 270
Maywood, IL 60153 (USA)
Tel. +1 708 327 3315, Fax +1 708 327 3248, E-Mail gpetruz@wpo.it.luc.edu
 Fig. 1. Genetic events associated with the stepwise progression for normal squamous epithelium to an invasive and
metastatic HNSCC [adapted from 9].
Acquisition of the Malignant Phenotype
HNSCC, like all solid tumors, is thought to arise after a
series of genetic events resulting in accumulation of DNA
damage. Targets of these mutations include inactivation
of growth-regulating tumor suppressor genes, or the acti-
vation of oncogenes, which drive cellular proliferation by
a variety of mechanisms.
Our current understanding of cancer supports the hy-
pothesis that the development of malignant tumors is due
to alterations in normal mechanisms of cellular prolifera-
tion, differentiation, and a failure of programmed cell
death (apoptosis). These genomic changes result in partic-
ular phenotypic changes such as defects in terminal differ-
entiation, loss of response to normal growth controls,
defects in response to intracellular signals for apoptosis
and resistance to cytotoxicity, all of which provide cancer
cells a particular growth advantage. These genetic altera-
tions may be spontaneous or inherited but are most often
due to the actions of viral or chemical mutagens or direct
radiation-induced DNA damage [2, 3]. Recently is has
been demonstrated that differential epigenetic mecha-
nisms may account for the development of HNSCC in
individuals without traditional exposures to mutagens
[4].
Not all cells within a given tumor will contain identical
cytogenetic abnormalities. First proposed by Fidler and
Hart [5], this concept of tumor heterogeneity proposes
that tumors are composed of subpopulations of cells, and
these subpopulations will differ with respect to their
immunogenicity, invasiveness, growth kinetics, sensitivi-
ty to cytotoxic drugs and ability to metastasize. While
neoplasms may be heterogeneous, the local tumor envi-
Lymph Node Metastasis
ronment may favor the expansion of more aggressive
clones in the formation of metastases. Hence the clinical
observation that supraglottic tumors will present more
frequently with metastasis than comparable stage glottic
tumors. Although the size of the subpopulation of metas-
tasizing cells in any given tumor may be quite large, a very
small percentage (! 0.01%) of circulating tumor cells will
initiate metastatic colonies.
Epithelial tumors represent excellent systems in which
to study the stepwise progression resulting in an invasive
malignancy. Fearon and Vogelstein [6] were the first to
present compelling evidence identifying a sequence of
reducible cytogenetic events in the development of colo-
rectal tumors and metastases. It is likely that a similar
series of cytogenetic alterations exist in the development
of HNSCC as well. Many investigators have begun to
examine the molecular pathogenesis of HNSCC in terms
of alterations in cytogenetic, proto-oncogene activation,
growth factor production loss of tumor suppressor genes,
and failure of apoptosis [7–9] Although no specific pat-
tern of genetic events in the development of HNSCC has
been accepted, a recent comprehensive review by Myers
[9] has proposed a hypothesis for HNSCC resembling the
multi-step colorectal carcinogenesis model (fig. 1).
The Biology of Invasion
Essential characteristics of cancer are the ability to
invade surrounding tissues and metastasize to regional
and distant sites. The events attendant to local invasion
by an epithelial tumor include loss of adhesion to sur-
rounding tumor cells and basement membrane, produc-
ORL 2000;62:178–185 179
tion of enzymes and mediators which facilitate the incur-
sion of malignant cells into the subjacent connective tis-
sue, attachment to extracellular membrane molecules,
neovascularization, entry to and exit from the circulation
via attachment to endothelial cell ligands, and a repeat of
this cascade at a distant (metastatic) site [10, 11]. Attach-
ment of tumor cells to extracellular matrix, production of
proteolytic enzymes, and neovascularization (angiogene-
sis) will be reviewed in more detail with specific regard to
molecular mechanisms and the production of growth fac-
tors (cytokines) by HNSCC.
HNSCC will progress from carcinoma in situ, to mi-
croinvasive carcinoma, to an invasive tumor with stromal
invasion, to a deeply invasive tumor with lymphatic
metastasis. The essential element in the transition from
carcinoma in situ or preinvasive to invasive carcinoma is
the destruction of the underlying basement membrane.
Although an exhaustive review of basement membrane
(basal lamina) biochemistry is beyond the scope of this
article, an understanding of the components within this
layer is important to the discussion of tumor-derived
mediators of invasion.
Major components of the basement membrane include
type IV collagen, heparan sulfate proteoglycan, laminin,
and entactin. On the molecular level type IV collagen is a
polypeptide composed of repeating hydroxyproline and
hydroxylysine residues which, when polymerized, forms a
sheet-like network. Interspersed within the collage net-
work is the large (850,000) kilodalton glycoprotein lamin-
in. Laminin is composed of three long polypeptide chains
held together by disulfide bonds in a cross-like configura-
tion. The functional domains of laminin serve as recep-
tors or binding site for other laminin molecules, collagen,
entactin, and the epithelial cell surface. Entactin is anoth-
er glycoprotein with two high affinity binding sites, one
for laminin and the other for type IV collagen, thus serv-
ing as an additional reinforcing bridge within the basal
lamina [12].
The distribution of basement membrane collagen has
been shown to correlate significantly with the presence of
lymph node metastases. Incomplete or reduced staining
of basement membrane collagen and discontinuous or
poor staining for laminin have been correlated with
increased nodal metastasis [13–15]. A reasonable inter-
pretation of these studies that increased degradation of
basement membrane correlates with increased invasion
and metastasis.
Adherence to the basement membrane and extracellu-
lar matrix components is another method by which tumor
cells can facilitate local invasion and metastasis. In 1986,
180 ORL 2000;62:178–185
while attempting to isolate a specific HNSCC tumor
marker, Carey’s group [16] identified a membrane asso-
ciate protein unique to head and neck carcinomas. This
antigen (A-9) was present in low levels of normal keratino-
cytes but in much higher levels in HNSCC and seemed to
be localized to the basal pole, leading to the speculation
that it may have a role in cell adhesion. The presence of
increased expression of the A-9 antigen was shown to sig-
nificantly correlate with early recurrence and reduced dis-
easefree survival in patients [17]. Biochemical and struc-
tural analysis of the A-9 antigen identified it as an ·6-ß4
integrin [18]. Integrins are a class of high-molecule-weight
transmembrane glycoproteins composed of two noncova-
lently bound subunits (· and ß) which attach to extracellu-
lar matrix and cytoskeletal components. Both the ·6 and
ß4 integrin subunits can function as laminin receptor and
bind laminin. Experimental studies using monoclonal an-
tibodies to the · or ß subunits and laminin receptor ana-
logs have shown inhibition of attachment to laminin in
vitro and reduced metastasis formation in vivo [19, 20].
Our laboratory has investigated alterations in the pat-
tern of integrin expression in tumor cells influenced by
endothelial cells and cytokines. Soluble factors derived
from endothelial cells transiently increase adherence of
HNSCC to fibronectin and vitronectin and increase sur-
face expression of the ß integrins 1 and 4, but not 3 [21].
Alterations in tumor cell adherence and the expression of
these cell surface ligands may facilitate invasion, metasta-
sis, and neovascularization. These studies continue to elu-
cidate the mechanisms of HNSCC local invasion. The
roles of integrins in the pathology of HNSCC invasion,
metastasis, and endothelial cell interactions continue to
be investigated.
Degradation of the Extracellular Matrix
In order to breech the basement membrane and invade
the connective tissue stroma, HNSSC must produce en-
zymes capable of degrading the extracellular matrix. Gen-
eral classes of these proteolytic molecules include the
matrix metalloproteinases (MMP), named for their de-
pendence on Zn2+ as a catalyst, and the plasminogen acti-
vators. MMP can be further subdivided based on their
respective substrates into (1) interstitial collagenases, (2)
stromelysins and (3) gelatinases (table 1). Tissue-derived
metalloproteinase inhibitors (TIMP-1 and TIMP-2) have
also been identified. These proteins bind to specific acti-
vated MMP and prevent matrix degradation [22–24].
Petruzzelli
 MMP-1, -2, and -9, responsible for the degradation of Table 1. MMP produced by HNSCC
fibrillar collagen (collagens I, II, III, V), laminins and oth-
MMP Name Substrate
er basement membrane components (collagen IV, gelatin)
have been identified in HNSCC in vitro and in vivo [25– Collagenases
29]. Recently, Charous et al. [30] attempted to demon- MMP-1 Interstitial Collagens I, II, III, V, IX
strate MMP proteins using in situ hybridization. Al- collagenase
though expression of MMP-2 and TIMP-1 was consistent MMP-8 Neutrophil Collagens I, II, III, V, IX
in 21 primary HNSCC tested, expression of MMP-1 and collagenase
MMP-12 Metalloelastase Elastin
-9 was variable. Stromelysins 2 and 3 have also been iden- MMP-13 Collagenase 3 Collagen III
tified in both HNSCC and chemically induced squamous
Stromelysins
cell carcinoma [31]. The genetic mechanisms regulating
MMP-3 Stromelysin 1 Proteoglycans, collagen IV, gelatins
the expression of these proteins has also been studied. MMP-7 Matrilysin Fibronectin, collagen IV
Overexpression of stromelysin 3 genes, demonstrated by MMP-10 Stromelysin 2 Proteoglycans, collagen IV, gelatins
Northern blot analysis, has been shown in 106 of 111 MMP-11 Stromelysin 3 Laminin and fibronectin
HNSCC [32]. Gelatinases
The plasminogen activators (PA) are another class of MMP-2 Gelatinase A Gelatin, collagens IV and V
proteases which have been studied in HNSCC invasion MMP-9 Gelatinase B Gelatin, collagens IV and V
and metastasis. PA are neutral serine proteases which cat-
alyze the synthesis of plasmin from plasminogen. Plasmin
is a fibrinolytic enzyme which also is active in degrading
type IV collagen and laminin. Although two forms of PA
exist, the urokinase type (uPA) has been shown by several mechanisms of action characterized. Common features of
investigators to be important in HNSCC invasion and these polypeptides are their relatively low molecular
metastasis [33, 34]. Clayman et al. [35] have shown that weights and their ability to bind to heparin [36, 37].
increased invasion on artificial basement membranes in The ability to stimulate new blood vessel growth (neo-
vitro is correlated with high levels of u-PA production and vascularization or angiogenesis) is an integral part of orga-
upregulation of uPA mRNA. A specific antibody directed nogenesis, reproduction, and wound healing and repair,
against the uPA catalytic site will prevent invasion of and in this context it is short term and self-limiting.
basement membrane-coated filters by HNSCC. Pathologic angiogenesis is not autoregulated and results
from alterations in growth control which are part of par-
ticular disease processes. Tumor angiogenesis as well as
Angiogenesis the neovascularization of diabetic retinopathy, psoriasis,
and the synovial inflammatory changes in arthritis are all
Local tissue invasion and migration into the subjacent examples of pathological angiogenesis [36].
connective tissue matrix by HNSCC are dependent of the Our current understanding of the biology of angiogene-
production of cell surface molecules, enzymes and motili- sis in solid tumors is due in greatest extent to the work of
ty factors. In addition to the production of these locally Folkman [38, 39]. In 1972, Folkman first articulated the
active molecules, HNSCC produce growth factors or cyto- hypothesis that tumor growth was angiogenesis-depen-
kines which target other cell types. Cytokines are low- dent. Since then, studies in several in vivo systems have
molecular-weight proteins which effect cell-cell communi- shown that tumorigenesis begins in a ‘prevascular phase’.
cation and signal cellular proliferation, differentiation, Characteristics of prevascular tumors include a linear
activation, and migration. Cytokines have most actively growth phase, absence of intratumoral vessels, and size
been studied in the immune system but their roles in the limited to !1 mm3. Once tumors become vascularized,
nervous and vascular system are also being examined. obtaining nutrients and exchanging metabolic waste
Unlike the endocrine hormones, cytokines usually effect products directly with the host become more efficient and
cell-cell communication over short distances. A class of the growth properties of the tumor change. Characteris-
cytokines which has been closely linked to the expansion tics of tumors in the ‘vascular phase’ are histological dem-
of the invasive and metastatic phenotypes are the angiog- onstration of intratumor capillary networks, size 11 mm3,
enic factors. Many ‘angiogenic cytokines’ have been iden- and an exponential growth phase [38, 39]. The clinical
tified, their structures sequenced, genes cloned, and their findings of scant vascularity and the absence of metas-

Lymph Node Metastasis ORL 2000;62:178–185 181

tases associated with in situ and microinvasive HNSCC
support these data as well.
Our laboratory has been studying the mechanisms of
tumor-induced angiogenesis in HNSCC for several years.
Initial studies served to demonstrate the angiogenic prop-
erties of explants of HNSCC, using the chick embryo cho-
rioallantoic membrane (CAM) as a bioassy of angiogene-
sis. When compared to nontumor control tissues, squa-
mous cell carcinoma xenograft stimulated an augmented
angiogenic response (p = 0.01). We concluded that
HNSCC can induce an angiogenic response in vivo. Since
the embryonic CAM produces little or no inflammatory
response we concluded that the proliferation in CAM ves-
sels was a response to the production of an unidentified
angiogenic factor, and that the chick embryo CAM is an
effective model for quantifying angiogenesis induced by
head and neck tumors [40].
The current work in our laboratory is directed to
defining the specific mechanism(s) and growth factors
associated with the angiogenic response induced by
HNSCC. We have focused specifically on the relation-
ship between tumor-derived factors and their effects on
the proliferation, migration and differentiation of endo-
thelial cells in the formation of new blood vessels [41].
We have examined the supernatants of several HNSCC
cell lines for the presence of these growth factors and
determined their ability to stimulate endothelial cell pro-
liferation. Five HNSCC lines were assayed with an en-
zyme-linked immunosorbent assay for the production of
prostaglandin E2 (PGE2), transforming growth factor-ß
(TGF-ß), basic fibroblast growth factor (FGF-2), and
vascular endothelial cell growth factor/vascular perme-
ability factor (VEGF/VPF). Cell-free supernatants were
also tested in a nonradioactive proliferation assay using
human umbilical vein endothelial cells. All lines pro-
duced detectable levels of the cytokines. Additionally, all
lines stimulated endothelial cell proliferation in a dose-
dependent fashion. The effects of heparin binding on the
ability of these supernatants to stimulate endothelial cell
proliferation was determined by fractionating the super-
natant on a Sephadex heparin-copper biaffinity column.
The antiproliferative effects of heparin-copper pretreat-
ment ranged from 31.7 to 46.23% reduction in endothe-
lial cell proliferation, which was statistically significant
at p = 0.001 [42]. In addition to stimulating endothelial
cells to proliferate, HNSCC also induce structural
changes in these cells. Taitz et al. [21] have demon-
strated that pretreating endothelial cells with superna-
tants from HNSCC increased adherence of endothelial
cells to fibronectin and laminin. The increased adher-
182 ORL 2000;62:178–185
ence of these cells corresponds to increased expression of
integrins ß1 and ß4 as demonstrated by fluorescence-acti-
vated cell-sorting analysis.
Factors derived from HNSCC have also been shown to
cause enhanced migration of endothelial cells. Benefield
et al. [41] combined two methods to demonstrate that
cell-free supernatants derived from two HNSCC lines
enhanced the migration of endothelial cells. The first
assay measured the capacity of endothelial cells to repo-
pulate a wound in their monolayer. Using computerized
image analysis (Image-Pro Plus, Silver Springs, Md.,
USA) endothelial cells in media containing supernatants
from HNSCC cultures were shown to cover 30–45% of
the designated wound space, compared to only 10% cov-
ered by endothelial cells in control media. Using a two-
chamber polycarbonate filter system, these authors also
demonstrated increased endothelial cell migration in re-
sponse to diffusable HNSCC-derived factors. The addi-
tion of PGE2 and TGF-ß but not VEGF/VPF to the endo-
thelial cultures resulted in similar patterns of enhanced
migration [41].
The effects of HNSCC-derived factors on endothelial
cell proliferation, migration and adherence continue to be
investigated. The components of HNSCC-induced angio-
genesis appear to be differentially regulated by several
cytokines, endothelial cell proliferation is induced by
VEGF/VPF and inhibited by TGF-ß while migration is
enhanced by TGF-ß and PGE2. Current work in our labo-
ratory is being directed at identifying intracellular signal
pathways associated with endothelial cell activation and
the cytoskeletal reorganization required.
The ability of a tumor to stimulate an angiogenic
response should directly determine the capability of a
tumor to metastasize and ultimately kill the host. In 1986,
Srivastava et al. [43] examined the vascular density in 20
intermediate-thickness (0.76–4.0 mm of invasion) cuta-
neous melanomas and demonstrated a more than two-
fold increase in the vascular area in the 10 metastasizing
tumors. All other histological and clinical parameters
were comparable in this study.
Since this initial study, many other solid tumor sys-
tems have been examined, using immunocytochemistry
for either human factor VIII or the CD34 antigen as an
endothelial cell marker, in an attempt to correlate micro-
vessel density with nodal metastasis and clinical outcome.
A clear correlation between tumor angiogenesis and nodal
metastasis (and subsequently outcome) has been demon-
strated in early and invasive breast carcinoma [44–46],
ovarian and endometrial carcinomas [47, 48], non-small
cell lung carcinomas [49], prostatic carcinoma [50], ade-
Petruzzelli
nocarcinoma of the colon [51], and squamous cell carci- Conclusions
noma of the esophagus [52].
The accumulated data regarding microvessel density HNSCC arises as a result of a series of genetic transfor-
as a predictor of nodal metastasis, survival, or response to mations of squamous epithelial cells giving rise to the
treatment in HNSCC remains conflicting, with initially malignant phenotype. Factors such as genetic susceptibili-
good correlations between microvessel density and out- ty of the host, immune suppression, and prolonged expo-
come recently being challenged. Gasparini et al. [53], in sure to tobacco, alcohol and viruses may facilitate these
1993, evaluated microvessel densities using the CD31 genetic derangements. More aggressive clones proliferate
monoclonal antibody in biopsy specimens of 70 patients and develop into clinically detectable tumors. Tumors
with advanced head and neck cancer treated with chemo- invade local connective tissues by the production of pro-
radiotherapy. In this study, patients with microvessel teinases and the expression of cell surface markers which
densities 625 per 200 ! field had a significantly higher facilitate attachment to components of the extracellular
(p ! 0.0046) incidence of local or distant metastases. matrix. Tumor size is limited by the diffusion of nutrients
Interestingly, tumor vascularity is not predictive of the from adjacent blood vessels, however tumors circumvent
response of a tumor to chemoradiotherapy. Others have this limitation by recruiting host capillaries to form an
reported good correlations between microvessel densities intratumor blood supply. Tumor invasion of capillaries
at the leading edge of the tumor and nodal metastases in and lymphatics leads to dissemination of tumors and the
carcinoma of the tongue [54–56], floor of mouth [56, 57] establishment of histologically identical tumors at second-
and nasopharynx [58, 59]. ary sites. Unfortunately, despite advances in surgical
Conflicting data exist regarding the predictability of techniques and more sophisticated radiotherapeutic mo-
lymph node metastasis based on the angiogenic capacity dalities the development of metastases will result in the
of the primary tumor. Angiogenesis has been reported to death of nearly one-half of the patients with advanced
not serve as a predictor of lymph node metastasis by sev- HNSCC.
eral authors examing tumors from various sites in the
head and neck [60, 61]. Additionally, the tongue [62–64],
supraglottic larynx [65] and tonsil [66] have been exam- Acknowledgment
ined independently, and no significant differences in vas-
This work was supported in part by Grant No. 95–74 from the
cularity at the tumor-host interface have been demon-
American Cancer Society.
strated between metastatic and nonmetastatic tumors.
Analysis of these studies reveals possible explanations
for the discrepancies in results. Principally, there was no
uniform method for the identification and calculation of
microvessel densities in the tumor specimens. Some stud-
ies used biopsy material prior to the initiation of chemo-
radiotherapy, while others examined surgical specimens
at the time of definitive resection. Additionally there was
no standardization of the endothelial antigen (factor VII
versus the CD31 or CD34 antigens) used to identify endo-
thelial cell profiles. Finally, in the head and neck, site of
origin may be an important factor in considering angio-
genesis data. The angiogenic requirements of tumors aris-
ing in richly vascularized organs such as the tongue or
buccal mucosa may be less than those arising in less well
vascularized sites; the local milieu surrounding the tumor
may provide an ample blood supply, and obviate the need
for additional angiogenesis. Methodological and site-spe-
cific differences must be considered in interpreting im-
munohistochemical data of this type.

Lymph Node Metastasis ORL 2000;62:178–185 183

 References
1 Myers EN, Fagan JJ: Management of the neck
in cancer of the larynx. Ann Otol Rhinol Laryn-
gol 1999;108:828–832.
2 Alberts B, Bray D, Lewis J, Raff M, Roberts K,
Watson JD: Molecular Biology of the Cell, ed 3.
New York, Garland Publishing, 1994, pp
1255–1291.
3 Somers KD, Schecter GL: Genetic alterations
in head and neck cancer. Otolaryngol Clin
North Am 1992;25:1065–1071.
4 Koch WM, Lango M, Sewell D, Zahurak M,
Sidransky D: Head and neck cancer in nons-
mokers: A distinct clinical and molecular enti-
ty. Laryngoscope 1999;109:1544–1551.
5 Fidler IJ, Hart IR: Biologic diversity in meta-
static neoplasms: Origins and implications.
Science 1982;217:998–1003.
6 Fearon ER, Vogelstein B: A genetic model for
colorectal tumorigenesis. Cell 1990;61:759–
767.
7 Grandis JR, Tweardy DJ: The role of peptide
growth factors in head and neck carcinoma.
Otolaryngol Clin North Am 1992;25:1105–
1115.
8 Hegde PU, Brenski AC, Caldarelli DD, Hut-
chinson J, Panje WR, Wood NB, Le HD, Tay-
lor SG IV, Caldarelli L, Coon JS: Tumor angio-
genesis and p53 mutations. Arch Otolaryngol
Head Neck Surg 1998;124:80–85.
9 Myers JN: Molecular pathogenesis of squa-
mous cell carcinoma of the head and neck; in
Myers EN, Suen JY (eds): Cancer of the Head
and Neck, ed 3. Philadelphia, Saunders, 1996,
pp 5–16.
10 Liotta LA: Cancer invasion and metastasis. Sci
Am 1992;266:54–59.
11 Liotta LA: Tumor invasion and metastasis –
Role of the extracellular matrix. Cancer Res
1986;46:1–7.
12 Bosman FT, Havenith MG, Visser R, Cleutj-
ens JPM: Basement membranes in neoplasia.
Prog Histochem Cytochem 1992;24:1–92.
13 Hirota J, Yoneda K, Osaki T: Basement mem-
brane type IV collagen in oral squamous cell
carcinoma. Head Neck 1990;12:400–405.
14 Kumagai S, Kojima S, Imai K, Nakagawa K,
Yamamoto E, Kawahara E, Nakanishi I: Im-
munohistologic distribution of basement mem-
brane in oral squamous cell carcinoma. Head
Neck 1994;16:51–57.
15 Noguchi M, Kohama G, Hiratshuka H, Sekigu-
chi T: Clinical significance of laminin deposi-
tion and T-cell infiltration in oral cancer. Head
Neck 1993;15:125–132.
16 Kimmel KA, Carey TE: Altered expression in
squamous cell carcinoma of an orientation re-
stricted epithelial antigen detected by mono-
clonal antibody A9. Cancer Res 1986;46:3614–
3623.
17 Wolf GT, Carey TE, Schmaltz SP, McClatchey
KD, Poore J, Glaser L, Hayashida DJ, Hsu S:
Altered antigen expression predicts outcome in
squamous cell carcinoma of the head and neck.
J Natl Cancer Inst 1990;82:1566–1572.
184 ORL 2000;62:178–185
18 Van Waes C, Carey TE: Overexpression of the
A9 antigen/·6 ß4 integrin in head and neck
cancer. Otolaryngol Clin North Am 1992;25:
1117–1139.
19 Castronovo V: Laminin receptors and laminin-
binding proteins during tumor invasion and
metastasis. Invasion Metastasis 1993;13:1–30.
20 Sakamoto N, Iwahana M, Tanaka NG, Osada
Y: Inhibition of angiogenesis and tumor growth
by a synthetic laminin peptide, CDPGYIGSR-
NH2. Cancer Res 1991;51:903–906.
21 Taitz A, Petruzzelli GJ, Lozano Y, Shankar R,
Young MRI: Bi-directional stimulation of ad-
herence to extracellular matrix components by
human head and neck squamous carcinoma
cells and endothelial cells. Cancer Lett 1995;
96:253–260.
22 Boyd D: Invasion and metastasis. Cancer Me-
tastasis Rev 1996;15:77–89.
23 Chambers AF, Matrisian LM: Changing views
of the role of matrix metalloproteinases in me-
tastasis. J Natl Cancer Inst 1997;89:1260–
1270.
24 Woodhouse EC, Chuaqui RF, Liotta LA: Gen-
eral mechanisms of metastasis. Cancer 1997;
80(suppl):1529–1537.
25 Juarez J, Clayman G, Nakajima M, Tanabe
KK, Saya H, Nicolson GL, Boyd D: Role and
regulation of expression of 92-kDa type IV col-
lagenase (MMP-9) in two invasive squamous-
cell-carcinoma cell lines of the oral cavity. Int J
Cancer 1993;55:10–18.
26 Kusukawa J, Sasaguri Y, Shima I, Kameyama
T, Morimatsu M: Production of matrix metal-
loproteinase 2 (gelatinase/type IV collagenase)
and 3 (stromelysin) by cultured oral squamous
cell carcinoma. J Oral Pathol Med 1992;21:
221–224.
27 Muller D, Breathnach R, Engelmann A, Millon
R, Bronner G, Flesch H, Dumont P, Eber M,
Abecassis J: Expression of collagenase-related
metalloproteinase genes in human lung or head
and neck tumours. Int J Cancer 1991;48:550–
556.
28 Polette M, Clavel C, Muller D, Abecassis J,
Binninger I, Birembaut P: Detection of
mRNAs encoding collagenase I and stromely-
sin 2 in carcinomas of the head and neck by in
situ hybridization. Invasion Metastasis 1991;
11:76–83.
29 Yoshizaki T, Sato H, Maruyama Y, Murono S,
Furukawa M, Park CS, Seiki M: Increased
expression of membrane type 1-matrix metal-
loproteinase in head and neck carcinoma. Can-
cer 1997;79:139–144.
30 Charous SJ, Stricklin GP, Nanney LB, Netter-
ville JL, Burkey BB: Expression of matrix me-
talloproteinases and tissue inhibitor of metallo-
proteinases in head and neck squamous cell
carcinoma. Ann Otol Rhinol Laryngol 1997;
106:271–278.
31 Matrisian LM, McDonnell S, Miller DB, Navre
M, Seftor EA, Hendrix MJ: The role of the
matrix metalloproteinase stromelysin in the
progression of squamous cell carcinomas. Am J
Med Sci 1991;302:151–162.
32 Muller D, Wolf C, Abecassis J, Millon R, En-
gelmann A, Bronner G, Rouyer N, Rio MC,
Eber M, Methlin G, et al: Increased stromely-
sin 3 gene expression is associated with in-
creased local invasiveness in head and neck
squamous cell carcinomas. Cancer Res 1993;
53:165–169.
33 Markus G: The relevance of plasminogen acti-
vators to neoplastic growth. A review of recent
literature. Enzyme 1988;40:158–172.
34 Björlin G, Ljungér H, Wennerberg J, Astedt B:
Plasminogen activators in human xenografted
oropharyngeal squamous cell carcinoma. Acta
Otolaryngol (Stockh) 1987;104:568–572.
35 Clayman G, Wang SW, Nicolson GL, el Naggar
A, Mazar A, Henkin J, Blasi F, Goepfert H,
Boyd DD: Regulation of urokinase-type plas-
minogen activator expression in squamous cell
carcinoma of the oral cavity. Int J Cancer 1993;
54:73–80.
36 Petruzzelli GJ: Tumor angiogenesis. Head
Neck 1996;18:283–291.
37 Presta M, Rifkin DB: New aspects of blood ves-
sel growth: Tumor and tissue-derived angio-
genesis factors. Haemostasis 1988;18:6–17.
38 Folkman J: Editorial. What is the evidence that
tumors are angiogenesis dependent? J Natl
Cancer Inst 1990;82:4–6.
39 Folkman J: The role of angiogenesis in tumor
growth. Semin Cancer Biol 1992;3:65–71.
40 Petruzzelli GJ, Snyderman CH, Johnson JT,
Myers EN: Angiogenesis induced by head and
neck squamous cell carcinoma xenografts in
the chick embryo chorioallantoic membrane
model. Ann Otol Rhinol Laryngol 1993;102:
215–221.
41 Benefield J, Petruzzelli GJ, Fowler S, Taitz A,
Kalkanis J, Young MRI: Regulation of the
steps of angiogenesis by human head and neck
squamous cell carcinomas. Invasion Metastasis
1996;16:291–301.
42 Petruzzzelli G, Benefield J, Taitz A, Fowler S,
Kalkanis J, Scobercea S, West D, Young MRI:
Heparin-binding growth factor(s) derived from
head and neck squamous cell carcinomas in-
duce endothelial cell proliferation. Head Neck
1997;19:576–582.
43 Srivastava A, Laidler P, Davies R, Horgan K,
Hughes LE: The prognostic significance of tu-
mor vascularity in intermediate-thickness
(0.76–4.0 mm thick) skin melanoma. A quanti-
tative histologic study. Am J Pathol 1986;133:
419–423.
44 Bosari S, Lee AK, DeLellis RA, Wiley BD,
Heatley GJ, Silverman ML: Microvessel quan-
titation and prognosis in invasive breast carci-
noma. Hum Pathol 1992;23:755–761.
45 Weidner N, Folkman J, Pozza, Bevilacqua P,
Allred EN, Moore DH, Meli S, Gasparini G:
Tumor angiogenesis: A new significant and in-
dependent prognostic indicator in early-stage
breast carcinoma. J Natl Cancer Inst 1992;84:
1875–1887.
Petruzzelli
46 Weidner N, Semple JP, Welch WR, Folkman J:
Tumor angiogenesis and metastasis – Correla-
tion in invasive breast carcinoma. N Engl J
Med 1991;324:1–8.
47 Kaku T, Kamura T, Kinukawa N, Kobayshi H,
Sasaki K, Tsuruchi N, Saito T, Kawauchi S,
Tsuneyoshi M, Nakano H: Angiogenesis in en-
dometrial cancer. Cancer 1997;80:741–747.
48 Schoell WM, Pieber D, Reich O, Lahousen M,
Janicek M, Guecer F, Winter R: Tumor angio-
genesis as a prognostic factor in ovarian carci-
noma: Quantification of endothelial immuno-
reactivity by image analysis. Cancer 1997;80:
2257–2262.
49 Macchiarini P, Fontanini G, Hardin MJ,
Squartini F, Angeletti CA: Relation of neovas-
cularisation to metastasis of non-small-cell lung
cancer. Lancet 1992;340:145–146.
50 Wakui S, Furusato M, Itoh T, Sasaki H, Akiya-
ma A, Kinoshita I, Asano K, Tokuda T, Aizawa
S, Ushigome S: Tumor angiogenesis in prostat-
ic carcinoma with and without bone marrow
metastasis: A morphometric study. J Pathol
1992;168:257–262.
51 Frank RE, Saclarides TJ, Leurgans S, Speziale
NJ, Drab EA, Rubin DB: Tumor angiogenesis
as a predictor of recurrence and survival in
patients with node-negative colon cancer. Ann
Surg 1995;222:695–699.
52 Tanigawa N, Matsumura M, Amaya H, Kitao-
ka A, Shimomatsuya T, Lu C, Muraoka R,
Tanaka T: Tumor vascularity correlates with
the prognosis of patients with esophageal squa-
mous cell carcinoma. Cancer 1997;79:220–
225.
Lymph Node Metastasis
53 Gasparini G, Weidner N, Maluta S, Pozza F,
Boracchi P, Mezzetti M, Testolin A, Bevil-
acqua P: Intratumoral microvessel density and
the p53 protein: Correlation with metastasis in
head-and-neck squamous-cell carcinoma. Int J
Cancer 1993;55:739–744.
54 Doyle KM, Scher RL, Richtsmeier W, Dodd L:
Microvessel quantitation and metastasis in
squamous cell carcinoma of the head and neck.
Otolaryngol Head Neck Surg 1995;113:79–80.
55 Klijanienko J, el Naggar AK, de Braud F, Ro-
driguez Peralto JL, Rodriguez R, Itzhaki M,
Russo A, Janot F, Luboinski B, Cvitkovic E:
Tumor vascularization, mitotic index, histo-
pathologic grade, and DNA ploidy in the as-
sessment of 114 head and neck squamous cell
carcinomas. Cancer 1995;75:1649–1656.
56 Williams JK, Carlson GW, Cohen C, Derose
PB, Hunter S, Jurkiewicz MJ: Tumor angio-
genesis as a prognostic factor in oral cavity
tumors. Am J Surg 1994;168:373–380.
57 Albo D, Granick MS, Jhala N, Atkinson B,
Solomon MP: The relationship of angiogenesis
to biological activity in human squamous cell
carcinomas of the head and neck. Ann Plast
Surg 1994;32:588–594.
58 Zatterstrom UK, Brun E, Willen R, Kjellen E,
Wennerberg J: Tumor angiogenesis and prog-
nosis in squamous cell carcinoma of the head
and neck. Head Neck 1995;17:312–318.
59 Roychowdhury DF, Tseng A Jr, Fu KK, Wein-
burg V, Weidner N: New prognostic factors in
nasopharyngeal carcinoma. Tumor angiogene-
sis and C-erbB2 expression. Cancer 1996;77:
1419–1426.
ORL 2000;62:178–185
60 Carrau RL, Barnes EL, Snyderman CH, Pe-
truzzelli GJ, Kachman K, Rueger R, D’Amico
F, Johnson JT: Tumor angiogenesis as a predic-
tor of tumor aggressiveness and metastatic po-
tential in squamous cell carcinoma of the head
and neck. Invasion Metastasis 1995;15:197–
202.
61 Dray TG, Hardin NJ, Sofferman RA: Angio-
genesis as a prognostic marker in early head
and neck cancer. Ann Otol Rhinol Laryngol
1995;104:724–729.
62 Gleich LL, Biddinger PW, Pavelic ZP, Gluck-
man JL: Tumor angiogenesis in T1 oral cavity
squamous cell carcinoma: Role in predicting
tumor aggressiveness. Head Neck 1996;18:
343–346.
63 Gleich LL, Biddinger PW, Duperier FD,
Gluckman JL: Tumor angiogenesis as a prog-
nostic indicator in T2–T4 oral cavity squa-
mous cell carcinoma: A clinical-pathologic cor-
relation. Head Neck 1997;19:276–280.
64 Leedy DA, Trune DR, Kronz JD, Weidner N,
Cohen JI: Tumor angiogenesis, the p53 anti-
gen, and cervical metastasis in squamous carci-
noma of the tongue. Otolaryngol Head Neck
Surg 1994;111:417–422.
65 Kinsella JB, Kumar D, Rassekh CR, Bailey BJ:
Angiogenesis by microvascular quantitation
and prognosis in supraglottic carcinoma. Oto-
laryngol Head Neck Surg 1994;108:84.
66 Dayan S, Goldenberg J, Portugal L, Wenig B,
Ferrer K, Sabnani J: Nodal metastasis in squa-
mous cell carcinoma: p53 mutation status and
microvessel density; in Abstracts of the Fourth
International Conference on Head and Neck
Cancer, Toronto 1996, abstract 535, p 203.
185
 ORL 2000;62:186–198
The New Imaging-Based Classification for
Describing the Location of Lymph Nodes in the
Neck with Particular Regard to Cervical Lymph
Nodes in Relation to Cancer of the Larynx
Peter M. Som a Hugh D. Curtin b Anthony A. Mancuso c
a Department of Radiology, Mount Sinai School of Medicine, City University, New York, N.Y.,
b Department of Radiology, Massachusetts Eye and Ear Infirmary, Boston, Mass., and
c Department of Radiology, Shands Hospital, University of Florida College of Medicine, Gainsville, Fla., USA
Key Words
Computed tomography W Head and neck neoplasms W
Lymph nodes W Lymphatic metastasis
Abstract
For over five decades, the principle landmarks used in
cervical nodal classification were clinical and defined
either by palpation or found at the operative table. How-
ever during the past two decades, sectional imaging has
consistently improved its quality and resolution and it
has been shown that imaging can identify deep struc-
tures and adenopathy not amenable to palpation. Such
disease can alter planned operative or radiation fields. In
the April 1999 issue of the Archives of Otolaryngology –
Head Neck Surgery, for the first time an imaging-based
classification was published that gave precise anatomic
landmarks for use in classifying metastatic cervical ade-
nopathy. This classification was developed in consulta-
tion with head and neck surgeons so that the nodal levels
classified by this imaging-based system would corre-
spond closely with the nodal levels determined by utiliz-
ing the most commonly employed clinically-based clas-
© 2000 S. Karger AG, Basel
ABC 0301–1569/00/0624–0186$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
sifications. This article describes this imaging-based
classification and demonstrates its use with axial dia-
grams.
Copyright © 2000 S. Karger AG, Basel
Introduction and Historical Review
In the first four decades of the 20th century, Charpy
[1], Trotter [2], and finally Rouvière [3] developed the
basis of our present understanding of cervical lymphatic
anatomy [1–3]. These authors mapped the location and
drainage of the cervical lymph nodes and referenced the
location of these nodes to landmarks assessed by palpa-
tion and anatomy seen at surgery. Such surgical land-
marks included the carotid bifurcation, the inferior belly
of the omohyoid muscle, the posterior belly of the digast-
ric muscle, the common facial vein, and the spinal acces-
sory nerve. These authors noted the importance of the
nodal chain surrounding the internal jugular vein and
these nodes were divided into upper, middle, and lower
jugular subgroups.
Peter M. Som, MD
Department of Radiology, Mount Sinai Hospital
One Gustave Levy Place, New York, NY 10029 (USA)
Tel. +1 212 241 7420, Fax +1 212 427 8137
E-Mail peter_som@smtplink.mssm.edu
 In 1972, Lindberg [4] described the distribution of cer-
vical metastases in head and neck cancer. When com-
pared to previous papers on the cervical nodes, this work
was far more pathologically oriented as it related the loca-
tion of primary head and neck cancers to specific nodal
disease. That is, Lindberg started the movement away
from pure anatomic studies and into the realm of the
pathophysiology of tumor spread.
In 1981, Shah et al. [5] suggested that the anatomically-
based terminology be replaced with a simpler ‘level’-
based system. This work not only suggested a change in
terminology, but more importantly related tumor spread
to specific nodal levels rather than particular nodal chains
as described by Rouvière [3]. Thus, there was no longer
any distinction made between the upper internal jugular
nodes and the upper spinal accessory nodes. Rather, all of
these nodes were referred to as their level II.
Following the work of Shah et al. [5], a number of clini-
cally-based papers proposed nodal classifications that
continued to relate the distribution of nodal metastasis to
nodal ‘level’, ‘groups’, or ‘regions’. These works included
those of Spiro [6] in 1985, Suen and Goepfert [7] in 1987,
the American Joint Committee on Cancer (AJCC) and the
International Union Against Cancer (UICC) [8] in 1988,
Medina [9] in 1989, the subcommittee for neck dissection
terminology and classification of the American Academy
of Otolaryngology-Head and Neck Surgery [10] in 1991,
van den Brekel [11] in 1992, the fifth edition of AJCC
Cancer Staging Manual [12] in 1997, and Robbins [13] in
1998. Within these articles there are various definitions of
the boundaries of the nodal ‘levels’, almost all of which
remained clinically defined. Some of the key points also
noted in these papers included Robbins’ emphasis on the
importance of considering the visceral nodes, van den
Brekel’s suggestion that the dorsal region of the subman-
dibular nodes is the dorsal margin of the submandibular
gland, and his agreement with Lindberg and Robbins to
separate the posterior triangle nodes into subgroups.
These various nodal classifications changed the em-
phasis of classifying nodes from that of pure anatomical
localization to providing information that assists the sur-
geon in choosing the best type of neck dissection for a par-
ticular patient [13].
Concurrent with the surgical interest in nodal staging,
clinical computed tomography (CT) had become widely
used to map primary tumors and cervical nodal disease.
Since the introduction of refined CT in the 1980s, radiolo-
gists have also been attempting to define the cervical
nodes. In 1983, Mancuso et al. [14] suggested imaging-
based landmarks that were easily identified on axial CT
Cervical Nodal Classification
scans. In an attempt to redirect the definitions of the ‘lev-
el’ boundaries from those identified by palpation or seen
at surgery, Som in 1985 [15] and 1987 [16], also re-
emphasized the preferential use on imaging landmarks as
seen on axial CT scans. In 1998, Curtin et al. [17] suggest-
ed that the anatomic landmarks used to separate the jugu-
lar nodes into three levels should be the caudal margin of
the body of the hyoid bone and the caudal margin of the
anterior arch of the cricoid cartilage. Curtin also support-
ed using the dorsal edge of the submandibular gland as the
plane of separation between level I and level II nodes.
However, despite the efforts of these and other radiolo-
gists to incorporate imaging-based landmarks into nodal
classification, as late as 1998 few of these landmarks were
accepted by clinicians.
Reasons to Design an Imaging-Based Nodal
Classification
After nearly two decades of clinical use, CT and subse-
quently MR imaging, have established their usefulness in
the assessment of patients with head and neck cancers. As
evidence of their benefit, today approximately 80% of
patients with head and neck cancers have treatment plan-
ning CT or MR scans. In general, it is only those patients
with small, superficial tumors that do not receive such
pretreatment imaging.
In addition to providing accurate displays of the com-
plex anatomy of the head and neck, imaging can assess
deep infiltration of the primary tumor, often not appre-
ciated by direct observation and palpation, and CT and
MR imaging can identify clinically silent nodes [14, 16,
18–24]. These nodes are usually in locations difficult to
palpate (i.e., deep to the sternocleidomastoid muscle or in
the tracheoesophageal groove) or they are nodes not am-
enable to palpation (i.e., retropharyngeal or superior me-
diastinal).
This advantage of imaging over palpation may be espe-
cially relevant when evaluating the retropharyngeal
nodes, which are inaccessible to palpation and of great
prognostic importance in pharyngeal malignancies. Thus,
it was felt that an imaging-based classification should spe-
cifically address the retropharyngeal nodes; nodes not
dealt with in the prior clinically-based systems. Similarly,
it was felt that the mediastinal and visceral nodes de-
scribed in the fifth edition of the AJCC Cancer Staging
Manual should be included in any imaging-based nodal
classification.
ORL 2000;62:186–198 187
 Taking into account these potential benefits of CT and
MR imaging and assuming that the imaging studies are
properly and reproducibly performed, imaging has the
potential to provide both precise anatomic landmarks by
which to define a nodal classification and the ability to
visualize virtually all potential nodal pathology. In addi-
tion, when imaging landmarks are used, it is no longer
necessary to resort to surgical definitions of nodal levels.
However, the creation of an imaging-based classification
has little practical application if the nodal levels deter-
mined are significantly different from those identified by
clinically-based classifications. It was therefore consid-
ered imperative that there be agreement between the lev-
els as determined by both the clinically-based and imag-
ing-based classifications.
This became a particular problem when attempting to
define a line of separation between level II, III and IV
nodes and level V nodes. At first there did not seem to be
any dilemma. The posterior border of the sternocleido-
mastoid muscle is the anterior border of the posterior
triangle and thus should serve well as the imaging border
between these nodes. In fact, this boundary works well in
the upper and middle neck, above the axial level of the
bottom of the arch of the cricoid cartilage. Thus, the sepa-
ration between level II and III and level V is the posterior
border of the sternocleidomastoid muscle.
However, on axial images in the lower neck in some
patients, the identifiable posterior border of the sterno-
cleidomastoid muscle is in a plane anterior to the scalene
nodes described by Rouvière [3] and Lingeman [25].
Because these scalene nodes are classically described as
being part of the lower internal jugular nodes, they should
be classified as level IV nodes and not level V nodes. That
is, the scalene nodes should lie anterior rather than poste-
rior to the back of the sternocleidomastoid muscle. But, if
the posterior border of the sternocleidomastoid muscle is
used as the division between levels IV and V, as men-
tioned in some people it could result in scalene nodes
being classified as level V nodes (posterior to the back of
the muscle) rather than as level IV nodes and this would
be in conflict with the clinically-based classifications. To
solve this potential problem, caudal to the bottom of the
cricoid arch, we utilized an oblique line extending from
the posterior border of the sternocleidomastoid muscle to
the lateral posterior edge of the anterior scalene muscle to
separate level IV and V nodes. This line consistently
places any scalene nodes in level IV.
With these concepts in mind, we created an imaging-
based nodal classification that first appeared in the April
issue of Archives of Otolaryngology – Head Neck Surgery
188 ORL 2000;62:186–198
[26]. Despite the fact that both the imaging-based and
clinically-based classifications are designed as stand-
alone classifications, the best possible evaluation of cervi-
cal nodal disease may be obtained by utilizing both clini-
cal palpation and imaging information. As an example,
due to the slope of the shoulders, the supraclavicular fossa
is not as well defined on axial CT and MR imaging as it is
to palpation, especially when Ho’s triangle is utilized as
the defining anatomic plane [12]. In addition, on imaging
it may be difficult in some cases to precisely classify some
lymph nodes that are located at the junction between lev-
els. However, in these instances, when clinical assessment
is added to the imaging classification, such problems are
easily resolved. Similarly as mentioned, imaging may pro-
vide knowledge of nodal pathology that is inaccessible to
palpation.
How to Scan the Neck
It is imperative that any nodal classification based on
CT and MR imaging be reproducible no matter what
scanner is utilized and no matter where the imaging study
is performed. In order to accomplish this, a consistent
technique must be used. This is especially true for CT,
where such technique includes patient positioning and
gantry angulation. There is no one universal technique
that is utilized to perform CT scans of the neck. However,
the following technique is used by many head and neck
radiologists and slight variations from it do not effectively
influence the nodal levels.
The axial plane referred to in this classification is
obtained with the patient’s head in a comfortable ‘neutral’
position with the hard palate perpendicular to the table-
top and the shoulders down as far as possible. The scanner
gantry is aligned along the inferior orbital meatal (IOM)
plane and, if possible, the examination should be per-
formed with the administration of intravenous contrast to
allow the best possible differentiation of nodes from ves-
sels. The recommended field of view is 16–18 mm. With
CT, the examination is performed as contiguous 3-mm
scans from the skull base to the manubrium or as a spiral
study reconstructed as contiguous 2- or 3-mm slices. With
MR imaging, the scans should be no thicker than 5 mm
(preferably 3–4 mm) with a 1-mm inter-slice gap. If there
is a history of thyroid or cervical esophageal cancer, the
caudal margin of the studies should be extended down to
the level of the carina, to ensure inclusion of the superior
mediastinum.
Som /Curtin/Mancuso
 Table 1. Summary of the imaging-based nodal classification

Level I These nodes lie above the hyoid bone, below the mylohyoid muscle and anterior to the back of
the submandibular gland (previously classified as the submental and submandibular nodes)
Level IA These nodes lie between the medial margins of the anterior bellies of the digastric muscles
above the hyoid bone and below the mylohyoid muscles (previously known as submental
nodes)
Level IB On each side of the neck, these nodes lie lateral to the level IA nodes and anterior to the back of
each submandibular gland
Level II These nodes extend from the skull base to the level of the bottom of the body of the hyoid bone.
They are posterior to the back of the submandibular gland and anterior to the back of the
sternocleidomastoid muscle
Level IIA These nodes are level II nodes that lie either anterior, lateral, medial, or posterior to the inter-
nal jugular vein. If posterior to the vein, the nodes are inseparable from the vein (previously
classified as upper internal jugular nodes)
Level IIB These are level II nodes that lie posterior to the internal jugular vein with a fat plane separating
the nodes and the vein (previously classified as upper spinal accessory nodes)
Level III These nodes extend from the level of the bottom of the body of the hyoid bone to the level of
the bottom of the cricoid arch. They lie anterior to the back of the sternocleidomastoid muscle
(previously known as the mid-jugular nodes)
Level IV These nodes extend from the level of the bottom of the cricoid arch to the level of the clavicle.
They lie anterior to a line connecting the back of the sternocleidomastoid muscle and the
posterior-lateral margin of the anterior scalene muscle. They are also lateral to the carotid
arteries (previously known as the low jugular nodes)
Level V These nodes lie posterior to the back of the sternocleidomastoid muscle from the skull base to
the level of the bottom of the cricoid arch. From the level of the bottom of the cricoid arch to
the level of the clavicle as seen on each axial scan, they lie posterior to a line connecting the
back of the sternocleidomastoid muscle and the posterior-lateral margin of the anterior scalene
muscle. They also lie anterior to the anterior edge of the trapezius muscle
Level VA Upper level V nodes extend from the skull base to the level of the bottom of the cricoid arch.
They are posterior to the back of the sternocleidomastoid muscle
Level VB Lower level V nodes extend from the level of the bottom of the cricoid arch to the level of the
clavicle as seen on each axial scan. They are posterior to a line connecting the back of the
sternocleidomastoid muscle and the posterior-lateral margin of the anterior scalene muscle
Level VI These nodes lie between the carotid arteries from the level of the bottom of the body of the
hyoid bone to the level of the top of the manubrium (previously known as the visceral nodes)
Level VII These nodes lie between the carotid arteries below the level of the top of the manubrium and
above the level of the innominate vein (previously known as the superior mediastinal nodes)
Supraclavicular These nodes lie at or caudal to the level of the clavicle as seen on each axial scan and lateral to
nodes the carotid artery on each side of the neck. They are also above and medial to the ribs
Retropharyngeal These nodes lie within 2 cm of the skull base and they are medial to the internal carotid arter-
nodes ies
The parotid nodes and other superficial nodes are referred to by their anatomic names

Reproduced and modified with permission of the Archives of Otolaryngology – Head Neck Surgery [26].

How to Use the Imaging-Based Classification
The classification was designed to be easily and readily
usable (fig. 1–6 illustrate the classification and table 1
summarizes the classification). Each side of the neck
should be evaluated separately. That is, the ‘lines’ that are
used to define the boundaries of the levels should be
‘drawn’ separately for each side of the neck. The lines
need not actually be drawn, as when one becomes familiar
with the classification, they can be easily visually approxi-

Cervical Nodal Classification ORL 2000;62:186–198 189

1

190 ORL 2000;62:186–198 Som /Curtin/Mancuso


Fig. 1. Diagram of the neck in the lateral projection outlining the
landmarks of the imaging-based classification. Level I nodes are cau-
dal to the mylohyoid muscle and extend down to the bottom of the
body of the hyoid bone and to the posterior edge of the submandibu-
lar gland. Level II nodes extend from the skull base to the bottom of
the body of the hyoid bone and from the posterior edge of the sub-
mandibular gland to the posterior edge of the sternocleidomastoid
muscle. Level III nodes extend from the inferior margin of the level II
nodes to the bottom of the cricoid arch. They also extend back to the
posterior edge of the sternocleidomastoid muscle. Level IV nodes
extend from the inferior margin of the level III nodes to the upper
margin of the clavicle as described in the text. Their posterior margin
is an oblique plane that extends from the posterior lateral aspect of
the anterior scalene muscle (dotted line) to the posterior edge of the
sternocleidomastoid muscle. This plane is represented by oblique
lines in the figure. Level V nodes extend from the skull base to the
clavicles and are anterior to the front edge of the trapezius muscle.
Above the level of the bottom of the cricoid cartilage they are posteri-
or to the back edge of the sternocleidomastoid muscle. Between the
Cervical Nodal Classification
2
level of the bottom of the cricoid cartilage and the clavicle, they are
posterior to the oblique plane described above. The region of the lev-
el VII nodes is outlined, extending from the top of the manubrium
down to the innominate vein. These nodes essentially lie at or anteri-
or to the level of the carotid arteries. Level VI nodes are not indicated
on the diagram. They are located below the bottom of the body of the
hyoid bone and above the top of the manubrium, situated between
the carotid arteries.
Fig. 2. Diagram of an axial slice of the neck at the level of C2. The
internal carotid artery (C) and internal jugular vein (J) are identified
on each side. Within 2 cm of the skull base, if a node is medial to the
inner aspect of either internal carotid artery, that node is classified as
a retropharyngeal node. Nodes anterior, lateral and behind the inter-
nal jugular vein are level IIA nodes. At this level of the neck, there
rarely are nodes posterior to (J) and anterior to back edge of the ster-
nocleidomastoid muscle. However, such a node would be a level IIA
node. Nodes posterior to the back of the sternocleidomastoid muscle
are level VA nodes (see text).
ORL 2000;62:186–198 191
Fig. 3. Diagram of an axial slice of the neck at a level just caudal to
the body of the mandible. DG = The anterior belly of the digastric
muscle, C = the internal carotid artery, J = the internal jugular vein,
and SMG = the submandibular gland. Level IA nodes are central to
the medial margin of the anterior belly of the each digastric muscle.
Level IB nodes are lateral to level IA nodes and anterior to the back
mated or a straight-line guide or ruler can be placed on the
film or monitor. Whenever a lymph node is transected by
one of the ‘lines’ that define the levels, the side of the line
on which the majority of the nodal cross-sectional area
lies is the level in which the lymph node should be classi-
192 ORL 2000;62:186–198
edge of the submandibular gland. Level IIA nodes are anterior, later-
al, or medial to the internal jugular vein or posterior to this vein but
touching it. Level IIB nodes are posterior to the internal jugular vein,
without touching it, and anterior to the back of the sternocleidomas-
toid muscle. Level VA nodes are posterior to the back of the sterno-
cleidomastoid muscle.
fied. The supraclavicular fossa is defined on each axial
scan whenever any portion of the clavicle is identified on
one side of the neck. That is, if the scan level is cranial to
any portion of the clavicle, the nodes in the lower lateral
neck should be classified as being in either level IV or lev-
Som /Curtin/Mancuso
Fig. 4. Diagram of an axial slice of the neck
just below the level of the bottom of the body
of the hyoid bone. The silhouette of the thy-
roid cartilage is seen anteriorly. Level III
nodes are anterior and lateral to the common
carotid artery (C) and the internal jugular
vein (J), but lie anterior to the back of the
sternocleidomastoid muscle. Level VA nodes
are posterior to the back of the sternocleido-
mastoid muscle.
el VB. Once any portion of the clavicle is seen on the scan,
such nodes are classified as supraclavicular nodes (fig. 6).
If nodes are seen below the level of the clavicle and lateral
to the ribs, they are axillary nodes (fig. 7). The clinically
important internal jugular nodes described by Rouvière
[3] are now classified as level II, III, or IV nodes, depend-
ing on their location with reference to the axial scan levels
of the bottom of the body of the hyoid bone and the bot-
tom of the arch (anterior rim) of the cricoid cartilage.
The Imaging-Based Classification
Level I includes all of the nodes above the hyoid bone,
below the mylohyoid muscles, and anterior to a transverse
line drawn on each axial image through the posterior edge
of the submandibular gland (fig. 1, 3). Thus, level I nodes
include the previously classified submental and subman-
Cervical Nodal Classification
dibular nodes. Level I nodes can be subclassified into lev-
els IA and IB.
Level IA represents those nodes which lie between the
medial margins of the anterior bellies of the digastric mus-
cles, above the hyoid bone and below the mylohyoid mus-
cle (previously classified as submental nodes) (fig. 3).
Level IB represents the nodes which lie below the mylo-
hyoid muscle, above the hyoid bone, posterior and lateral
to the medial edge of the anterior belly of the digastric
muscle, and anterior to a transverse line drawn on each
axial image tangent to the posterior surface of the sub-
mandibular gland on each side of the neck (previously
classified as submandibular nodes) (fig. 3).
Level II extends from the skull base, at the lower level
of the bony margin of the jugular fossa, to the level of the
lower body of the hyoid bone (fig. 1–3). Level II nodes lie
anterior to a transverse line drawn on each axial image
through the posterior edge of the sternocleidomastoid
ORL 2000;62:186–198 193
Fig. 5. Diagram of an axial slice of the neck just below the level of the
bottom of the cricoid arch. The trachea (T) is seen anteriorly in the
midline. C = The common carotid artery, J = the internal jugular
vein, SCM = the sternocleidomastoid muscle, and AS = the anterior
scalene muscle. Level IV nodes are lateral to the medial margin of the
muscle and lie posterior to a transverse line drawn on
each axial scan through the posterior edge of the subman-
dibular gland. If a node situated within 2 cm of the skull
base lies anterior, lateral or posterior to the carotid sheath,
it is classified as a level II node. If the node lies medial to
the internal carotid artery, it is classified as a retropharyn-
geal node (fig. 2). Caudal to 2 cm below the skull base,
level II nodes can lie anterior, lateral, medial and posteri-
or to the internal jugular vein. Level II nodes can be sub-
classified into levels IIA and IIB.
Level IIA nodes are level II nodes that lie posterior to
the internal jugular vein and are inseparable from the vein
or they are nodes that lie anterior, lateral or medial to the
vein (previously classified as upper internal jugular
nodes) (fig. 2, 3).
194 ORL 2000;62:186–198
common carotid artery and anteromedial to a line (oblique dotted
line) drawn from the lateral aspect of the anterior scalene muscle to
the posterior margin of the sternocleidomastoid muscle. Level VB
nodes are posterolateral to this line. Level VI nodes are medial to the
medial margin (vertical dotted line) of the common carotid arteries.
Level IIB nodes are level II nodes that lie posterior to
the internal jugular vein and have a fat plane separating
the nodes and the vein (previously classified as upper spi-
nal accessary nodes) (fig. 3).
Level III nodes lie between the level of the lower body
of the hyoid bone and the level of the lower margin of the
cricoid cartilage arch (fig. 1, 4). These nodes lie anterior to
a transverse line drawn on each axial image through the
posterior edge of the sternocleidomastoid muscle. Level
III nodes also lie lateral to the medial margin of either the
common carotid artery or the internal carotid artery. On
each side of the neck, the medial margin of these arteries
separates level III nodes (which are lateral) from level VI
nodes (which are medial). Level III nodes were previously
known as the mid-jugular nodes.
Som /Curtin/Mancuso
Fig. 6. Diagram of an axial slice of the neck just below the level of the
bottom of the thyroid gland. The trachea (T) is seen anteriorly in the
midline. C = The common carotid artery, J = the internal jugular
vein, and AS = the anterior scalene muscle. As in figure 5, level IV
nodes are seen lateral to the medial margins of the common carotid
arteries and anteromedial to an oblique line drawn from the lateral
Level IV nodes lie between the level of the lower mar-
gin of the cricoid cartilage arch and the level of the clavi-
cle on each side as seen on each axial scan. These nodes lie
anterior and medial to an oblique line drawn through the
posterior edge of the sternocleidomastoid muscle and the
lateral posterior edge of the anterior scalene muscle on
each axial image (fig. 1, 5, 6). The medial aspect of the
common carotid artery is the landmark which separates
level IV nodes (which are lateral) from level VI nodes
(which are medial) to this artery (fig. 5, 6). Level IV nodes
were previously known as the low jugular nodes.
Level V nodes extend from the skull base, at the poste-
rior border of the attachment of the sternocleidomastoid
muscle, to the level of the clavicle as seen on each axial
Cervical Nodal Classification
aspect of the anterior scalene muscle to the posterior margin of the
sternocleidomastoid muscle. Level V nodes are posterolateral to
these oblique lines. In this figure, both of the ‘level V’ nodes are clas-
sified as supraclavicular nodes because portions of the clavicle are
seen on each side.
scan (fig. 1–5). Level V nodes all lie anterior to a trans-
verse line drawn on each axial scan through the anterior
edge of the trapezius muscle. Between the levels of the
skull base and the bottom of the cricoid arch, these nodes
are situated posterior to a transverse line drawn on each
axial scan through the posterior edge of the sternocleido-
mastoid muscle (fig. 1, 2–4). Between the axial level of the
bottom of the cricoid arch and the level of the clavicle,
level V nodes lie posterior and lateral to an oblique line
through the posterior edge of the sternocleidomastoid
muscle and the lateral posterior edge of the anterior scal-
ene muscle (fig. 5, 6). The level V nodes can be subdivid-
ed into VA and VB nodes.
ORL 2000;62:186–198 195
 Fig. 7. Diagram of an axial slice of the neck just below the level of the top of the manubrium which is seen anteriorly
in the midline. LBv = the left brachiocephalic vein, RBv = the right brachiocephalic vein, BA = brachial artery, LC =
left carotid artery, LS = left subclavian artery, and T = trachea. Level VII nodes are caudal to the top of the manub-
rium. Axillary nodes are caudal to the clavicle and lateral to the ribs.

Level VA (upper level V) nodes lie between the skull
base and the level of the lower margin of the cricoid carti-
lage arch. They are behind the posterior edge of the ster-
nocleidomastoid muscle (fig. 1–4).
Level VB (lower level V) nodes on each side lie between
the level of the lower margin of the cricoid cartilage arch
and the level of the clavicle as seen on each axial scan.
They are behind an oblique line through the posterior
edge of the sternocleidomastoid muscle and the lateral
posterior edge of the anterior scalene muscle (fig. 5).
Level VI nodes lie inferior to the lower body of the
hyoid bone, superior to the top of the manubrium, and
between the medial margins of the left and right common
carotid arteries or the internal carotid arteries. They are
the visceral nodes (fig. 5, 6).

196 ORL 2000;62:186–198 Som /Curtin/Mancuso

 Level VII nodes lie caudal to the top of the manubrium
in the superior mediastinum, between the medial margins
of the left and right common carotid arteries (fig. 7).
These superior mediastinal nodes extend caudally to the
level of the innominate vein.
In keeping consistency with the prior classifications,
the following nodal groups continue to be referred by their
anatomic names: supraclavicular, retropharyngeal, paro-
tid, facial, occipital, postauricular, and the other superfi-
cial nodes, etc.
affected, extending down to the lower internal jugular
nodes and the supraclavicular nodes [32]. Converting this
nodal nomenclature into that of the imaging-based classi-
fication means that in cases of glottic and subglottic can-
cers, nodes in levels IV, VI and the supraclavicular nodes
may be involved.
Related to the larynx, and often virtually inseparable
from the larynx, are post cricoid and upper cervical
esophageal cancers which may metastasize to the paratra-
cheal and superior mediastinal nodes [33]. That is, level
VI and VII nodes are at risk in these cancers.

The Classification and Laryngeal Cancer

Metastasis Conclusions

As the imaging-based nodal classification encompasses
all of the cervical lymph nodes, it is easy to apply the clas-
sification when describing lymph node metastases from
laryngeal cancer. Ogura [27] found that positive nodes
from laryngeal cancers can occur in all triangles of the
neck except in the submental triangle. Translating this
into the imaging-based nodal classification means that all
nodal levels except level IA are at risk [28]. Although sub-
mandibular nodes (level IB) may uncommonly be in-
volved in advanced supraglottic cancers, this appears to
occur only in cases with extensive internal jugular chain
disease (levels II, III and IV). In general, supraglottic can-
cers metastasize to levels II and III, however, there is
some discrepancy in the literature regarding metastasis of
these tumors to the posterior triangle nodes [29, 30].
When the spinal accessory nodes are involved, it is most
commonly to the nodes in the superior portion of this
nodal chain [31]. Thus, while level IIB (and rarely level
VA nodes) may be affected in supraglottic cancers, level
VB are usually not involved.
In cases of glottic and subglottic cancers, the prelaryn-
geal nodes and occasionally the pretracheal nodes may be
Today, CT and MR imaging form an integral part of
the assessment of the majority of cases of head and neck
cancer. The imaging findings clearly compliment the
physical examination and the imaging-based classifica-
tion provides the radiologist with clinically acceptable
guidelines with which to classify the cervical nodes and
communicate these findings to the clinicians in a mutual-
ly acceptable way. This new classification provides added
precision and reproducibility to nodal localization and it
is hoped that imaging will now become a necessary com-
ponent of patient classification and staging. It is also
hoped that this classification can add precision and repro-
ducibility to the nodal localization required in the accu-
mulation of data in planned multi-institutional studies
involving laryngeal cancer [34].
Acknowledgement
The authors want to thank Bradley Delman, MD, for the line
drawings that he created for this paper.

References

1 Poirer P, Charpy A: Traité d’anatomie hu-
maine, ed 2, vol 2, fasc 4. Paris, 1909.
2 Trotter HA: The surgical anatomy of the lym-
phatics of the head and neck. Ann Otol Rhinol
Laryngol 1930;39:384–397.
3 Rouvière H: Lymphatic system of the head and
neck; in Tobias MJ (translator): Anatomy of
the Human Lymphatic System. Ann Arbor, Ed-
wards Bros, 1938.
4 Lindberg R: Distribution of cervical lymph
node metastases from squamous cell carcino-
ma of the upper respiratory and digestive
tracts. Cancer 1972;29:1446–1449.
5 Shah JP, Strong E, Spiro RH, Vikram B: Surgi-
cal grand rounds. Neck dissection: Current sta-
tus and future possibilities. Clin Bull 1981;11:
25–33.
6 Spiro RH: The management of neck nodes in
head and neck cancer: A surgeon’s view. Bull
NY Acad Med 1985;61:629–637.
7 Suen JY, Goepfert H: Standardization of neck
dissection nomenclature. Head Neck Surg
1987;10:75–77.
8 Beahrs OH, Henson DE, Hutter RVP, Meyers
MH: Manual for Staging Cancer, ed 3. Phila-
delphia, Lippincott, 1988.
9 Medina JE: A rational classification of neck
dissections. Otolaryngol Head Neck Surg 1989;
100:169–176.

Cervical Nodal Classification ORL 2000;62:186–198 197

10 Robbins KT: Pocket Guide to Neck Dissection
and TNM Staging of Head and Neck Cancer.
Alexandria, American Academy of Otolaryn-
gology-Head and Neck Surgery Foundation,
1991, pp 1–31.
11 Van den Brekel MWM: Assessment of Lymph
Node Metastases in the Neck: A Radiological
and Histopathological Study. Utrecht, Univer-
sity of Amsterdam, 1992, pp 1–152.
12 American Joint Committee on Cancer: Flem-
ing ID, Cooper JS, Henson DE, Hutter RVP,
Kennedy BJ, Murphy GP, O’Sullivan B, Sobin
LH, Yarbro JW (eds): Manual for Staging of
Cancer, ed 5. Philadelphia, Lippincott-Raven,
1997.
13 Robbins KT: Classification of neck dissection:
Current concepts and future considerations.
Otolaryngol Clin North Am 1998;31:639–655.
14 Mancuso AA, Harnsberger HR, Muraki AS,
Stevens MH: Computed tomography of cervi-
cal and retropharyngeal lymph nodes: Normal
anatomy, variants of normal, and application
in staging head and neck cancer. Part II. Radi-
ology 1983;148:715–723.
15 Som PM: An approach to tumors of the head
and neck: The role of computed tomography in
the staging and follow-up of patients; in Margu-
lis AF, Gooding CA (eds): Diagnostic Radiolo-
gy. San Francisco, University of California,
1985.
16 Som PM: Lymph nodes of the neck. Radiology
1987;165:593–600.
17 Curtin HD, Ishwaran H, Mancuso AA, Dalley
RW, Daryl J, Caudry J, McNeil BJ: Compari-
son of CT and MR imaging in staging of neck
metastases. Radiology 1998;207:123–130.
198 ORL 2000;62:186–198
18 Mancuso AA, Maceri D, Rice D, Hanafee WN:
CT of cervical lymph node cancer. AJR 1981;
136:381–385.
19 van den Brekel MWM, Stel HV, Castelijns JA,
Nauta JJP, van der Waal I, Valk J, Meyer CJ,
Snow GB: Cervical lymph node metastasis: As-
sessment of radiologic criteria. Radiology
1990;177:379–384.
20 Friedman M, Shelton VK, Mafee M, Bellity P,
Grybauskar V, Skolnik E: Metastatic neck dis-
ease: Evaluation by computed tomography.
Arch Otolaryngol Head Neck Surg 1984;110:
443–447.
21 Stevens MH, Harnsberger R, Mancuso AA,
Davis RK, Johnson LP, Parkin JL: Computed
tomography of cervical lymph nodes: Staging
and management of head and neck cancer.
Arch Otolaryngol Head Neck Surg 1985;111:
735–739.
22 Close LG, Merkel M, Vuitch MF, Reisch J,
Schaefer SD: Computed tomographic evalua-
tion of regional lymph node involvement in
cancer of the oral cavity and oropharynx. Head
Neck 1989;11:309–317.
23 Feinmesser R, Freeman JL, Nojek AM, Birt
BD: Metastatic neck disease: A clinical/radio-
graphic/pathologic correlative study. Arch Oto-
laryngol Head Neck Surg 1987;113:1307–
1310.
24 Som PM: Detection of metastasis in cervical
lymph nodes: CT and MR criteria and differ-
ential diagnosis. AJR 1992;158:961–969.
25 Lingeman RE: Surgical anatomy; in Cummings
CW, Fredrickson JM, Harker LA, Krause CJ,
Schuller DE (eds): Otolaryngology – Head and
Neck Surgery. St Louis, Mosby-Year Book,
1993, vol. 2.
26 Som PM, Curtin HD, Mancuso AA: An imag-
ing-based classification for the cervical nodes
designed as an adjunct to recent clinically
based nodal classifications. Arch Otolaryngol
Head Neck Surg 1999;125:388–396.
27 Ogura JH: Surgical pathology of cancer of the
larynx. Laryngoscope 1955;65:867–926.
28 Ferlito A, Rinaldo A: Level I dissection for
laryngeal and hypopharyngeal cancer: Is it indi-
cated? J Laryngol Otol 1998;112:438–440.
29 Gregor RT, Oei SS, Hilgers FJM, Hart AAM,
Balm AJM, Keus RB: Management of cervical
metastases in supraglottic cancer. Ann Otol
Rhinol Laryngol 1996;105:845–850.
30 Moe K, Wolf GT, Fisher SG, Hong WK, The
Department of Veterans Affairs Laryngeal
Cancer Study Group: Regional metastases in
patients with advanced laryngeal cancer. Arch
Otolaryngol Head Neck Surg 1996;122:644–
648.
31 Schuller DE, Platz CE, Krause CJ: Spinal ac-
cessory lymph nodes: A prospective study of
metastatic involvement. Laryngoscope 1978;
88:439–449.
32 Berman JM: Surgical anatomy of the larynx; in
Bailey BJ, Biller HF (eds): Surgery of the La-
rynx. Philadelphia, Saunders, 1985.
33 Feind CR: The head and neck; in Haagensen
CD, Feind CR, Herter FP, Slanetz CA Jr,
Weinberg LA (eds): The lymphatics in cancer.
Philadelphia, Saunders, 1972, pp 59–230.
34 Weymuller EA: Clinical staging and operative
reporting for multi-institutional trials in head
and neck squamous cell carcinoma. Head Neck
1997;19:650–658.
Som /Curtin/Mancuso
 ORL 2000;62:199–203
Diagnostic Procedures for Detection of
Lymph Node Metastases in Cancer of the
Larynx
Reinhardt J. Kau a Christoph Alexiou b Herbert Stimmer c
Wolfgang Arnold b
a Department of Otorhinolaryngology-Head and Neck Surgery, Klinikum Krefeld, b Department of
Otorhinolaryngology-Head and Neck Surgery and c Department of Radiology, Technical University of Munich,
Klinikum rechts der Isar, Munich, Germany
Key Words
Laryngeal cancer W Lymph node metastases W
Ultrasound W Computed tomography W Magnetic
resonance imaging W Positron emission tomography
Abstract
Squamous cell carcinoma is the most common malig-
nant neoplasm of the larynx. One of the most important
influences on prognosis is the presence of metastases to
the cervical lymph nodes. Accurate determination of
lymph node involvement is therefore a prerequisite for
individualized therapy in patients with squamous cell
carcinoma of the larynx. Clinical palpation of the neck is
not very accurate and the role of imaging techniques
such as ultrasound, ultrasound-guided fine needle aspi-
ration cytology, color Doppler ultrasound, computed to-
mography, magnetic resonance imaging and positron
emission tomography is being applied in order to im-
prove upon the results of clinical investigation alone.
According to our investigations and review of the litera-
ture, the accuracy of computed tomography scanning
(84.9%) and magnetic resonance imaging (85%) was
superior to palpation (69.7%) and ultrasound (72.7%).
Ultrasound-guided fine needle aspiration cytology
showed an accuracy of 89% and was in the same range
with positron emission tomography (90.5%).
Copyright © 2000 S. Karger AG, Basel
© 2000 S. Karger AG, Basel
ABC 0301–1569/00/0624–0199$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
Introduction
Cervical lymph node staging in patients with laryngeal
cancer remains a major concern for all head and neck can-
cer surgeons. In the past, staging was based completely on
clinical examination results. The inaccuracy of clinical
examination, however, has been documented in a series of
studies. Snyderman et al. [1] retrospectively reviewed the
data on a group of patients with squamous cell carcinoma
of the supraglottic larynx. Forty-one percent (20 out of 49
patients) with no palpable adenopathy were found to have
metastatic disease on histologic evaluation of neck-dissec-
tion specimens. Conversely, 17% of patients judged clini-
cally to have a single cervical metastasis !3 cm in diame-
ter and 7% of patients judged to have cervical metastases
staged N2 or N3, had no evidence of histologic metas-
tases. The rapid advances in imaging technology intro-
duced in the past decade appear to have affected the phy-
sician’s ability to identify metastatic disease in the head
and neck.
Lymphatic Drainage of the Larynx
According to the pioneering work of Pressman et al. [2]
who injected dyes and radioactive isotopes into differ-
ent sites within the larynx to demonstrate submucosal
Prof. Dr. Reinhardt J. Kau
Direktor der Hals-Nasen-Ohren Klinik
Klinikum Krefeld, Lutherplatz 40
D–47805 Krefeld (Germany)
Tel. +49 2151 322501, Fax +49 2151 322011
compartments of the larynx and their lymphatic drain-
age, there appear to be two lymphatic drainage systems:
(1) one superficial intramucosal system forming an inter-
connecting web spreading over the entire mucosal surface
without limitation to the side and (2) a deep submucosal
system forming an independent network with no commu-
nications between the right and left sides.
Drainage into the cervical lymph nodes is essentially
ipsilateral. However, if the efferent flow to the ipsilateral
side is obstructed (as it could be by metastatic involve-
ment), then contralateral flow may occur [2, 3].
The site of the primary tumor within the larynx is an
important factor affecting the frequency and the pattern
of lymph node metastases to the neck. Thus, glottic carci-
nomas are much less likely to metastasize than are supra-
glottic lesions [3].
Diagnosis of Lymph Node Metastases
For an appropriate, definitive treatment to be planned
for any laryngeal tumor, it is of utmost importance to
determine the status of the regional lymph nodes in the
neck. The International Union Against Cancer (UICC)
TNM classification defines the regional lymph node (N)
categories as follows [4]:
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph nodes
N1 Metastasis in a single ipsilateral lymph node, X3 cm in
greatest dimension
N2 Metastasis in a single ipsilateral lymph node, 13 cm but not
1 6 cm in greatest dimension; or in multiple ipsilateral
lymph nodes, none 1 6 cm in greatest dimension; or in bilat-
eral or contralateral lymph nodes, none 1 6 cm in greatest
dimension
N2a Metastasis in a single ipsilateral lymph node, 1 3 cm but not
1 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none 1 6 cm
in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none
1 6 cm in greatest dimension
N3 Metastasis in a lymph node 1 6 cm in greatest dimension
Note: Midline nodes are considered ipsilateral nodes.
Because the majority of patients with head and neck
malignancies presently undergo sectional imaging prior to
treatment planning, Som et al. [5] integrated anatomical
imaging criteria with the two most commonly used nodal
classifications: those of the American Academy of Otola-
200 ORL 2000;62:199–203
ryngology, Head and Neck Surgery [6] and those of the
American Joint Committee on Cancer (AJCC) [7].
Although clinical palpation of the head and neck is still
widely used for staging of the neck, it is generally accepted
that this is not very accurate. More recently, computed
tomography (CT), magnetic resonance imaging (MRI),
ultrasound (US) and ultrasound-guided fine needle aspi-
ration cytology (US-guided FNAC), color Doppler ultra-
sound (CDUS) and positron emission tomography (PET)
have also been used to improve the results of clinical stag-
ing.
Clinical Palpation
Palpation of the neck lymph nodes has the advantage
of being both easy and inexpensive, but it is inaccurate
and of low sensitivity. Micrometastases are difficult to
evaluate and their reported incidence depends on the skill
and commitment of the pathologist and of the techniques
involved (conventional pathologic methods, semiserial
sections, immunohistochemistry, molecular biology) [8–
10]. Since treatment modalities and prognostic informa-
tion are also based on staging of the presence of neck
nodes, an improvement in both sensitivity (so that pa-
tients who require treatment to the neck are selected to
receive it) and specificity (so that patients who do not
require treatment to the neck are spared the unnecessary
treatment and morbidity) are desirable.
Computed Tomography
CT (B contrast medium) is generally considered supe-
rior to palpation [11, 12]. In a collective of 25 patients and
33 performed neck dissections, CT revealed an accuracy
of 84.9% in terms of screening the N0 neck compared with
palpation (69.7%) and US alone (72.7%) [13]. Typical cri-
teria for considering a lymph node suspicious for meta-
static disease included a round shape, size 11 cm, a
necrotic center, rim enhancement with contrast or group-
ing of three or more lymph nodes in an area of high-risk
nodal drainage. CT is clearly more useful than US for
defining the extent of primary cancers of the upper aero-
digestive tract. The ability to detect bony erosion of the
mandible, base of skull invasion, laryngeal cartilage inva-
sion or carotid encasement by tumor represent some of
the indications for using CT imaging as a preoperative
staging tool. Furthermore, CT is superior to US in detect-
ing involved retropharyngeal nodes, although the majori-
Kau/Alexiou/Stimmer/Arnold
ty of tumors with specific drainage to this area would
usually require a CT for staging of the primary tumor.
Magnetic Resonance Imaging
MRI (B contrast medium) has a better soft tissue con-
trast resolution than CT. In a large study group, van den
Brekel et al. [14] investigated retrospectively the sensitivi-
ty and specificity of MRI vs. palpation in detection of cer-
vical lymph node metastases. They examined 100 pa-
tients with head and neck cancer, who underwent surgery.
On these patients, 136 neck dissections were performed
(64 patients had unilateral, 36 patients bilateral neck dis-
sections). Contrast-enhanced MRI showed a sensitivity of
81% and specificity of 88% and was superior to palpation
(sensitivity 68%, specificity 67%). Nodes were inter-
preted as malignant on MRI if central necrosis was
depicted, minimal axial diameter exceeds 11 mm in the
subdigastric level (II) or 10 mm in other lymph node lev-
els (I, III, IV, V) and the presence of grouping of three or
more borderline nodes (minimal axial diameter 9 or
10 mm for level II, 8 or 9 mm for all other levels) is seen in
the lymph node drainage region of the tumor. MRI was
also superior to CT in lymph node detection on head and
neck squamous cell carcinomas (HNSCC) in a study
group investigated at our university hospital. MRI and/or
CT scan were previously performed on 70 patients with
HNSCC, who had neck dissection (34 ipsilateral, 36 bilat-
eral). MRI had a sensitivity of 88% and specificity of
40%, compared with CT scans, which revealed a sensitivi-
ty of 65% and a specificity of 47% [15].
Peripheral enhancement of contrast medium is often
seen in lymph node metastases and some problems of CT,
like radiation and dental artifacts, can be avoided by
MRI.
Central necrosis and extracapsular spread also have
characteristics on CT and MRI that can be mimicked by
other pathological processes. Central necrosis usually ap-
pears as a central area of low attenuation with a surround-
ing irregular wall but can be simulated by abscesses or
cysts and spontaneous lymph node necrosis. Extracapsu-
lar spread is correlated with a poorly defined nodal border
that may or may not enhance and is typically associated
with obliteration of fat planes. These characteristics
usually indicate metastatic disease, but prior surgery, irra-
diation or infection can also cause similar findings [16].
Lymph Node Metastases
Fig. 1. US image of the neck (right side). RF = A hypoechogenic mass
with a diameter of 18.5 ! 15.7 mm (metastasis of a laryngeal can-
cer); MSCL = sternocleidomastoid muscle; GL.THY. = thyroid
gland; VJI = internal jugular vein; ACC = carotid artery (common).
Ultrasound and Ultrasound-Guided Fine Needle
Aspiration Cytology
Although US is able to detect lymph node metastases
(fig. 1), in a majority of patients the accuracy of this tech-
nique is low. Van den Brekel et al. [17] found in a study
with 107 patients, who suffered from a HNSCC that US
alone never exceeded the accuracy of 70% [17]. Com-
bined with US-guided FNAC the accuracy was 89%. In
another study, 132 patients with HNSCC were examined
radiologically before undergoing a total of 180 neck dis-
sections as part of their treatment. CT, US and MRI
proved to be significantly more accurate than palpation
for cervical lymph node staging. The accuracy of US-
guided FNAC was significantly better than of any other
technique used in this investigation [18]. Beside these
results it should be noted that US is a dynamic investiga-
tion, highly operator-dependent and a learning curve
exists for even experienced ultrasonographer. Lymph
nodes near the mandible are sometimes difficult to visual-
ize on US due to the ‘shadow’ cast by the mandible. Nodes
in this location can also be difficult to evaluate on CT due
to the effects of dental amalgams. US-guided FNAC is the
only method among the techniques described above,
which can show the benign or malignant nature of such
lymph node preoperatively, but it should kept in mind
that especially false benign cytologic findings are possible
and that there is a risk of injury (i.e. bleeding, nerve palsy
etc.) during this invasive investigation.
ORL 2000;62:199–203 201
Fig. 2. Nonattenuation corrected PET
images of a patient with metastatic lymph
nodes on the left side (A transversal, B sagit-
tal, C coronal). The primary tumor has not
been found by morphologic procedures or by
PET. However, PET demonstrated one pre-
viously unknown metastatic lymph node
contralateral (C) which has not been re-
ported as suspicious on MRI.
Color Doppler Ultrasound
Color flow imaging allows simultaneous two-dimen-
sional imaging and evaluation of blood flow. CDUS is a
sensitive noninvasive imaging technique capable of de-
tecting vessels as small as those found in lymph nodes. In
a prospective study, 63 untreated patients with palpable
cervical lymph node enlargement underwent examination
with CDUS. Reactively enlarged lymph nodes showed
characteristically intense hilar perfusion, whereas nodal
metastases had mainly peripherally located flow [19].
Lymph nodes invaded by malignant lymphoma were
highly perfused, showing color signals in the center as well
as in the nodal periphery [19]. Perfusional patterns may
provide therefore useful additional information in the dif-
ferential diagnosis of cervical lymphadenopathy. Further-
more, in experimental studies the value of US contrast
medium is ongoing investigated to improve the accuracy
of US and to give additional information about tumor
patterns [20].
Positron Emission Tomography
Imaging procedures as described above are used for the
detection and localization of the primary tumor, regional
lymph node involvement and their relationship to adja-
cent anatomical structures. Differentiation between reac-
tive enlargement of lymph nodes and tumor-infiltrated
nodes may be difficult on the basis of radiological criteria
[16]. Fluorine-18 fluorodeoxyglucose (18F-FDG) is a
202 ORL 2000;62:199–203
marker of tumor viability, based upon the increased gly-
colysis that is associated with malignancy as compared
with normal tissues. It has been proven that head and
neck carcinomas have high glycolytic activity and in-
creased FDG uptake (fig. 2) [21].
We could demonstrate in a nonselected patient group
that a short PET protocol, which is suitable for routine
clinical use, is superior to morphologic procedures (CT or
MRI) for lymph node staging of HNSCCs [15]. PET
investigation revealed a higher sensitivity (87%) and spec-
ificity (94%) compared with CT values of 65 and 47% and
MRI values of 88 and 40%, respectively [15].
Conclusions
At present, we are unable to establish lymph node
involvement accurately using current available noninva-
sive methods. Nevertheless, imaging procedures like CT
and MRI do have clearer roles in evaluating lymph nodes
that are not easily accessible to clinical and US examina-
tions such as the retropharyngeal, upper mediastinal and
paratracheal lymph nodes. They are also valuable tools in
defining the relation of metastases to critical structures
such as carotid artery, cervical spine or brachial plexus.
Despite the high accuracy of the invasive US-guided
FNAC, there remains an uncertainty of false results
(110%). PET has also a high accuracy in detecting malig-
nant lymph nodes, however, since this investigation is
expensive and limited to certain locations, the use in a
routine clinical setting is at present not practicable.
Kau/Alexiou/Stimmer/Arnold
 With this in mind, it must be considered that in these Acknowledgement
times of cost containment the routine use of imaging stud-
We thank the Margarete Ammon Foundation, Munich, for sup-
ies may not be justified in all laryngeal cancer patients.
porting this study.
The examination of patients with laryngeal cancer should
be performed ‘stepwise’ and in an individualized manner.

References

1 Snyderman NL, Johnson JT, Schramm VL Jr,
Myers EN, Bedetti CD, Thearle P: Extracapsu-
lar spread of carcinoma in cervical lymph
nodes. Impact upon survival in patients with
carcinoma of the supraglottic larynx. Cancer
1985;56:1597–1599.
2 Pressman JJ, Simon MD, Monell C: Anatomi-
cal studies related to the dissemination of can-
cer of the larynx. Trans Am Acad Ophthalmol
Otolaryngol 1960;64:628–638.
3 Welsh LW, Welsh JJ, Rizzo TA: Internal anat-
omy of the larynx and the spread of cancer.
Ann Otol Rhinol Laryngol 1989;98:228–234.
4 International Union Against Cancer: Sobin
LH, Wittekind Ch (eds): TNM Classification of
Malignant Tumours, ed 5. New-York, Wiley-
Liss, 1997.
5 Som PM, Curtin HD, Mancuso AA: An imag-
ing-based classification for the cervical nodes
designed as an adjunct to recent clinically
based nodal classifications. Arch Otolaryngol
Head Neck Surg 1999;125:388–396.
6 Robbins KT, Medina JE, Wolfe GT, Levine
PA, Sessions RB, Pruet CW: Standardizing
neck dissection terminolgy: Official report of
the Academy’s Committee for Head and Neck
Surgery and Oncology. Arch Otolaryngol Head
Neck Surg 1991;117:601–605.
7 American Joint Committee on Cancer: Flem-
ing ID, Cooper JS, Henson DE, Hutter RPV,
Kennedy BJ, Murphy GP, O’Sullivan B, Sobin
LH, Yarbro JW (eds): Manual for Staging of
Cancer ed 5. Philadelphia, Lippincott-Raven,
1997.
8 Ferlito A, Rinaldo A: False negative conven-
9 Ferlito A, Devaney KO, Rinaldo A, Devaney
SL, Carbone A: Micrometastases: Have they an
impact on prognosis? Ann Otol Rhinol Laryn-
gol 1999;108:1185–1189.
10 Devaney SL, Ferlito A, Rinaldo A, Devaney
KO: Pathologic detection of occult metastases
in regional lymph nodes in patients with head
and neck cancer. Acta Otolaryngol (Stockh)
2000;120:344–349.
11 Stern WBR, Silver CE, Zeifer BA, Persky MS,
Heller KS: Computed tomography of the clini-
cally negative neck. Head Neck 1990;12:109–
113.
12 Lenz M, Kersting-Sommerhoff B, Gross M:
Diagnosis and treatment of the N0 neck in car-
cinomas of the upper aerodigestive tract: Cur-
rent status of diagnostic procedures. Eur Arch
Otorhinolaryngol 1993;250:432–438.
13 Righi PD, Kopecky KK, Caldemeyer KS, Ball
VA, Weisberger EC, Radpour S: Comparison
of ultrasound-fine needle aspiration and com-
puted tomography in patients undergoing elec-
tive neck dissection. Head Neck 1997;19:604–
610.
14 Van den Brekel MWM, Castelijns JA, Croll
GA, Stel HV, Valk J, van der Waal I, Golding
RP, Meyer CJLM, Snow GB: Magnetic reso-
nance imaging vs. palpation of cervical lymph
node metastasis. Arch Otolaryngol Head Neck
Surg 1991;117:663–673.
15 Kau RJ, Alexiou Ch, Laubenbacher C, Werner
M, Schwaiger M, Arnold W: Lymph node de-
tection of head and neck squamous cell carci-
nomas by positron emission tomography with
18 F-fluorodeoxyglucose in a routine clinical
16 Van den Brekel MWM, Stel HV, Castelijns JA,
Nauta JJ, van der Waal, Valk J, Meyer CJ,
Snow GB: Cervical lymph node metastasis: As-
sessment of radiological criteria. Radiology
1990;177:379–384.
17 Van den Brekel MWM, Stel HV, Castelijns JA,
Croll GJ, Snow GB: Lymph node staging in
patients with clinically negative neck examina-
tions by ultrasound and ultrasound-guided as-
piration cytology. Am J Surg 1991;162:362–
366.
18 Van den Brekel MWM, Castelijns JA, Stel HV,
Golding RP, Meyer CJL, Snow GB: Modern
imaging techniques and ultrasound-guided as-
piration cytology for the assessment of neck
node metastases: A prospective comparative
study. Eur Arch Otorhinolaryngol 1993;250:
11–17.
19 Steinkamp HJ, Mueffelmann M, Böck JC,
Thiel T, Kenzel P, Felix R: Differential diagno-
sis of lymph node lesions: A semiquantitative
approach with colour Doppler ultrasound. Br J
Radiol 1998;71:828–833.
20 Brown JM, Chaloupka J, Taylor KJ, Quedens-
Case C, Alderman J, Greener Y: Contrast-
enhanced ultrasound for guidance of local tu-
mor ablation. Ultrasound Med Biol 1999;25:
1213–1219.
21 Jabour BA, Choi Y, Hoh CK, Rege SD, Soong
JC, Lufkin RB, Hanafee WN, Maddahi J,
Chaiken L, Bailet J, et al: Extracranial head
and neck: PET imaging with 2-[18 F] fluoro-2-
deoxy-D-glucose and MR imaging correlation.
Radiology 1993;186:27–35.

tional histology of lymph nodes in patients with setting. Arch Otolaryngol Head Neck Surg
head and neck cancer. ORL J Otorhinolaryngol 1999;125:1322–1328.
Relat Spec 2000;62:112–114.

Lymph Node Metastases ORL 2000;62:199–203 203

 ORL 2000;62:204–211
The Pathology of Neck Dissection in
Cancer of the Larynx
Stephanie L. Devaney a Alfio Ferlito b Alessandra Rinaldo b
Kenneth O. Devaney a
a Department of Pathology, University of Michigan, Ann Arbor, Mich., USA, and
b Department of Otolaryngology-Head and Neck Surgery, University of Udine, Italy
Key Words
Cervical node metastases W Pathology W Specimen
processing
Abstract
Cancer of the larynx is a common problem in a head and
neck oncological surgical practice; as such, pathology
departments supporting such surgical practices will ex-
amine cervical lymph node dissection specimens with
some frequency. Issues to be settled among pathologists
and surgeons include – How precise an anatomic dissec-
tion of the specimen is called for? What histological fea-
tures of the specimen will be of most use to the clinicians
who are devising a course of postoperative therapy for
the patient? What sorts of methods are needed to identi-
fy the maximum number of micrometastases which may
be lurking within the lymph nodes of the specimen? Is
there a role for routine application of special techniques –
such as immunohistochemistry or molecular biology – in
the analysis of these specimens? While the answers to
these questions are likely to vary somewhat from one
center to another, patients are best served when these
© 2000 S. Karger AG, Basel
ABC 0301–1569/00/0624–0204$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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questions are discussed amongst the respective physi-
cians before surgical procedures are undertaken, rather
than after the fact.
Copyright © 2000 S. Karger AG, Basel
Introduction
Surgical therapy is an essential element in the compre-
hensive treatment of many patients with laryngeal cancer
[1, 2]. As understanding of the modes of spread of primary
laryngeal cancer has crystallized, the routine practice of
cervical lymph node dissection as an adjunct to treatment
of the primary tumor has likewise assumed an essential
role in the care of many of these patients [3–10].
A robust surgical literature discusses the relative merits
and demerits of a host of techniques for cervical node dis-
section – particularly in the patient with either low stage
disease or a clinically negative neck [11–22]. At the same
time, the radiological literature is filled with studies of the
efficacy of imaging methods at detecting occult cervical
node disease [23–29]. At present, it appears as though nei-
ther clinical examination (including even intraoperative
Stephanie L. Devaney
Department of Pathology, University of Michigan
1500 E Medical Center Drive
Ann Arbor, MI 48109-0054 (USA)
Tel. +1 734 997 0853, Fax +1 517 780 7295, E-Mail devaney@umich.edu
examination) nor radiographic study will suffice to uner-
ringly segregate out all of those patients who have devel-
oped metastatic disease involving their regional lymph
nodes [30]. As a consequence, the pathologic study of the
cervical node dissection occupies a particularly critical
role in the planning of a laryngeal cancer patient’s subse-
quent therapy.
Before turning to a consideration of the specific tech-
niques which might be applied to the laboratory study of a
neck dissection specimen, it bears noting that practice is
likely to diverge widely from one center to another – both
amongst the pathologists and surgeons. As such, it can
only be viewed as prudent for the various participants to
discuss the issues raised by this review and adapt them to
the particular needs of their own clinical settings.
The Initial Processing of a Cervical Node
Dissection Specimen in the Surgical Pathology
Suite – Gross Examination
In most instances, the surgical pathologist should alrea-
dy be familiar with the microscopic appearances of the
patient’s primary laryngeal cancer, either by virtue of hav-
ing handled that initial diagnostic specimen him or her-
self, or through preoperative review of the histologic sec-
tions of the biopsy specimen which were obtained from
another facility [31–35]. This is of great import, of course,
for foreknowledge of the primary tumor’s appearances
may be a great aid in interpreting a confusing picture on
frozen section examination at the time of definitive sur-
gery.
The first meeting of the pathologist and node dissec-
tion specimen usually comes after the specimen has un-
dergone some period of formalin fixation – a process
which typically alters the color and the configuration of
that specimen from its appearance in the fresh state. This
is not a trivial matter, insofar as it relates to the ability of
the pathologist to expertly dissect the specimen. This, in
turn, relates to the degree of anatomical detail in the final
pathology report which will be required by the patient’s
surgeons and oncologists. While some investigators have
attempted to develop methods for more readily identi-
fying individual nodes in a dissection specimen (as, for
example, clearing of fat by solvent application), patholog-
ic practice in most centers does not rely on any such ancil-
lary techniques and the pathologist’s dissection is carried
out on the routinely fixed specimen [36].
It is customary for pathology protocols to suggest that
pathologists dissect a radical neck specimen with a high
The Pathology of Neck Dissection
degree of precision, being careful to segregate and identify
nodes from each of a great many different anatomical
regions [14, 37–44]. To this end, valuable landmarks for
orientation purposes include the sternocleidomastoid
muscle (SCM), the internal jugular vein, the submandibu-
lar gland, the tail of the parotid. As some or all of these
landmark structures may be absent in a particular speci-
men (as a function of the surgical procedure performed),
it may be necessary for the surgeon and the pathologist to
collaborate on the dissection of the specimen.
Irrespective of the details of the planned dissection of
the neck specimen, it should be possible at the conclusion
of this gross examination for the pathologist to record the
side of the neck the specimen came from, the number of
lymph nodes identified on gross examination, their rela-
tive anatomic locations, and the number of grossly posi-
tive lymph nodes. In addition, the sizes (usually recorded
as the greatest single dimension) of the grossly identified
nodes (both grossly positive and grossly negative) can be
recorded as well (often, as a range – from largest to smal-
lest, for example). Matted groups of confluent nodes (pre-
sumably replaced by metastatic tumor) should be noted as
well. Should it appear on naked eye examination as
though metastatic tumor has penetrated the node capsule
and grown into the adjacent soft tissue, this finding too
should be recorded in the formal gross examination
report. The salivary glands and SCM should be briefly
described, as should the associated soft tissue (with an eye
toward documenting the presence of gross tumor); the
internal jugular vein should be opened along its length, in
a search for either tumor or thrombus in its lumen. Final-
ly, the margins of excision as a whole should be assessed
for the presence of grossly identifiable tumor. As it is not
routine to obtain large numbers of random sections of sur-
gical margin in a large neck dissection specimen, the sur-
geon with a particular concern about a particular margin
would be well advised both to mark the area of interest
and to bring this to the attention of the pathologist.
It is fair to confess at this point that many surgical
pathologists are not likely to appreciate the precise dis-
tinctions between a radical neck dissection (the standard
by which the other variants are judged; a sampling of all
cervical node groups one side of the neck, from inferior
mandible to the clavicle, and from lateral to the sterno-
hyoid to the anterior trapezius; the specimen includes the
spinal accessory nerve internal jugular vein and SCM), a
modified radical neck dissection (where one or more non-
lymphatic structures such as the spinal accessory nerve,
internal jugular vein, and/or the SCM are preserved), a
selective neck dissection (where some lymphatic levels
ORL 2000;62:204–211 205
which would have been removed in a standard radical
neck dissection are instead preserved), and an extended
radical neck dissection (in which lymphatic and/or non-
lymphatic structures – in addition to those removed in a
standard radical neck dissection – are excised as well) [3,
5, 7, 19, 43].
At least two anatomical methods of grouping cervical
nodes are used in modern practice. In one, five nodal
regions are recognized – anterior to the SCM (including
the submental and submandibular nodes), deep to the
superior 1/3 of the SCM, deep to the middle 1/3 of the
SCM, deep to the inferior 1/3 of the SCM (these three
groups comprising the jugular nodes), and, finally, poste-
rior to the SCM (posterior triangle nodes).
Alternatively, the cervical node dissection specimen
may first be divided from to bottom into two equal por-
tions – an upper half and a lower half. Each of these halves
is then divided from dorsal to ventral (or anterior to pos-
terior) into thirds, as a function of their relation to the
anterior and posterior borders of the SCM. This, ultimate-
ly, yields six nodal regions – upper, anterior to the SCM
(superior anterior cervical triangle nodes – including sub-
mental and submandibular nodes); upper, deep to the
SCM (superior jugular nodes); upper, posterior to the
SCM (posterior cervical triangle, including spinal accesso-
ry nodes); lower, anterior to the SCM (inferior anterior
cervical triangle nodes), lower, deep to the SCM (inferior
jugular nodes), and lower, posterior to the SCM (posterior
cervical triangle, including supraclavicular nodes) [37–
41].
Once the individual lymph nodes have been identified,
it is customary to take a single cross section through the
longest axis of each node and submit that section for
microscopic examination. In this way, each cross section
of a node on a glass slide corresponds to a single node
identified on gross dissection (unless, of course, the indi-
vidual node is too large to fit into a single tissue cassette,
in which case it may be subdivided into a pair of cas-
settes).
At this preliminary stage, one pertinent consideration
comes into play – and that is the role of frozen section
diagnosis in the intraoperative management of patients
with laryngeal cancer [30]. Some surgeons employ routine
intraoperative frozen section as an adjunct to intraopera-
tive staging, while others do not. It is here – in the inter-
pretation of frozen section material – that the pathologist
will be particularly aided by having reviewed in advance
the diagnostic biopsy material, so as to fix in his or her
mind the appearance of the tumor which is being sought
on the frozen section slide.
206 ORL 2000;62:204–211
One perfectly reasonable question for the surgeon to
pose might be – Was the cervical node excision, or the
subsequent analysis of that specimen by the pathologist,
adequate? In other words, can some simple factor such as
the number of lymph nodes identified in the final patholo-
gy report serve to gauge the probable success of the surgi-
cal procedure? The cervical region has been estimated to
hold some 300 or so lymph nodes [45]. As a rough general-
ization, neck dissections from patients with head and
neck cancer contain on average 20–30 nodes – although
the range in individual patients varies quite widely indeed
[46]. As such, the number of nodes reported out by the
pathologist can only serve as a very crude proxy for the
adequacy of either surgical or pathologic efforts, and so is
not likely to be entirely useful for this purpose.
Microscopic Study of the Cervical Node
Dissection Specimen
Cervical metastases are currently regarded as the sin-
gle most important prognostic factor in patients with
cancers of the head and neck [47–53]. As a consequence,
the pathologic examination of the cervical node dissec-
tion specimen supplies information which is an irre-
placeable element of the approach to the laryngeal can-
cer patient.
Microscopic examination of selected histologic sec-
tions of the neck dissection specimen relies, in most
instances, on routine light microscopy and hematoxylin
and eosin stained slides cut from paraffin-embedded
blocks of tissue trimmed from the specimen. At the out-
set, what might otherwise seem a simple matter may pose
unexpected questions – for example, How many individu-
al slides from each paraffin-embedded tissue block should
the pathologist routinely examine? Typically, the answer
would be a resounding ‘one, of course’ – taking into
account the time and expense involved in preparing and
then examining a great many more microscopic sections
than is customary.
While this remains current practice in virtually all hos-
pitals, there has been at least one study which has exam-
ined this question critically [54]. These authors found
metastatic deposits in 40 of 802 cervical lymph nodes
studied microscopically by examination of a single histo-
logic section from each tissue block; serial sectioning of
the putatively negative nodes revealed an additional two
nodes which harbored small deposits of metastatic tumor
which were missed by the initial sectioning.
Devaney/Ferlito/Rinaldo/Devaney
 At present, the added data yielded by undertaking such
a heroic effort does not appear to warrant doing this rou-
tinely [54]; nonetheless, this emphasizes one truth
threaded throughout all of surgical pathology practice –
selection of sections for microscopic study is, of necessity,
ultimately a process of sampling. Pathologists should be
expected to carry out that sampling which is calculated to
yield valuable information, but it should be borne in mind
that this is still a sorting process – sections from one area
will be studied, while sections from elsewhere will not.
The alternative – creating thousands upon thousands of
slides from a single large surgical specimen which has
been totally embedded in paraffin – is simply not practic-
able with current techniques.
Once the threshold matter of how many slides from
each block to examine has been settled, the pathologist
next turns to a microscopic examination of each lymph
node sampled. While it is usually no great challenge to
recognize the many centimeter diameter lymph node
which has been wholly replaced by metastatic cancer, it
can be more difficult to recognize the presence of small
tumor deposits – that is, ‘micrometastases’. The number
of positive lymph nodes should be tallied, and compared
with the gross impression of the number of positive nodes
by naked eye examination. It is customary to report the
maximum dimension of the largest positive node; some
pathologists will also report separately the number of pos-
itive nodes with macro- and with micrometastases. It is a
matter to be settled between pathologists and clinicians
whether the report should separately designate occult me-
tastases (micrometastases) as a distinct category, separate
from macrometastases; while we do not do this in our
practice, others may find this information to be valuable
and so request that it be routinely recorded.
In tallying up the number of positive nodes, correlation
with the anatomic dissection performed at the time of
gross examination is usually carried out, so that the num-
ber of metastatic deposits in whichever anatomic regions
were segregated by the pathologist can be reported.
In clinical practice, a macrometastasis is usually
thought of as a nodal deposit which can be identified ei-
ther by the surgeon on physical examination or by the
radiologist via imaging studies. In both instances, this
usually translates into a measure of size – cervical nodes
11 cm or so in greatest dimension are clinically suspicious
and usually detectable by surgeons and radiologists
(macrometastases); nodes measuring !1 cm or so in great-
est dimension are, by contrast, less readily detected prior
to microscopic study and thus regarded as occult metas-
tases or micrometastases [25]. As a general rule, the
The Pathology of Neck Dissection
pathologist can expect that these clinically occult positive
cervical nodes will measure !10 mm in greatest dimen-
sion, and usually will show neither extension of tumor
beyond the node capsule or central necrosis [25]. Micro-
metastases should be aggressively sought by the surgical
pathologist, as their presence in an otherwise negative
neck dissection may have an impact on prognosis –
although this is a controversial area [18, 30, 55–58].
All experienced microscopists have at one time or
another been impressed by the ability of tiny deposits of
metastatic tumor lurking in a lymph node (on the order of
a scant few cells) to escape detection by the pathologist
making a routine scan of the lymph node landscape, look-
ing for larger, more readily detected metastases. As it hap-
pens, there are ancillary techniques (immunohistochemis-
try and molecular biology) available to increase the pa-
thologist’s ability to detect lymph node micrometastases
[59–62]. In particular, immunohistochemical staining for
cytokeratin has been shown to be particularly effective in
pinpointing tiny metastases which might have otherwise
escaped notice [63, 64]. In primary oral and pharyngeal
cancers, it has been suggested that between 5 and 10% of
nodes negative by routine light microscopy may prove to
be positive by immunohistochemical staining for cytoker-
atin [63, 64]. Usually the number of patients with mi-
crometastases is underestimated [65–67].
In deciding whether or not to routinely employ such an
ancillary modality of testing, this calculus should be
applied: balance disadvantages (the cost – both technical
and professional – of preparing and studying these addi-
tional immunohistochemical slides; and the possibility
that any additional information yielded by this procedure
will add nothing to the care of the patient) against the
advantages (greater incidence of identification of mi-
crometastases in cervical lymph nodes; and the possibility
that any additional information thus produced will add
measurably to the patient’s care). In our practice, we do
not routinely stain all negative lymph nodes for cytokera-
tin.
Once the presence or absence of metastatic deposits
within individual lymph nodes has been noted and re-
corded, it is then possible for the microscopist to assess
discrete microscopic changes within individual positive
lymph nodes. Such factors include: differentiation of the
metastatic deposit; presence or absence of invasion of
tumor beyond the lymph node capsule; host response to
tumor invasion beyond the lymph node capsule, and the
presence or absence of vascular space invasion by tumor
[68]. Of these, the presence or absence of extracapsular
extension of tumor has traditionally been regarded by
ORL 2000;62:204–211 207
Table 1. Neck dissection – the surgical pathology report
Gross report
Side of neck, type of surgical procedure
Number of negative nodes by anatomic region
(with maximum dimension or largest node)
Number of positive nodes by anatomic region
(with maximum dimension or largest node)
Number of positive nodes by anatomic region with apparent
invasion of tumor beyond the node capsule
Any other unexpected gross findings (including status of margins,
soft tissues, salivary glands, SCM, and jugular vein)
Microscopic report
Number of negative nodes (with maximum dimension or largest
node)
Number of positive nodes by anatomic region
(with maximum dimension or largest node)
Number of positive nodes by anatomic region with apparent
invasion of tumor beyond the node capsule
Microscopic features of metastatic tumor (differentiation,
host response, vascular space invasion)
Results of any ancillary testing (immunohistochemistry,
molecular studies)
Any other unexpected gross findings (including status of margins,
soft tissues, salivary glands, SCM, and jugular vein)
most – but not all – observers as the most critical factor, in
terms of its impact on prognosis; some question this, how-
ever [10, 47, 48, 68–70]. De Carvalho [71] believes that
the macroscopic extracapsular spread of cervical lymph
node disease is the most significant adverse prognostic
factor. The risk of recurrence and death are higher when
there is a macroscopic extracapsular extension. When the
tumor is confined to the lymph node or shows a micro-
scopic invasion beyond the capsule, there are no statisti-
cally significant differences in risk rates [71]. For the
present, we continue to report the presence or absence of
the extracapsular spread.
The pathologist should at this point recall those out-
standing abnormalities noted on gross examination (a sus-
picion of tumor in the jugular vein, for example, or an
impression of a grossly positive margin of resection) and
attempt to confirm them on microscopic study of sections
from those same areas.
While the historical data provided by the surgeon will
vary tremendously from one practitioner to another, there
is one piece of information which really should always be
noted – and that is the presence or absence of preopera-
tive radiation therapy. Radiation therapy can result in a
slight decrease in the number of both positive and nega-
208 ORL 2000;62:204–211
tive nodes; in some instances, it can convert an obvious
metastatic deposit of squamous carcinoma into a ‘keratin
granuloma’– a featureless mass of keratin material, but no
recognizable neoplastic cells [72]. This, presumably, re-
presents a response of that tumor mass to the radiation
therapy; however, it might be subject to misinterpretation
if the pathologist has not been informed of the prior
course of irradiation.
One final caveat – despite the best efforts of surgeons,
radiologists and gross pathologists, there remain some
clinically suspicious lymph nodes which, on microscopic
study, prove unexpectedly to harbor changes other than
metastatic cancer – changes such as malignant lympho-
ma, or mycobacterial or fungal infection [73]. An explana-
tion in the pathology report of the reason for this discor-
dance (a note, perhaps, explaining that the clinically
enlarged node contained in reality a benign lymphoid
hyperplasia) would be prudent. While serious complica-
tions of cervical nodes dissection are not particularly
common, they can occur – which provides all the more
reason to note unexpected findings (sizable portions of
nerve, for example) when they are encountered [74–77].
Table 1 summarizes these elements which, taken to-
gether, should provide clinicians with the maximum in-
formation needed to continue the patient’s care. It is not
expected that each hospital will employ this scheme pre-
cisely – rather, the needs of individual groups will result in
the adaptation of such a stylized model as this one for use
in each discrete practice setting.
Future Prospects
The scheme outlined above captures the procedures
followed in the majority of hospitals at the present time.
However, pathologic methods have never been static;
rather, they are subject to (sometimes radical) revision as
new information about disease accumulates. It has been
suggested that the next frontier in the pathologic analysis
of cervical node dissection specimens might be the rou-
tine application of molecular biologic techniques. Re-
searchers have already attempted to exploit the presence
or absence of proliferating cell nuclear antigen (PCNA),
MIB-1, and the cell adhesion molecule E-cadherin in the
primary tumor as a means of predicting the presence of
nodal metastases [78]. It is not difficult to imagine the
application of similar techniques to the metastases in an
attempt at extracting yet more information from those
specimens.
Devaney/Ferlito/Rinaldo/Devaney
 Some researchers have advocated the use of RFGR
and p53 gene detection, and cell adhesion molecules (E-
cadherin) detection as an adjunct to routine hematoxylin
and eosin analysis of histologic sections [41]. Other in-
vestigators have suggested that searching negative lymph
nodes (negative, that is, by routine light microscopy) for
the presence of p53 mutations might reveal the presence
of additional unsuspected metastatic deposits which
otherwise would have escaped detection [61]. All of
these approaches are presently in the investigative stage;
nonetheless, it would seem reasonable to predict that
most current practitioners can expect to see some of
them, or their progeny, adopted in their lifetimes [62,
79–81].
While it seems that, for the foreseeable future, the neck
dissection will continue to be the specimen most often
seen by the pathologist for the assessment of cervical
nodes in patients with cancer of the larynx, other tech-
niques for studying these nodes are also being explored.
Fine needle aspiration cytology, for example, has proven
useful in patients with clinically obvious nodal disease for
making a relatively quick, simple diagnosis of metastasis
[26, 82, 83]. The principal drawback to this technique as a
definitive means of staging seems to be its inability to
sample the same number of nodes as can be studied in a
surgical neck dissection; in addition, the needle aspiration
process seems unlikely to be able to reliably sample small
occult metastases.
While the processing of a neck dissection specimen can
be a complicated, time-consuming process, it is likely that
the use of a protocol such as the one discussed here – or
some variation on this theme – will serve the twin aims of
making the pathologist’s efforts more efficient while at the
same time maximizing the valuable information which
will be available to the clinicians caring for the patient.

References

1 Shah JP, Lydiatt W: Treatment of cancer of the
head and neck. CA Cancer J Clin 1995;45:352–
368.
2 Snow GB: Evaluation and staging of the patient
with head and neck cancer; in Myers EN, Suen
JY (eds): Cancer of the Head and Neck, ed 2.
New York, Churchill Livingstone, 1989, pp
435–438.
3 Robbins KT: Classification of neck dissection:
Current concepts and future considerations.
Otolaryngol Clin North Am 1998;31:639–655.
4 Banerjee AR, Alun-Jones T: Neck dissection.
Clin Otolaryngol 1995;20:286–290.
5 Spiro RH, Strong EW, Shah JP: Classification
of neck dissection: Variations on a new theme.
Am J Surg 1994;168:415–418.
6 Shah JP: Editorial: dissection: Which and
when? Aust NZ J Surg 1994;64:225.
7 Robbins KT, Medina JE, Wolfe GT, Levine
PA, Sessions RB, Pruet CW: Standardizing
neck dissection terminology. Official report of
the Academy’s Committee for Head and Neck
Surgery and Oncology. Arch Otolaryngol Head
Neck Surg 1991;117:601–605.
8 Byers RM: Neck dissection: Concepts, contro-
versies, and technique. Semin Surg Oncol
1991;7:9–13.
9 Medina JE: A rational classification of neck
dissections. Otolaryngol Head Neck Surg 1989;
100:169–176.
10 Sizeland AM, Millar HS: Lymph node dissec-
tion for head and neck cancer. Aust NZ J Surg
1987;57:161–167.
11 Pitman KT, Johnson JT, Myers EN: Effective-
ness of selective neck dissection for manage-
ment of the clinically negative neck. Arch Oto-
laryngol Head Neck Surg 1997;123:917–922.
12 Stringer SP: Current concepts in surgical man-
agement of neck metastases from head and
neck cancer. Oncology (Huntingt) 1995;9:547–
558.
13 Van den Brekel MW, Leemans CR, Snow GB:
Assessment and management of lymph node
metastases in the neck in head and neck cancer
patients. Crit Rev Oncol Hematol 1996;22:
175–182.
14 Kowalski LP, Franco EL, de Andrade Sobrinho
J: Factors influencing regional lymph node me-
tastasis from laryngeal carcinoma. Ann Otol
Rhinol Laryngol 1995;104:442–447.
15 Shah JP, Andersen PE: The impact of patterns
of nodal metastasis on modifications of neck
dissection. Ann Surg Oncol 1994;1:521–532.
16 Eicher SA, Weber RS: Surgical management of
cervical lymph node metastases. Curr Opin
Oncol 1996;8:215–220.
17 Shah JP, Medina JE, Shaha AR, Schantz SP,
Marti JR: Cervical lymph node metastasis.
Curr Probl Surg 1993;30:273–344.
18 Jones AS, Phillips DE, Helliwell TR, Roland
NJ: Occult node metastases in head and neck
squamous carcinoma. Eur Arch Otorhinolaryn-
gol 1993;250:446–449.
19 Robbins KT: Classification of neck dissection:
Current concepts and future considerations.
Otolaryngol Clin North Am 1998;31:639–655.
20 Traynor SJ, Cohen JI, Gray J, Andersen PE,
Everts EC: Selective neck dissection and the
management of the node-positive neck. Am J
Surg 1996;172:654–657.
21 Breau RL, Suen JY: Management of the N0
neck. Otolaryngol Clin North Am 1998;31:
657–669.
22 Van den Brekel MW, Castelijns JA, Snow GB:
Diagnostic evaluation of the neck. Otolaryngol
Clin North Am 1998;31:601–620.
23 Van den Brekel MW, Castelijns JA, Snow GB:
The size of lymph nodes in the neck on sono-
grams as a radiologic criterion for metastasis:
How reliable is it? Am J Neuroradiol 1998;19:
695–700.
24 Tschammler A, Ott G, Schang T, Seelbach-
Goebel B, Schwager K, Hahn D: Lymphadeno-
pathy: Differentiation of benign from malig-
nant disease – color Doppler US assessment of
intranodal angioarchitecture. Radiology 1998;
208:117–123.
25 Feinmesser R, Freeman JL, Feinmesser M,
Noyek A, Mullen JB: Role of modern imaging
in decision-making for elective neck dissection.
Head Neck 1992;14:173–176.
26 Righi PD, Kopecky KK, Caldemyer KS, Ball
VA, Weisberger EC, Radpour S: Comparison
of ultrasound-fine needle aspiration and com-
puted tomography in patients undergoing elec-
tive neck dissection. Head Neck 1997;19:604–
610.
27 Anzai Y, Brunberg JA, Lufkin RB: Imaging of
nodal metastases in the head and neck. J Magn
Reson Imaging 1997;7:774–783.
28 Merritt RM, Williams MF, James TH, Porub-
sky ES: Detection of cervical metastasis. A
meta-analysis comparing computed tomogra-
phy with physical examination. Arch Otolaryn-
gol Head Neck Surg 1997;123:149–152.

The Pathology of Neck Dissection ORL 2000;62:204–211 209

29 Shingaki S, Suzuki I, Nakajima T, Hayashi T,
Nakayama H, Nakamura M: Computed tomo-
graphic evaluation of lymph node metastasis in
head and neck carcinomas. J Craniomaxillofac
Surg 1995;23:233–237.
30 Rassekh CH, Johnson JT, Myers EN: Accuracy
of intraoperative staging of the N0 neck in
squamous cell carcinoma. Laryngoscope 1995;
105:1334–1336.
31 Ferlito A, Rinaldo A, Devaney KO, Devaney
SL, Milroy CM: Impact of phenotype on treat-
ment and prognosis of laryngeal malignancies.
Ann Otol Rhinol Laryngol 1998;112:710–714.
32 Devaney K, Hunter BC, Ferlito A, Rinaldo A:
Pre-treatment pathologic prognostic factors in
squamous carcinomas of the head and neck.
Ann Otol Rhinol Laryngol 1997;106:983–988.
33 Carter RL: Pathology of squamous carcinomas
of the head and neck. Curr Opin Oncol 1993;5:
491–495.
34 Zarbo RJ, Crissman JD: The surgical patholo-
gy of head and neck cancer. Semin Oncol 1988;
15:10–19.
35 Sessions DG: Surgical pathology of cancer of
the larynx and hypopharynx. Laryngoscope
1976;86:814–839.
36 Scott KW, Grace RH: Detection of lymph node
metastasis in colorectal carcinoma before and
after fat clearance. Br J Surg 1989;76:1165–
1167.
37 Min KW, Houck JR: Protocol for the examina-
tion of specimens removed from patients with
carcinoma of the upper aerodigestive tract.
Arch Pathol Lab Med 1998;122:222–230.
38 Gillies EM, Luna MA: Histological evaluation
of neck dissection specimens. Otolaryngol Clin
North Am 1998;31:759–771.
39 Siegel RJ: Surgical pathology of lymph nodes in
cancer staging: Routine and specialized tech-
niques. Surg Oncol Clin North Am 1996;5:25–
31.
40 Jones AS, Roland NJ, Field JK, Phillips DE:
The level of cervical lymph node metastases:
Their prognostic relevance and relationship
with head and neck squamous carcinoma pri-
mary sites. Clin Otolaryngol 1994;19:63–69.
41 Carter RL: The pathologist’s appraisal of neck
dissections. Eur Arch Otorhinolaryngol 1993;
250:429–431.
42 Candela FC, Shah J, Jaques DP, Shah JP: Pat-
terns of cervical node metastases from squa-
mous carcinoma of the larynx. Arch Otolaryn-
gol Head Neck Surg 1990;116:423–435.
43 Rhys Evans PH, Morgan D, Smallman L: Pres-
ervation of neck dissection for histological
study. J Laryngol Otol 1987;101:823–827.
44 Barnes L, Johnson JT: Clinical and pathologi-
cal considerations in the evaluation of major
head and neck specimens resected for cancer.
Part II. Pathol Annu 1986;21:83–110.
45 Som PM: Lymph nodes of the neck. Radiology
1987;165:593–600.
46 Friedman M, Lim JW, Dickey W, Tanyeri H,
Kirshenbaum GL, Phadke DM, Caldarelli D:
Quantification of lymph nodes in selective
neck dissection. Laryngoscope 1999;109:368–
370.
210 ORL 2000;62:204–211
47 Pinsolle J, Pinsolle V, Majoufre C, Durous S,
Demeaux H, Siberchicot F: Prognostic value of
histologic findings in neck dissections for squa-
mous carcinoma. Arch Otolaryngol Head Neck
Surg 1997;123:145–148.
48 Alvi A, Johnson JT: Extracapsular spread in
the clinically negative neck (N0): Implications
and outcome. Otolaryngol Head Neck Surg
1996;114:65–70.
49 Moe K, Wolf GT, Fisher SG, Hong WK: Re-
gional metastases in patients with advanced
laryngeal cancer. Department of Veterans Af-
fairs Laryngeal Cancer Study Group. Arch Oto-
laryngol Head Neck Surg 1996;122:644–648.
50 Don DM, Anzai Y, Lufkin RB, Fu YS, Calca-
terra TC: Evaluation of cervical lymph node
metastases in squamous cell carcinoma of the
head and neck. Laryngoscope 1995;105:669–
674.
51 Olsen KD, Caruso M, Foote RL, Stanley RJ,
Lewis JE, Buskirk SJ, Frassica DA, DeSanto
LW, O’Fallon WM, Hoverman VR: Primary
head and neck cancer. Histopathologic predic-
tors of recurrence after neck dissection in pa-
tients with lymph node metastases. Arch Otola-
ryngol Head Neck Surg 1994;120:1370–1374.
52 Leemans CR, Tiwari R, Nauta JJ, Van der
Waal I, Snow GB: Regional lymph node in-
volvement and its significance in the develop-
ment of distant metastases in head and neck
carcinoma. Cancer 1993;71:452–456.
53 Grandi C, Alloisio M, Moglia D, Podrecca S,
Sala L, Salvatori P, Molinari R: Prognostic sig-
nificance of lymphatic spread in head and neck
carcinomas: Therapeutic implications. Head
Neck Surg 1985;8:67–73.
54 Shingaki S, Ohtake K, Nomura T, Nakajima T:
The value of single versus multiple sections for
detection of lymph node metastasis. J Oral
Maxillofac Surg 1991;49:461–463.
55 Ferlito A, Devaney KO, Rinaldo A, Devaney
SL, Carbone A: Micrometastases: Have they an
impact on prognosis? Ann Otol Rhinol Laryn-
gol 1999;108:1185–1189.
56 Van den Brekel MWM, Leemans CR, Snow
GB: Assessment and management of lymph
node metastases in the neck in head and neck
cancer patients. Crit Rev Oncol Hematol 1996;
22:175–182.
57 Van den Brekel MW, Van der Waal I, Meijer
CJ, Freeman JL, Castelijns JA, Snow GB: The
incidence of micrometastases in neck dissec-
tion specimens obtained from elective neck dis-
sections. Laryngoscope 1996;106:987–991.
58 Van der Brekel MWM, Snow GB: Assessment
of lymph node metastases in the neck. Eur J
Cancer B Oral Oncol 1994;30B:88–92.
59 Ferlito A, Rinaldo A: False negative conven-
tional histology of lymph nodes in patients with
head and neck cancer. ORL J Otorhinolaryngol
Relat Spec 2000;62:112–114.
60 Devaney SL, Ferlito A, Rinaldo A, Devaney
KO: Pathologic detection of occult metastases
in regional lymph nodes in patients with head
and neck cancer. Acta Otolaryngol (Stockh)
2000;120:344–349.
61 Brennan JA, Mao L, Hruban RH, Boyle JO,
Eby YJ, Koch WM, Goodman SN, Sidransky
D: Molecular assessment of histopathological
staging in squamous-cell carcinoma of the head
and neck. N Engl J Med 1995;332:429–435.
62 Brennan JA, Sidransky D: Molecular staging of
head and neck squamous carcinoma. Cancer
Metastasis Rev 1996;15:3–10.
63 Enepekides DJ, Sultanem K, Nguyen C, She-
nouda G, Black MJ, Rochon L: Occult cervical
metastases: Immunoperoxidase analysis of
the pathologically negative neck. Otolaryngol
Head Neck Surg 1999;120:713–717.
64 Ambrosch P, Brinck U: Detection of nodal
micrometastases in head and neck cancer by
serial sectioning and immunostaining. Oncolo-
gy (Huntingt) 1996;10:1221–1226.
65 Allred DC, Elledge RM: Editorial: Caution
concerning micrometastatic breast carcinoma
in sentinel lymph nodes. Cancer 1999;86:905–
907.
66 Dowlatshahi K, Fan M, Bloom KJ, Spitz DJ,
Patel S, Snider HC Jr: Occult metastases in the
sentinel lymph nodes of patients with early
stage breast carcinoma. A preliminary study.
Cancer 1999;86:990–996.
67 Reintgen D, Shivers S: Sentinel lymph node
micrometastases from melanoma. Proven
methodology and evolving significance. Cancer
1999;86:551–552.
68 Hirabayashi H, Koshii K, Uno K, Ohgaki H,
Nakasone Y, Fujisawa T, Syouno N, Hinohara
T, Hirabayashi K: Extracapsular spread of
squamous cell carcinoma in neck lymph nodes:
Prognostic factor of laryngeal cancer. Laryngo-
scope 1991;101:502–506.
69 Leemans CR, Tiwari R, Nauta JJ, Van der
Waal I, Snow GB: Regional lymph node in-
volvement and its significance in the develop-
ment of distant metastases in head and neck
carcinoma. Cancer 1993;71:452–456.
70 Mamelle G, Pampurik J, Lubionski B, Lancar
R, Lusinshi A, Bosq J: Lymph node prognostic
factors in head and neck squamous cell carci-
nomas. Am J Surg 1994;168:494–498.
71 De Carvalho MB: Quantitative analysis of the
extent of extracapsular invasion and its prog-
nostic significance: A prospective study of 170
cases of carcinoma of the larynx and hypopha-
rynx. Head Neck 1998;20:16–21.
72 Carter RL, Bliss JM, Soo KC, O’Brien CJ:
Radical neck dissections for squamous carcino-
mas: Pathological findings and their clinical
implications with particular reference to trans-
capsular spread. Int J Radiat Oncol Biol Phys
1987;13:825–832.
73 Ratcliffe RJ, Soutar DS: Unexpected lymph
node pathology in neck dissection for head and
neck cancer. Head Neck 1990;12:244–246.
74 Davidson BJ, Newkirk KA, Harter KW, Pick-
en CA, Cullen KJ, Sessions RB: Complications
from planned, posttreatment neck dissections.
Arch Otolaryngol Head Neck Surg 1999;125:
401–405.
75 Ohtawa T, Katagiri M, Harada T: A study of
sternocleidomastoid muscular atrophy after
modified neck dissection. Surg Today 1998;28:
46–58.
Devaney/Ferlito/Rinaldo/Devaney
76 Newman JP, Terris DJ, Pinto HA, Fee WE,
Goode RL, Goffinet DR: Surgical morbidity of
neck dissection after chemoradiotherapy in ad-
vanced head and neck cancer. Ann Otol Rhinol
Laryngol 1997;106:117–122.
77 Olofsson J, Tytor M: Complications in neck
dissection. ORL J Otorhinolaryngol Relat Spec
1985;47:123–130.
78 Franchi A, Gallo O, Boddi V, Santucci M: Pre-
diction of occult neck metastases in laryngeal
carcinoma: Role of proliferating cell nuclear
antigen, MIB-1, and E-cadherin immunohisto-
chemical determination. Clin Cancer Res
1996;2:1801–1808.
The Pathology of Neck Dissection
79 Shin DM, Lee JS, Lippman SM, Lee JJ, Tu ZN,
Choi G, Heyne K, Shin HJ, Ro JY, Goepfert H,
Hong WK, Hittelman WN: p53 expressions:
Predicting recurrence and second primary tu-
mors in head and neck squamous cell carcino-
ma. J Natl Cancer Inst 1996;88:519–529.
80 Sidransky D: Molecular genetics of head and
neck cancer. Curr Opin Oncol 1995;7:229–
233.
81 Brachman DG: Molecular biology of head and
neck cancer. Semin Oncol 1994;21:320–329.
ORL 2000;62:204–211
82 Atula TS, Grenman R, Varpula MJ, Kurki TJ,
Klemi PJ: Palpation, ultrasound, and ultra-
sound-guided fine-needle aspiration cytology
in the assessment of cervical lymph node status
in head and neck cancer patients. Head Neck
1996;18:545–551.
83 Van den Brekel WM, Castelijns JA, Stel HV,
Golding RP, Meyer CJ, Snow GB: Modern
imaging techniques and ultrasound-guided as-
piration cytology for the assessment of neck
node metastases: A prospective comparative
study. Eur Arch Otorhinolaryngol 1993;250:
11–17.
211
 ORL 2000;62:212–216
Classification and Terminology of
Neck Dissections
Alfio Ferlito a Peter M. Som b Alessandra Rinaldo a Vanni Mondin a
a Department of Otolaryngology-Head and Neck Surgery, University of Udine, Italy, and
b Department of Radiology, Mount Sinai School of Medicine, City University of New York, N.Y., USA
Key Words
Neck dissection W Head and neck cancer W Classification
Abstract
With the proliferation of operations designed to treat cer-
vical metastatic nodal disease, it has become ever appar-
ent for the need to more clearly and precisely communi-
cate the location of the metastatic cervical nodes and the
specific surgery performed. To this end, this paper re-
views the variety of operations and the resultant confus-
ing terminology that has emerged over the past five
decades. It is suggested that a simplified technology be
used that specifically describes the nodal levels dis-
sected, the relevant nonlymphatic structures removed,
and those structures that are preserved. It is also sug-
gested that the new imaging-based nodal classification
be used to standardize the definition of the nodal levels.
It is hoped that this approach will eliminate many of the
often confusing and nondescriptive terms and there by
facilitate better inter-physician and inter-institutional
communication.
Copyright © 2000 S. Karger AG, Basel
© 2000 S. Karger AG, Basel
ABC 0301–1569/00/0624–0212$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
Historical Perspective
Since the 19th century, surgeons were aware of the fact
that cancers of the upper aero-digestive tract tended to
metastasize to the cervical lymph nodes. However, the
surgical treatment of the neck was woefully inadequate
and often resulted in progressive and rapid dissemination
of the malignant tumor [1]. In 1906, George Crile [2] pub-
lished a report that is now considered the first surgical
method of ‘en-bloc’ resection of the cervical lymph nodes.
Prior to the Second World War, the radical neck dissec-
tion technique of Crile underwent only modest technical
improvements and there was little clarification of the
indications for this procedure. It was only after the 1950s
that this surgical procedure received significant support
thanks to the studies of Martin et al. [3], Ogura and Bello
[4] and Barbosa [5].
During the 1960s, Suarez and Ballantyne each devel-
oped the technique of conservative neck dissection [6].
For the first time only the lymph nodes between the apon-
eurotic compartments of the neck were removed, while
the nonlymphatic structures (i.e. spinal accessory nerve,
internal jugular vein, sternocleidomastoid muscle) were
spared [7]. Suarez’s technique was then popularized by
Italian otolaryngologists [8–11] and this type of neck dis-
section was called a functional neck dissection [7].
Alfio Ferlito, MD, Professor and Chairman
Department of Otolaryngology-Head and Neck Surgery
University of Udine, Policlinico Città di Udine
Viale Venezia 410, I–33100 Udine (Italy)
Tel. +39 0432 239302, Fax +39 0432 532179, E-Mail clorl@dsc.uniud.it
 Today there are a variety of different types of neck dis-
section that are considered oncologically, functionally
and cosmetically effective in the therapeutic or prophylac-
tic treatment of the neck in patients with head and neck
cancers. These less radical surgical procedures are often
performed bilaterally and may be followed by postopera-
tive radiotherapy. In properly selected patients, the inci-
dence of neck recurrences observed with these neck dis-
sections is the same as that obtained with radical or modi-
fied radical neck dissections [6, 12–14].
Neck Dissection Terminology and
Classification
As the various modified neck dissection techniques
have appeared in the literature, there has resulted a
nomenclature that is both nonuniform and often confus-
ing. The need to use a common nomenclature for these
different neck dissections appears obvious, but it is not
easy to avoid the current confusion on this subject. In
1987, Suen and Goepfert [15] were the first to suggest a
classification of neck dissections, which was simplified
2 years later by Medina [16]. The basic idea behind both
proposed classifications was to identify three broad cate-
gories of neck dissections: (1) the standard radical neck
dissection; (2) the comprehensive modified radical neck
dissection, and (3) the selective neck dissection, where
one or more selected groups of nodes considered at risk
are removed, depending on the site of the primary cancer
and its expected lymphatic spread.
In 1991 the Committee for Head and Neck Surgery
and Oncology created by the American Academy of Oto-
laryngology-Head and Neck Surgery, in conjunction with
the Education Committee of the American Society for
Head and Neck Surgery [17], developed a classification
system based on the following concepts: (1) the radical
neck dissection is the fundamental procedure with which
every other neck dissection has to be compared; (2) the
modified radical neck dissection denotes preservation of
one or more nonlymphatic structures; (3) the selective
neck dissection denotes sparing of one or more lymph
node levels, and (4) the extended neck dissection denotes
removal of more lymphatic and/or nonlymphatic struc-
tures. The following classification has been therefore rec-
ommended and table 1 summarizes these different types
of neck dissections [17].
Both the radical and modified radical neck dissections
can be grouped in the same category (‘comprehensive’
neck dissection) as the lymphatic structures removed are
Classification of Neck Dissections
Table 1. The Academy’s classification of the
neck dissections [from 17]
Comprehensive neck dissection
Radical neck dissection
Modified radical neck dissection
Type I
Type II
Type III
Selective neck dissection
Supraomohyoid neck dissection
Posterolateral neck dissection
Lateral neck dissection
Anterior neck dissection
Extended neck dissection
the same. The two surgical techniques differ only with
respect to the nonlymphatic structures spared.
The radical neck dissection includes complete removal
of all the lymph node levels I–V and sacrifices the spinal
accessory nerve, the internal jugular vein, and the sterno-
cleidomastoid muscle. The boundaries of this kind of
neck dissection are the lower border of the mandible supe-
riorly, the clavicle inferiorly, the anterior border of the
trapezius muscle posteriorly, and the lateral border of the
sternohyoid muscle, hyoid bone, and contralateral anteri-
or belly of the digastric muscle anteriorly.
The modified radical neck dissection preserves one or
more nonlymphatic structures. In type I, only the spinal
accessory nerve is preserved; in type II, both the spinal
accessory nerve and the internal jugular vein are spared;
in type III, all the three nonlymphatic structures (i.e. spi-
nal accessory nerve, internal jugular vein and sternoclei-
domastoid muscle) are preserved. The boundaries of the
dissection are the same as those of the radical neck dissec-
tion.
The selective neck dissection refers to any type of lym-
phadenectomy that spares one or more lymphatic levels.
In the suprahyoid neck dissection, only the nodes in levels
I and II are removed. The inferior boundary of this surgi-
cal procedure is represented by the carotid bifurcation. In
the supraomohyoid neck dissection, the nodes in level III
are also removed. The inferior boundary of this dissection
is the omohyoid muscle. In the extended supraomohyoid
neck dissection, all of the nodes in levels I–IV are removed
extending from the inferior border of the mandible to the
clavicle. In the posterolateral neck dissection, the nodes in
levels II–V and the suboccipital and retroauricular nodes
are removed. In the lateral neck dissection, only the upper,
ORL 2000;62:212–216 213
 Table 2. Terminology of current classification of the neck dissection [modified from 18]

Type of neck dissection Lymph node levels removed Structures preserved

Comprehensive
Radical I, II, III, IV, V None
Modified radical
Type 1 I, II, III, IV, V SAN
Type 2 I, II, III, IV, V SAN, IJV
Type 3 I, II, III, IV, V SAN, IJV, SCM

Selective
Suprahyoid I, II SAN, IJV, SCM
Supraomohyoid I, II, III SAN, IJV, SCM
Extended supraomohyoid I, II, III, IV SAN, IJV, SCM
Posterolateral II, III, IV, V, SAN, IJV, SCM
suboccipital and retroauricolar nodes
Lateral II, III, IV SAN, IJV, SCM
Anterior VI SAN, IJV, SCM
Anterolateral II, III, IV, VI SAN, IJV, SCM

Extended neck dissection I, II, III, IV, V None

and one or more additional lymph and structures that are not routinely
node groups (such as the paratracheal removed by radical neck dissection
nodes or anterior compartment (such as the carotid artery, the hypoglossal
lymph nodes) nerve, the vagus nerve) are removed

SAN = Spinal accessory nerve; IJV = internal jugular vein; SCM = sternocleidomastoid muscle.

middle and lower jugular nodes (levels II, III and IV) are
removed. In the anterior neck dissection, the lymph nodes
(level VI) surrounding the visceral structures of the anteri-
or compartment of the neck are removed (this procedure
may be extended to include level VII nodes). Finally, the
anterolateral neck dissection groups these two previous
surgical procedures together so that levels II, III, IV and
VI are removed. It is important to emphasize the fact that
the posterior border of dissection in all these selective pro-
cedures, except for the anterior dissection, is the cuta-
neous branches of the cervical plexus [18]; otherwise the
risk of neck recurrences can be high [19, 20]. Another
aspect to be taken into consideration is the fact that
although the spinal accessory nerve, the internal jugular
vein, and the sternocleidomastoid muscle are preserved in
the majority of these types of dissections, there is no rea-
son why at least one of these three nonlymphatic struc-
tures cannot be sacrified [14]. In such cases, it is necessary
to modify the actual classification of selective neck dissec-
tions, specifying the specific nonlymphatic structures re-
moved.
The extended neck dissection is the most aggressive of
these surgical techniques because additional lymph node
groups and/or nonlymphatic structures not encompassed
by the radical neck dissection are removed. Examples are
the lymph nodes of the anterior compartment of the neck,
the carotid artery, and the hypoglossal or vagus nerve.
Table 2 summarizes the different types of neck dissec-
tions and shows the lymph node levels removed and the
structures preserved [18].
In 1994, Spiro et al. [21] from the Memorial Sloan-
Kettering Cancer Center, New York, pointed out that the
classification of neck dissections according to Robbins et
al. [17] does not cover all possible operations and suggest-
ed a new classification. They defined a neck dissection as
radical when four or five lymph node levels are excised
(this includes patients who have an otherwise classical
neck dissection for supraglottic or hypopharyngeal cancer
sparing level I nodes). A selective neck dissection was
defined as any lymphadenectomy that encompassed no
more than three nodal levels, usually the supraomohyoid
(levels I, II and III), or jugular (levels II, III and IV) nodes.
A limited neck dissection is any lymphadenectomy that
removes no more than two nodal levels. Table 3 summa-
rizes their proposed neck dissection classification [21].

214 ORL 2000;62:212–216 Ferlito/Som/Rinaldo/Mondin

Table 3. Neck dissection classification [from 21]
1 Radical (4 or 5 node levels resected)
a Conventional radical neck dissection
b Modified radical neck dissection
c Extended radical neck dissection
d Modified and extended radical neck dissection
2 Selective (3 node levels resected)
a Supraomohyoid neck dissection
b Jugular neck dissection
c Any other 3 node level dissection levels specified
3 Limited (no more than 2 node levels resected)
a Paratracheal node dissection
b Mediastinal node dissection
c Any other 1 or 2 level dissection levels specified
Other Terminology
The term ‘comprehensive’ neck dissection includes
radical neck dissection and the three types of modified
radical neck dissections which remove the nodes in levels
I–V. The terms ‘classical’, ‘elective’ or ‘prophylactic’ neck
dissection were proposed by Conley and Von Frankel [22]
to distinguish the radical (classical) procedure from the
modified (functional procedure). The term ‘functional’
neck dissection is less precise than the ‘type III modified
neck dissection’, but has been used so extensively in the
literature that these two names may be considered synon-
ymous. In addition, many authors prefer the term func-
tional neck dissection. Medina [16] recognizes a subcate-
gory of radical or modified radical neck dissections in
which the level I is not removed. These operations can be
simply distinguished from their counterparts in which the
level I nodes are removed by designating them as subtype
A (I–V lymph node groups) and subtype B (II–V lymph
node groups) respectively. ‘Conservative’ neck dissection
usually refers to the same procedure [23], but the term
should be avoided because of its lack of precision. Simi-
larly, the term ‘limited’ neck dissection proposed by Tur-
kula and Woods [24] is not precise. That is, terms such as
functional, conservative and limited neck dissection are
not precise and are primarily nondescriptive [16].
The ‘therapeutic’ neck dissection is performed for pre-
operative diagnosis, usually of palpable cervical metasta-
sis. The prophylactic or preferably the ‘elective’ neck dis-
section is employed for the management of potential sub-
clinical disease in the neck. The terms ‘therapeutic’ and
‘elective’ refer to the indication for neck dissection, but do
not specify the extent of dissection. In current surgical
Classification of Neck Dissections
Table 4. Lymph node groups corresponding to levels I–VII and the
various subzones [modified from 26]
Level Lymph node group
Ia Submental nodes
Ib Submandibular nodes
IIa Upper jugular, anterior to IX
IIb Upper jugular, posterior to IX (submuscular recess)
III Middle jugular nodes
IVa Lower jugular nodes (behind sternal head of
sternocleidomastoid muscle)
IVb Lower jugular nodes (behind clavicular head of
sternocleidomastoid muscle)
Va Posterior triangle nodes (spinal accessory group)
Vb Posterior triangle nodes (transverse cervical artery group,
supraclavicular group)
VI Anterior (central) compartment lymph nodes
(paratracheal, perithyroidal, Delphian)
VII Superior mediastinal nodes
practice, however, ‘complete neck dissection’ either mod-
ified or radical, is usually performed for a ‘therapeutic’
indication, whereas selective neck dissection is often per-
formed in ‘elective’ situations [6]. Other terms include
conservation neck dissection, complete functional neck
dissection, fascial neck dissection, precautional neck dis-
section, Bocca neck dissection, Suarez neck dissection,
modified neck dissection, nerve-sparing radical neck dis-
section, nerve/muscle-sparing radical neck dissection,
nerve/muscle/vein-sparing radical neck dissection, total
neck dissection, regional node dissection, minor neck dis-
section, upper-lateral node dissection, infrahyoid neck
dissection, upper neck dissection, lower neck dissection,
lower-lateral neck dissection, anterior compartment dis-
section, posterior neck dissection, anterior/posterior neck
dissection, radical posterolateral neck dissection, subocci-
pital node dissection, retropharyngeal and parapharyn-
geal node dissection, interjugular node dissection, jugular
neck dissection, extended selective neck dissection, sub-
mental triangle dissection, submandibular triangle dissec-
tion, paratracheal node dissection, mediastinal node dis-
section, etc.
Proposal
To classify neck dissections, we must first adopt a com-
mon nomenclature for the lymph node groups of the neck
and the classification recently proposed by Som et al. [25]
ORL 2000;62:212–216 215
is simple and clear. This classification includes seven lev-
els and proposes precise imaging-based anatomic land-
marks for use in classifying metastatic cervical adenopa-
thy. The lymph node groups that correspond to the neck
levels and subgroups are outlined in table 4 [26]. It has
been proposed that this imaging-based nodal classifica-
tion be utilized to help standardize the terminology of
nodal classification. The current classification defines in a
more precise manner the anatomical zones or levels of the
neck which were previously classified by Shah et al. [27]
and by Robbins et al. [17].
To avoid confusion, redundancy and misinterpreta-
tion among head and neck oncologists, any neck dissec-
tion should be described specifying the levels dissected
and the relevant nonlymphatic structures removed, as well
as those that are preserved. Many other terms are often
confusing and nondescriptive and do not facilitate inter-
institutional communication.

References
1 Beahrs OH: Surgical anatomy and technique of
radical neck dissection. Surg Clin North Am
1977;57:663–700.
2 Crile G: Excision of cancer of the head and
neck with special reference to the plan of dis-
section based upon one hundred thirty-two
operations. JAMA 1906;47:1780–1786.
3 Martin H, Del Valle B, Ehrlich H, Cahan WB:
Neck dissection. Cancer 1951;4:441–499.
4 Ogura JH, Bello JA: Laryngectomy and radical
neck dissection for carcinoma of the larynx.
Laryngoscope 1952;62:1–52.
5 Barbosa JF: Radical laryngectomy with bilater-
al neck dissection in continuity. Arch Otolaryn-
gol 1965;63:372–383.
6 Ferlito A, Silver CE: Neck dissection; in Silver
CE, Ferlito A (eds): Surgery for Cancer of the
Larynx and Related Structures. Philadelphia,
Saunders, 1996, pp 299–324.
7 Suarez O: El problema de las metastasis linfáti-
cas y alejadas del cáncer de laringe e hipofa-
ringe. Rev Otorrinolaringol 1963;23:83–99.
8 Bocca E, Pignataro O: A conservation tech-
nique in radical neck dissection. Ann Otol
1967;76:975–987.
9 Calearo CV, Teatini G: Functional neck dissec-
tion. Anatomical grounds, surgical technique,
clinical observations. Ann Otol Rhinol Laryn-
gol 1983;92:215–222.
10 Bocca E, Pignataro O, Oldini C, Cappa C:
Functional neck dissection: An evaluation and
review of 843 cases. Laryngoscope 1984;94:
942–945.
11 Bocca E: Surgical management of supraglottic
cancer and its lymph node metastases in a con-
servative perspective. Ann Otol Rhinol Laryn-
gol 1991;100:261–267.
12 Houck JR, Medina JE: Management of cervical
lymph nodes in squamous carcinomas of the
head and neck. Semin Surg Oncol 1995;11:
228–239.
13 Traynor SJ, Cohen JI, Gary J, Andersen PE,
Everts EC: Selective neck dissection and the
management of the node-positive neck. Am J
Surg 1996;172:654–657.
14 Pellitteri PK, Robbins KT, Neuman T: Ex-
panded application of selective neck dissection
with regard to nodal status. Head Neck 1997;
19:260–265.
15 Suen JY, Goepfert H Editorial: Standardiza-
tion of neck dissection nomenclature. Head
Neck Surg 1987;10:75–77.
16 Medina JE Editorial: A rational classification
of neck dissections. Otolaryngol Head Neck
Surg 1989;100:169–176.
17 Robbins KT, Medina JE, Wolfe GT, Levine
PA, Sessions RB, Pruet CW: Standardizing
neck dissection terminology. Official report of
the Academy’s Committee for head and neck
surgery and oncology. Arch Otolaryngol Head
Neck Surg 1991;117:601–605.
18 Ferlito A, Rinaldo A: Selective lateral neck dis-
section for laryngeal cancer in the clinically
negative neck: Is it justified? J Laryngol Otol
1998;112:921–924.
19 Spiro RH, Gallo O, Shah JP: Selective jugular
node dissection in patients with squamous car-
cinoma of the larynx or pharynx. Am J Surg
1993;166:399–402.
20 Clayman GL, Frank DK: Selective neck dissec-
tion of anatomically appropriate levels is as
efficacious as modified radical neck dissection
for elective treatment of the clinically negative
neck in patients with squamous cell carcinoma
of the upper respiratory and digestive tracts.
Arch Otolaryngol Head Neck Surg 1998;124:
348–352.
21 Spiro RH, Strong EW, Shah JP: Classification
of neck dissection: Variations on a new theme.
Am J Surg 1994;168:415–418.
22 Conley JJ, Von Frankel PH: Historical aspects
of head and neck surgery. Ann Otol 1956;65:
643–655.
23 Skolnik EM, Deutsch EC: Conservative neck
dissection. J Laryngol Otol 1983;8(suppl):105–
107.
24 Turkula LD, Woods JE: Limited or selective
nodal dissection for malignant melanoma of
the head and the neck. Am J Surg 1984;148:
446–448.
25 Som PM, Curtin HD, Mancuso AA: An imag-
ing-based classification for the cervical nodes
designed as an adjunct to recent clinically
based nodal classifications. Arch Otolaryngol
Head Neck Surg 1999;125:388–396.
26 Robbins KT: Classification of neck dissection.
Current concepts and future considerations.
Otolaryngol Clin North Am 1998;31:639–655.
27 Shah JP, Strong E, Spiro RH, Vikram B: Neck
dissection: Current status and future possibili-
ties. Clin Bull 1981;11:25–33.

216 ORL 2000;62:212–216 Ferlito/Som/Rinaldo/Mondin

 ORL 2000;62:217–225
Surgical Treatment of the Neck in
Cancer of the Larynx
Alfio Ferlito a Carl E. Silver b Alessandra Rinaldo a Richard V. Smith c
a Department of Otolaryngology-Head and Neck Surgery, University of Udine, Italy; Departments of
b Surgery and c Otolaryngology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, N.Y., USA
Key Words
Larynx W Lymph nodes W Metastasis W Neck dissection
Abstract
Current concepts in management of the clinically nega-
tive and clinically positive neck in laryngeal cancer are
reviewed. Occult disease in the neck not detected by
physical and radiographic examination may also be diffi-
cult to identify on routine histologic examination. Immu-
nohistochemistry or molecular analysis may detect met-
astatic involvement not apparent by light microscopy.
The surgeon should be aware of the relatively high inci-
dence of micrometastases in patients with laryngeal can-
cer to establish optimal treatment approaches. Elective
treatment of the neck is recommended for supraglottic
tumors staged T2 or higher, and glottic or subglottic
tumors staged T3 or higher.
The neck may be treated electively by either surgery or
irradiation, but irradiation is best reserved for cases
where that modality is employed for the primary tumor.
Elective neck dissection provides important information
for prognostic purposes and therapeutic decisions, by
establishing the presence, number, location and nature
of occult lymph node metastases. The selective lateral
neck dissection (levels II, III and IV), unilateral or bilateral,
is the procedure of choice for elective treatment. Paratra-
© 2000 S. Karger AG, Basel
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E-Mail karger@karger.ch Accessible online at:
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cheal nodes (level VI) should be dissected in cases of
advanced glottic and subglottic cancer. Complete radical
or functional neck dissections are excessive in extent, as
levels I and V are almost never involved. Sentinel lymph
node biopsy may fail to detect tumor on frozen section
examination or may not reveal ‘skip’ metastases.
The clinically involved neck is usually treated by com-
plete radical or functional neck dissection of levels I
through V. Selective neck dissection has been employed
successfully in selected cases, particularly for N1 or
occasionally N2 nodal involvement. The selective neck
dissection can be extended to include structures at risk.
More advanced disease has been treated in this manner
often in association with adjuvant chemotherapy and/or
irradiation. While the benefit of adjuvant treatment is dif-
ficult to assess, it appears most useful in cases with
extranodal spread of disease, a factor associated with
the worst prognosis.
Copyright © 2000 S. Karger AG, Basel
Treatment of the Neck in Laryngeal Cancer
While management of both early and advanced prima-
ry laryngeal cancer has undergone revolutionary change
during the past decade, regional disease in the neck repre-
Alfio Ferlito, MD, Professor and Chairman
Department of Otolaryngology-Head and Neck Surgery
University of Udine, Policlinico Città di Udine
Viale Venezia 410, I–33100 Udine (Italy)
Tel. +39 0432 239302, Fax +39 0432 532179, E-Mail clorl@dsc.uniud.it
sents a source of potential failure that exceeds the risk of
failure at the primary site. Our concepts of appropriate
management of the neck in laryngeal and other head and
neck cancers have also evolved extensively during the
same period, with development of an armamentarium of
surgical procedures of various extent as well as the use of
irradiation for definitive or adjuvant therapy. Decisions
regarding management of the neck in laryngeal cancer
must be considered for the patient with no clinical evi-
dence of neck disease (elective treatment of the neck), as
well as for the patient with clinically evident cervical
metastases (therapeutic treatment of the neck).
Elective Treatment of the Neck
Staging the Clinically Negative Neck
Detection and staging of cervical lymph node disease,
particularly when not clinically evident, continues to
present a major challenge to the head and neck oncologist.
The status of the cervical lymph nodes, important for its
prognostic and therapeutic implications, is difficult to
evaluate in the absence of palpable or radiologically
obvious metastases. The reported false negative rate in
assessing the presence or absence of cervical lymph node
metastasis by palpation is 20–51% [1]. Factors affecting
this large variance include not only the experience of the
examiner and the patient’s body habitus, but also pre-
vious treatment such as surgery or radiotherapy. There is
extensive evidence that even the most sensitive and tech-
nologically advanced procedures (computed tomography,
magnetic resonance imaging, ultrasound, ultrasound-
guided fine needle aspiration biopsy, single photon emis-
sion computed tomography, positron emission tomogra-
phy, lymphangiography, radioimmunoscintigraphy, and
radionuclide scanning) may be unable to reveal microme-
tastases preoperatively [2–4].
Clinical and pathologic assessment of lymphatic me-
tastases may also be difficult to assess. Evidence of meta-
static infiltration in neck nodes may be minimal, showing
no change in size, macroscopic morphology, or consisten-
cy [5]. The surgeon often cannot distinguish whether a
node is positive for cancer by palpating and closely exam-
ining it intraoperatively. Frozen section biopsy is a valu-
able tool for intraoperative evaluation of suspect nodes
[6], although even neck nodes reported as pathologically
disease-free following light microscopic study may not
truly be free of occult metastases. This may be due to dis-
ease located at another level in the lymph node or, rarely,
to having been overlooked by the microscopist [7]. It is
218 ORL 2000;62:217–225
disconcerting to note that approximately 20–30% of no-
dal metastases may be unrecognized by pathologists on
routine final histological examination [8]. Reintgen and
Shivers [9], in a recent editorial published in Cancer,
emphasize the fact that such examination may fail to
detect low volume micrometastatic disease.
It has become conventional to describe any neck that
appears clinically negative as N0. However, the classifica-
tion of N0 necks suggested by Ferlito and Rinaldo [10]
may be more useful. The N0 neck may be either clinically,
radiologically or pathologically negative. The pathologi-
cally negative neck may further be defined by convention-
al histological examination (pN0, hematoxylin and eosin),
immunohistochemistry (pN0, immunohistochemistry),
or molecular analysis (pN0, molecular analysis). In fact, a
neck that is N0 on conventional pathologic evaluation
may be positive by either immunohistochemical or mo-
lecular analysis. The reported incidence of micrometas-
tases may vary according to the method used for detection
(e.g. semiserial sections and/or histochemistry for cyto-
keratins and molecular analysis) [7, 11–13]. While such
reporting obviously has staging implications, the clinical
impact of such information is unclear, as the staging sys-
tems and treatment reports have previously been based
upon standard hematoxylin and eosin staining.
Treatment of the Clinically Negative Neck
The surgeon should be aware of the relatively high inci-
dence of micrometastases in patients with laryngeal can-
cer to establish optimal treatment approaches. Therapeu-
tic decisions regarding the neck must also be undertaken
in context with the size, site, phenotype and treatment
plan for the primary cancer. Elective neck dissection or
elective neck irradiation, using a dose of 5,000 rad, are
indicated in reducing the incidence of recurrence in the
clinically negative neck, and these treatments may reduce
the risk of distant metastases. The choice of surgery or
irradiation for elective treatment of the clinically negative
neck often depends on the treatment chosen for the pri-
mary cancer: neck dissection if surgery has been used to
treat the primary cancer, or irradiation if that modality
has been employed for the primary tumor.
The role of elective treatment of the neck in laryngeal
cancer continues to be controversial, and variations in
type and extent of surgical dissection have evolved. Op-
tions for elective treatment include neck dissection, irra-
diation, observation with subsequent salvage neck dissec-
tion if clinical evidence of metastases emerges (the ‘wait-
and-see’ policy), or intraoperative examination of the sen-
tinel lymph node (sentinel lymphadenectomy) with im-
Ferlito/Silver/Rinaldo/Smith
mediate lymph node dissection in the case of identifica-
tion of metastasis.
Elective Neck Dissection
Elective neck dissection refers to the dissection of cer-
vical lymphatics in the absence of metastatic disease, for
either staging or treatment purposes. This is a generic
term used for any type of neck dissection, such as conven-
tional radical neck dissection, modified radical neck dis-
section, selective neck dissection (3 node levels resected),
or limited neck dissection (no more than 2 node levels
resected) [14]. Elective (prophylactic) neck dissection has
been recommended for the N0 neck in patients with T2–
T4 supraglottic cancers [15–17], T3–T4 glottic cancers
[17–22], T3–T4 subglottic cancers [17, 22–24] and in
patients with recurrent supraglottic and advanced glottic
cancers treated by radiotherapy and salvaged by laryngec-
tomy [25].
The Role of Irradiation in Elective Treatment of the
Neck
The role of radiation therapy as an alternative, or
adjunct, to surgery for neck disease remains controversial.
Primary irradiation for elective treatment of the neck has
been considered as effective as surgery in preventing neck
recurrence since the report of Fletcher [26] in 1972. Nev-
ertheless, the value of such irradiation may be questioned.
For example, Goffinet et al. [27] found no difference in
the rate of neck recurrence, after supraglottic laryngecto-
my, between patients who received radiation therapy, and
those whose necks were observed. Lutz et al. [28] found
radiation therapy ineffective for preventing metastasis in
the contralateral neck, in patients who had unilateral neck
dissection. Elective neck dissection provides important
information for prognostic purposes and therapeutic deci-
sions, by establishing the presence, number, location and
nature of occult lymph node metastases. The use of pri-
mary irradiation to treat these patients, however, makes it
impossible to establish whether there were metastases in
the treated lymph nodes [29], and therefore makes it diffi-
cult to compare the efficacy of elective neck dissection
versus elective neck irradiation. Another disadvantage of
irradiation is that surgical treatment retains the ability to
employ subsequent radiotherapy for second primary tu-
mors, which develop in 11–19% of patients with cancer of
the larynx [19, 30–33], most often within the first 5 years
after treatment [34].
Surgical Treatment of the Neck
Choice of Surgical Procedure for Elective Treatment
of the Neck
The location of cervical lymph node metastases is
closely linked with the site of the primary lesion. The
supraglottic area is richly supplied with lymphatics, and
tumors of the supraglottic region metastasize in 25–75%
of cases when all stages are considered [35]. Bilateral
metastases are common [36], as the supraglottis is a mid-
line structure. Several authors have noted a high inci-
dence of recurrence on the contralateral side of the neck in
patients treated by unilateral neck dissection, and im-
provement in survival and local-regional control when
patients were treated with bilateral neck dissection [28,
37–40]. Weber et al. [41] demonstrated the efficacy of
bilateral neck dissection in the management of the cervi-
cal lymphatics in patients with supraglottic cancer, with
an observed decrease in neck recurrence from 20 to 9%.
Not all authors agree that elective bilateral neck dissection
is necessary in all cases. Gregor et al. [42] reviewed 89
patients treated from 1979 to 1988. One third of patients
presenting with N2a nodes had contralateral metastases,
while 100% of patients with N2b nodes had contralateral
metastases. Although no morbidity was observed from
dissecting the contralateral side, only 1 of 7 patients with
clinically negative necks had a histologically positive neck
specimen. Ninety-five percent of N0 patients never devel-
oped cervical metastasis, and none developed distant me-
tastases. The authors felt that their data did not support
routine bilateral neck dissections in patients with clinical-
ly negative necks. DeSanto et al. [43] have recommended
that the ipsilateral neck dissection be performed routinely
in the clinically N0 neck, and if frozen sections confirm
the presence of metastasis, the ‘second’ side of the neck
should be dissected. Güney and Yiǧitbasi [44] do not rec-
ommend an elective treatment of the second side in
patients with T1–T2 unilateral supraglottic cancer, if the
first specimen is negative.
Lymphatic spread from glottic or subglottic tumors is
also highly predictable. The nodes at high risk for T3 and
T4 glottic cancers include level II–IV and VI [19]. Shenoy
et al. [45] found metastases in the ipsilateral paratracheal
nodes in 9% of the 22 positive necks and contralateral
metastases in 4.5% of advanced glottic cancers. Moe et al.
[46] found that no patients with advanced glottic cancers
had level I and V involvement. Yuen et al. [18] advocated
a policy of watchful waiting also for T3 and T4 N0 glottic
cancer. Conversely, Johnson [19] recommends an ipsilat-
eral neck dissection including levels II–IV and VI. Sub-
glottic cancers spread initially to the paratracheal and
recurrent lymph nodes, which are located within level VI
ORL 2000;62:217–225 219
and VII of the recent classification of cervical lymph
nodes proposed by Som et al. [47]. The jugular chain of
lymph nodes should be considered as a secondary site of
lymphatic spread for subglottic cancers [48]. The inci-
dence of supraclavicular (level V), middle (level III) and
lower jugular (level IV) node metastases, which are only
present after the involvement of the paratracheal nodes, is
low [24]. Glottic, supraglottic, transglottic and subglottic
cancers may metastasize to precricoid or prelaryngeal
lymph node or Delphian node and to sub-Delphian nodes
in the anterior tracheal compartment of level VI [23, 49–
55]. Rarely, laryngeal cancer has metastasized to the axil-
lary lymph nodes [56–58], and the axilla can become the
major lymphatic drainage site from the anterior and later-
al neck [58]. However, axillary node metastasis remains
an uncommon occurrence in squamous carcinoma of the
upper aerodigestive tract [59, 60].
The extent of neck dissection for laryngeal cancers has
been debated for many years. Suarez [61] developed the
concept of ‘functional’ neck dissection to permit removal
of disease-bearing lymphatic tissue, while avoiding the
prohibitive morbidity of bilateral standard radical neck
dissection. Bocca [37] popularized this method and re-
ported an overall 5-year cure rate of 78% for supraglottic
cancer treated by supraglottic laryngectomy with bilateral
functional neck dissections. In the surgical management
of the clinically N0 neck in supraglottic cancer, Hicks et
al. [62] recommend bilateral neck dissection of levels I
through IV to adequately address those regions at highest
risk of occult disease. Surprisingly, of the 17 patients who
had clinically N0 necks but pathologically positive nodes,
14 (82%) had involvement of the submandibular triangle.
This finding represents a significant departure from pre-
viously reported series [22, 42, 46, 49, 50, 63–75]. This
probably depends on accuracy in definition of levels I and
II. All patients (100%) with pathologically positive nodes
had level II involvement [62].
At present, conventional radical neck dissection is not
indicated for elective neck dissection unless the surgeon
rejects the modified neck dissection procedure or lacks
experience in its performance. The procedure of choice
for elective surgery, until recently, was usually modified
neck dissection, in particular the ‘type III’ (or functional
neck dissection) [15, 61, 67, 76–82], which removes
lymph node levels I, II, III, IV and V and preserves the
sternocleidomastoid muscle, the internal jugular vein, the
spinal accessory nerve and the submandibular gland.
Preservation of the spinal accessory nerve, however, does
not guarantee normal shoulder function [83], and Talmi
et al. [84] suggest that the postero-superior jugular lymph
220 ORL 2000;62:217–225
nodes (the ‘submuscular recess’) may not need to be dis-
sected in the clinically N0 neck, thereby limiting injury to
spinal accessory nerve without compromising the remov-
al of lymph nodes at risk for involvement with cancer.
This concept, however, remains to be adequately studied.
More recently, complete functional neck dissection has
been considered an unnecessarily extensive procedure for
treatment of the clinically negative neck as levels I and V
are rarely involved, particularly in the absence of clinical-
ly or radiologically apparent neck metastases [85]. Thus
selective lateral neck dissection is a valid option in laryn-
geal cancer as this procedure preserves levels I and V,
where laryngeal tumors rarely metastasize. This concept
was introduced by surgeons at M.D. Anderson Cancer
Center who suggested removing only those lymph node
groups that, based on the location of the primary cancer,
are at highest risk of containing metastases [86]. The mor-
bidity of this surgical procedure is minimal in experi-
enced hands. The number of lymph nodes removed in
selective lateral neck dissection should be comparable to
that of the corresponding levels in radical neck dissection,
provided that strict adherence to surgical boundaries is
maintained [87]. Selective lateral neck dissection (called
also jugular neck dissection) includes the dissection of lev-
els II–IV. Spiro et al. [14] defined as a limited neck dissec-
tion any lymphadenectomy that involved removal of no
more that two nodal levels. Tu [88] suggests a limited neck
dissection, called upper neck (level II) dissection for N0
supraglottic cancer, considering such type of resection of
upper neck nodes a diagnostic as well as a therapeutic
modality. Ambrosch et al. [89] mentioned that Steiner
advocates performing limited neck dissection, clearing
only levels II and III, for cancer of the larynx. Ferlito and
Rinaldo [90] suggest including level IV, as this has virtual-
ly no effect on the morbidity or duration of the procedure
and it provides additional valuable information. In a
recent multi-institutional prospective study designed to
compare type III modified radical neck dissection with
lateral neck dissection in the management of clinically
negative neck findings in patients with supraglottic and
transglottic squamous cell carcinoma, the rates of 5-year
overall survival, neck recurrence, and complications were
similar in the two treatment groups of patients [98]. These
results confirm the efficacy of lateral neck dissection in
elective treatment of the neck in patients with laryngeal
cancer. At present, several institutions have adopted se-
lective neck dissection as the standard treatment for
patients with clinically negative necks in order to reduce
regional recurrence rates [14, 22, 89–98].
Ferlito/Silver/Rinaldo/Smith
 Sentinel node biopsy has also been considered in the
management of the lymphatic spread of cancer. This con-
cept has been rapidly adopted by the surgical community
for assessment of lymph nodes status in patients with pri-
mary cutaneous malignant melanoma and breast cancer.
The technique is minimally invasive, with low morbidity.
Biopsy of the ‘first level’ node may be less effective, how-
ever, in predicting the lymph node status of head and neck
cancer patients. Intraoperative examination by frozen
section analysis and routine pathological assessment of
the sentinel lymph node may fail to detect metastases lat-
er revealed by serial sections, or by immunohistochemical
or molecular biology assays. In addition, the occurrence of
‘skip’ metastases, which bypass the first draining lymph
node, has been well documented in patients with head
and neck cancers, particularly in patients with tumors of
the tongue [99], the floor of the mouth [100], and larynx
[69, 98].
There is ample evidence that the presence of microme-
tastases has clinical and prognostic implications [101].
These findings argue in favor of using selective lateral
neck dissection for cancer of the larynx, for staging pur-
poses, and point to the importance of immunohistochem-
istry and molecular biology in the staging of these tumors
[101].
Treatment of the Clinically Positive Neck
Therapeutic Neck Dissection
Treatment of the clinically positive neck must be based
on the extent and location of lymph node involvement.
Radical neck dissection, modified radical neck dissection
and selective lateral neck dissection may be employed
depending on the extent and location of metastatic dis-
ease. Dissection of nodes in level VI is an important fea-
ture of neck dissection for treatment of primary tumor
that may metastasize to this region. The value of postop-
erative irradiation and/or chemotherapy must be consid-
ered.
Despite its name, radical neck dissection, as intro-
duced by Crile [102] in 1906 and popularized by Martin
et al. [103], fails to dissect pretracheal and paratracheal
lymph nodes (level VI), which may be metastatic in sub-
glottic and advanced glottic cancers, while it includes lev-
el I and V lymph nodes which are seldom involved in
laryngeal cancer. Level I may occasionally be involved
(1 or 2% or less of the cases) [42, 65, 74, 75], particularly if
there is extensive involvement along the jugular chain,
often only in patients with N2 or N3 neck disease. Dissec-
Surgical Treatment of the Neck
tion of the anterior aspect of level I, the submental trian-
gle, is not indicated, as nodal involvement occurs only in
the submandibular triangle, not in the submental triangle.
Metastases have been found in level V in 1% or less of the
cases [72, 75]. Skolnik et al. [104] demonstrated no meta-
static involvement of the posterior triangle lymphatic sys-
tem in either the therapeutic or elective neck dissection
groups for cancer of the larynx. Recently, Nicolai et al.
[75] observed that in a series of 402 consecutive patients
treated for supraglottic squamous cell carcinoma, level V
nodes were never involved.
As the goal of neck dissection is to remove all clinically
evident metastatic nodal disease and the nodal groups at
greatest risk, conservative modifications of the therapeu-
tic radical neck dissection may be indicated [105]. There
is little evidence to support the routine dissection of lev-
els I and V in N1 laryngeal cancer because involvement of
the lymph nodes at these levels is virtually nonexistent
[74, 104, 106–108]. On the other hand, the N1 category
may include lesions that differ considerably in size and
extent. The fifth edition of the TNM appearing in 1997
(International Union Against Cancer) defines N1 as ‘Me-
tastasis in a single ipsilateral lymph node, 3 cm or less in
greatest dimension’ [109]. Thus a small metastatic lymph
node, with no capsular invasion, and one that is fixed,
nearly 3 cm in diameter, and has macroscopic infiltration
of the capsule, may both be classified N1, but represent
entirely different pathological and clinical situations.
Such factors, rather than simple staging classification,
must be assessed by the clinician to determine which type
of neck dissection is most appropriate [108].
While radical or modified radical neck dissection (with
inclusion of level VI as indicated) is generally employed
for treatment of the clinically involved neck, selective
neck dissection has also been advocated for more ad-
vanced stages of neck metastases. Some groups have
employed selective lateral neck dissection for laryngeal
cancer with metastatic disease staged as N1 [8, 91]. This
type of neck dissection has generally not been advocated
for the management of more advanced nodal status,
although some authors have employed selective neck dis-
section for metastatic disease staged as N2a [8, 86] or
even N2b [8]. Traynor et al. [110] extend the indications
for this operation also for N2c, where the individual
nodes are not fixed. Davidson et al. [106] noted that
patients who developed ipsilateral regional recurrences
did so within previously dissected neck zones which sug-
gests that earlier dissection of additional ipsilateral zones
would not have been beneficial.
ORL 2000;62:217–225 221
 Selective lateral neck dissection may be extended to
include the spinal accessory nerve, the internal jugular
vein and the sternocleidomastoid muscle [111]. The struc-
ture most frequently sacrificed is the internal jugular vein
[94].
Adjuvant Treatment
Adjuvant treatment may improve results in treatment
of patients with advanced stage neck disease, regardless of
the type of neck dissection employed. The value of adju-
vant radiation postoperatively for patients with patholog-
ically positive necks is controversial. Suárez et al. [112]
reviewed 193 patients with primary supraglottic cancer
who received a total of 284 elective or therapeutic neck
dissections. Approximately half the patients received
postoperative radiation therapy. Neck recurrence was ob-
served in 12.9% of patients, with no apparent influence of
postoperative radiotherapy on recurrence in the dissected
neck. Overall survival of the whole series, and by stage,
was not statistically altered by combined therapy, com-
pared to surgery alone.
Macroscopic extracapsular spread of cervical lymph
node disease is the most significant, independent adverse
prognostic factor [113], and patients with extracapsular
spread in their neck specimens have the highest incidence
of regional recurrence, as well as distant metastases. Post-
operative irradiation may perhaps best be employed se-
lectively in patients with extranodal spread of disease.
Myers and Alvi [40] reported minimum 2 year results of
treatment in 103 patients with cancer of the supraglottis
treated between 1987 and 1992. Eighty-four percent of
patients without nodal metastasis survived at least 2
years, compared with only 46% of patients with nodal
metastasis. Of this latter group, 72% of patients without
extracapsular spread of disease survived 2 years, in com-
parison with only 31% of patients with extracapsular
spread. Nine of 14 patients who had recurrence in the
neck had extracapsular spread at initial surgery, leading
the authors to recommend postoperative irradiation with
chemotherapy for patients who are found to have extra-
capsular spread of their cervical lymph node disease.
Robbins et al. [114] believe that targeted chemoradia-
tion with the use of intra-arterial supradose cisplatin and
concomitant radiation therapy followed by planned se-
lective neck dissection for patients with cancer of the
upper aerodigestive tract with N2 to N3 neck nodes is
highly effective for controlling regional disease. This use
of multimodality treatment in association with limited
surgery may best represent current thinking in the man-
agement of advanced head and neck cancer. Nevertheless,
222 ORL 2000;62:217–225
adequate evaluation of this approach has been limited to
date. It is difficult to compare the results achieved with
selective lateral neck dissection at various institutions
[22, 67, 89, 91, 92, 94, 95] because of differences in
patient selection (N0 and N1; laryngeal and hypopharyn-
geal cancers), extent of the dissection (Steiner – cf. Am-
brosch et al. [89] – advocates clearing only levels II and
III), and the use of postoperative radiotherapy. Addition-
ally, some studies report results that include both lateral
and supraomohyoid neck dissections [94] and supraomo-
hyoid, anterolateral and lateral neck dissections [106],
further complicating the issue.
Conclusions
Management of the neck in laryngeal cancer has
evolved from more radical historical techniques to lim-
ited dissections, often combined with appropriate adju-
vant therapy. Selective lateral neck dissection has become
the procedure of choice for elective treatment of the clini-
cally negative neck. The information obtained by evalua-
tion of specimens from selective neck dissection renders
this modality more useful than elective irradiation of the
neck as primary treatment.
Management of the clinically positive neck may also be
modified according to the stage and location of neck
involvement, as well as the characteristics of the primary
tumor. While complete conventional or modified radical
neck dissections constitute appropriate treatment for
many patients, the selective lateral neck dissection, ex-
tended as necessary to include resection of accessory
nerve, sternocleidomastoid muscle or internal jugular
vein, may offer a more efficient and effective treatment
tailored to the requirements of the particular situation.
Traditional radical neck dissection is clearly indicated for
patients with massive adenopathy, with macroscopic ex-
tracapsular spread and infiltration of the fascial compart-
ments of the neck. The efficacy of adjuvant chemotherapy
and irradiation remains under investigation, but these
modalities would appear indicated for the most advanced
cases, particularly when extracapsular spread of tumor is
present. Adjuvant therapy may be employed in associa-
tion with selective or extended selective neck dissection to
increase its effectiveness while limiting surgical morbidi-
ty.
Ferlito/Silver/Rinaldo/Smith
 References
1 Breau RL, Suen JY: Management of the N0
neck. Otolaryngol Clin North Am 1998;31:
657–669.
2 Van den Brekel MWM, van der Waal I, Meijer
CJLM, Freeman JL, Castelijns JA, Snow GB:
The incidence of micrometastases in neck dis-
section specimens obtained from elective neck
dissections. Laryngoscope 1996;106:987–991.
3 Ferlito A, Rinaldo A, Devaney KO, Carbone A:
Management of the clinically negative cervical
lymph nodes in patients with non-conventional
squamous carcinoma of the larynx. J Laryngol
Otol 1999;113:619–623.
4 Ferlito A, Rinaldo A: False negative conven-
tional histology of lymph nodes in patients with
head and neck cancer. ORL J Otorhinolaryngol
Relat Spec 2000;62:112–114.
5 Ferlito A, Silver CE: Neck dissection; in Silver
CE, Ferlito A (eds): Surgery for Cancer of the
Larynx and Related Structures. Philadelphia,
Saunders, 1996, pp 299–324.
6 Rassekh CH, Johnson JT, Myers EN: Accuracy
of intraoperative staging of the N0 neck in
squamous cell carcinoma. Laryngoscope 1995;
105:1334–1336.
7 Van den Brekel MWM, Stel HV, van der Valk
P, van der Waal I, Meyer CJLM, Snow GB:
Micrometastases from squamous cell carcino-
ma in neck dissection specimens. Eur Arch
Otorhinolaryngol 1992;249:349–353.
8 Shah JP, Medina JE, Shaha AR, Schantz SP,
Marti JR: Cervical lymph node metastasis.
Curr Probl Surg 1993;30:284–335.
9 Reintgen D, Shivers S: Sentinel lymph node
micrometastatis from melanoma. Proven
methodology and evolving significance. Cancer
1999;68:551–552.
10 Ferlito A, Rinaldo A: Controversies in treat-
ment for N0 neck in laryngeal cancer: Neck dis-
section, no surgery, or sentinel lymph node
biopsy? ORL J Otorhinolaryngol Relat Spec, in
press.
11 Brennan JA, Mao L, Hruban RH, Boyle JO,
Eby YJ, Koch WM, Goodman SN, Sidransky
D: Molecular assessment of histopathological
staging in squamous-cell carcinoma of the head
and neck. N Engl J Med 1995;332:429–435.
12 Ambrosch P, Brinck U: Detection of nodal
micrometastases in head and neck cancer by
serial sectioning and immunostaining. Oncolo-
gy (Huntingt) 1996;10:1221–1229.
13 Enepekides DJ, Sultanem K, Nguyen C, She-
nouda G, Black MJ, Rochon L: Occult cervical
metastases: Immunoperoxidase analysis of the
pathologically negative neck. Otolaryngol
Head Neck Surg 1999;120:713–717.
14 Spiro RH, Strong EW, Shah JP: Classification
of neck dissection: Variations on a new theme.
Am J Surg 1994;168:415–418.
15 Gavilán C, Gavilán J: Five-year results of func-
tional neck dissection for cancer of the larynx.
Arch Otolaryngol Head Neck Surg 1989;114:
1193–1196.
16 Herranz-González J, Gavilán J, Martı́nez-Vi-
dal J, Gavilán C: Supraglottic laryngectomy:
Functional and oncologic results. Ann Otol
Rhinol Laryngol 1996;105:18–22.
Surgical Treatment of the Neck
17 Pillsbury HC III, Clark M: A rationale for ther-
apy of the N0 neck. Laryngoscope 1997;107:
1294–1315.
18 Yuen A, Medina JE, Goepfert H, Fletcher G:
Management of stage T3 and T4 glottic carci-
nomas. Am J Surg 1984;148:467–472.
19 Johnson JT: Carcinoma of the larynx: Selective
approach to the management of cervical lym-
phatics. Ear Nose Throat J 1994;73:303–305.
20 Hao SP, Myers EN, Johnson JT: T3 glottic car-
cinoma revisited – Transglottis vs. pure glottic
carcinoma. Arch Otolaryngol Head Neck Surg
1995;121:166–170.
21 Yang CY, Andersen PE, Everts EC, Cohen JI:
Nodal disease in purely glottic carcinoma: Is
elective neck treatment worthwhile? Laryngo-
scope 1998;108:1006–1008.
22 Myers EN, Fagan JJ: Management of the neck
cancer of the larynx. Ann Otol Rhinol Laryngol
1999;108:828–832.
23 Dahm JD, Sessions DG, Paniello RC, Harvey
J: Primary subglottic cancer. Laryngoscope
1998;108:741–746.
24 Ferlito A, Rinaldo A: The pathology and man-
agement of subglottic cancer. Eur Arch Otorhi-
nolaryngol 2000;257:168–173.
25 Wax MK, Touma BJ: Management of the N0
neck during salvage laryngectomy. Laryngo-
scope 1999;109:4–7.
26 Fletcher GH: Elective irradiation of subclinical
disease in cancers of the head and neck. Cancer
1972;29:1450–1454.
27 Goffinet DR, Gilbert EH, Weller SA, Bagshaw
MA: Irradiation of clinically uninvolved cervi-
cal lymph nodes. Can J Otolaryngol 1975;4:
927–933.
28 Lutz CK, Johnson JT, Wagner RL, Myers EN:
Supraglottic carcinoma: Patterns of recurrence.
Ann Otol Rhinol Laryngol 1990;99:12–17.
29 Prim MP, De Diego JI, Hardisson D, Madero
R, Nistal M, Gavilán J: Extracapsular spread
and desmoplastic pattern in neck lymph nodes:
Two prognostic factors of laryngeal cancer.
Ann Otol Rhinol Laryngol 1999;108:672–676.
30 Hordijk GJ, de Jong JMA: Synchronous and
metachronous tumours in patients with head
and neck cancer. J Laryngol Otol 1983;97:619–
621.
31 Roberts TJ, Epstein B, Lee DJ: Second neo-
plasms in patients with carcinomas of the vocal
cord: Incidence and implications for survival.
Int J Radiat Oncol Biol Phys 1991;21:583–
589.
32 Rovirosa A, Bellmunt J, López A, Fernández
M, Guerra M, Montagut J: The incidence of
second neoplasms in advanced laryngeal can-
cer. Impact on survival. Med Clin (Barc) 1994;
102:121–124.
33 León X, Quer M, Diez S, Orús C, López-Pousa
A, Burgués J: Second neoplasm in patients with
head and neck cancer. Head Neck 1999;21:
204–210.
ORL 2000;62:217–225
34 Terhaard CH, Hordijk GJ, van den Broek P, de
Jong PC, Snow GB, Hilgers FJ, Annyas BA,
Tjho Heslinga RE, de Jong JM: T3 laryngeal
cancer. A retrospective study of the Dutch
Head and Neck Oncology Cooperative Group:
Study design and general results. Clin Otolar-
yngol 1992;17:393–402.
35 Sinard RJ, Netterville JL, Garrett CG, Ossoff
RH: Cancer of the larynx; in Myers EN, Suen
JY (eds): Cancer of the Head and Neck, ed 3.
Philadelphia, Saunders, 1996, pp 381–421.
36 Marks JE, Devineni VR, Harvey J, Sessions
DG: The risk of contralateral lymphatic metas-
tases for cancers of the larynx and pharynx. Am
J Otolaryngol 1992;13:34–39.
37 Bocca E: Supraglottic cancer. Laryngoscope
1975;85:1318–1326.
38 Bocca E: Surgical management of supraglottic
cancer and its lymph node metastases in a con-
servative perspective. Ann Otol Rhinol Laryn-
gol 1991;100:261–267.
39 Levendag P, Sessions R, Vikram B, Strong EW,
Shah JP, Spiro R, Gerold F: The problem of
neck relapse in early stage supraglottic larynx
cancer. Cancer 1989;63:345–348.
40 Myers EN, Alvi A: Management of carcinoma
of the supraglottic larynx: Evolution, current
concepts, and future trends. Laryngoscope
1996;106:559–567.
41 Weber PC, Johnson JT, Myers EN: The impact
of bilateral neck dissection on pattern of recur-
rence and survival in supraglottic carcinoma.
Arch Otolaryngol Head Neck Surg 1994;120:
703–706.
42 Gregor RT, Oei SS, Hilgers FJM, Hart AAM,
Balm AJM, Keus RB: Management of cervical
metastases in supraglottic cancer. Ann Otol
Rhinol Laryngol 1996;105:845–850.
43 DeSanto LW, Magrina C, O’Fallon WM: The
‘second’ side of the neck in supraglottic cancer.
Otolaryngol Head Neck Surg 1990;102:351–
361.
44 Güney E, Yiǧitbasi OG: Management of N0
neck in T1–T2 unilateral supraglottic cancer.
Ann Otol Rhinol Laryngol 1999;108:998–
1003.
45 Shenoy A, Nanjundappa A, Kumar P, Kumar
RV, Reddy BKM, Kannan V, Anantha N: In-
terjugular neck dissection and post-operative
irradiation for neck control in advanced glottic
cancers – Are we justified? J Laryngol Otol
1994;108:26–29.
46 Moe K, Wolf GT, Fisher SG, Hong WK: Re-
gional metastases in patients with advanced
laryngeal cancer. Arch Otolaryngol Head Neck
Surg 1996;122:644–648.
47 Som PM, Curtin HD, Mancuso AA: An imag-
ing-based classification for the cervical nodes
designed as an adjunct to recent clinically
based nodal classifications. Arch Otolaryngol
Head Neck Surg 1999;125:388–396.
48 Johnson JT, Myers EN: Cervical lymph node
disease in laryngeal cancer; in Silver CE (ed):
Laryngeal Cancer. New York, Thieme, 1991,
pp 22–26.
223
49 Ogura JH: Surgical pathology of cancer of the
larynx. Laryngoscope 1955;65:867–926.
50 McGavran MH, Bauer WC, Ogura JH: The
incidence of cervical lymph node metastases
from epidermoid carcinoma of the larynx and
their relationship to certain characteristics of
the primary tumor. Cancer 1961;14:655–666.
51 Olofsson J, van Nostrand AWP: Growth and
spread of laryngeal and hypopharyngeal carci-
noma with reflections on the effect of preopera-
tive irradiation. 139 cases studied by whole
organ serial sectioning. Acta Otolaryngol
(Stockh) 1973;308(suppl):1–84.
52 Resta L, Micheau C, Cimmino A: Prognostic
value of the prelaryngeal node in laryngeal and
hypopharyngeal carcinoma. Tumori 1985;71:
361–365.
53 Olsen KD, DeSanto LW, Pearson BW: Positive
Delphian lymph node: Clinical significance in
laryngeal cancer. Laryngoscope 1987;97:1033–
1037.
54 Weber RS, Marvel J, Smith P, Hankins P, Wolf
P, Goepfert H: Paratracheal lymph node dis-
section for carcinoma of the larynx, hypo-
pharynx, and cervical esophagus. Otolaryngol
Head Neck Surg 1993;108:11–17.
55 Thaler ER, Montone K, Tucker J, Weinstein
GS: Delphian lymph node in laryngeal carcino-
ma: A whole organ study. Laryngoscope 1997;
107:332–334.
56 Sun CC, Hall-Craggs M, Adler B: Oat cell carci-
noma of larynx. Arch Otolaryngol 1981;107:
506–509.
57 Gnepp DR, Ferlito A, Hyams V: Primary ana-
plastic small cell (oat cell) carcinoma of the
larynx. Review of the literature and report of
18 cases. Cancer 1983;51:1731–1745.
58 Nelson WR, Sisk M: Axillary metastases from
carcinoma of the larynx: A 25-year survival.
Head Neck 1994;16:83–87.
59 Alavi S, Namazie A, Sercarz JA, Wang MB,
Blackwell KE: Distant lymphatic metastasis
from head and neck cancer. Ann Otol Rhinol
Laryngol 1999;108:860–863.
60 Koch WM: Axillary nodal metastases in head
and neck cancer. Head Neck 1999;21:269–
272.
61 Suarez OG: Le problème chirurgical du cancer
du larynx. Ann Otolaryngol 1962;79:22–34.
62 Hicks WL, Kollmorgen DR, Kuriakose MA,
Orner J, Bakamjian VY, Winston J, Loree TR:
Patterns of nodal metastasis and surgical man-
agement of the neck in supraglottic laryngeal
carcinoma. Otolaryngol Head Neck Surg 1999;
121:57–61.
63 Pietrantoni L, Fior R: Clinical and surgical
problems of cancer of the larynx and hypo-
pharynx. A review of 570 consecutive cases
operated on in the Ear, Nose and Throat Clinic
of the University of Milan between 1948 and
1954, with special regard to the problem of
metastases. Acta Otolaryngol (Stockh) 1958
(suppl 142):1–61.
64 Feind CR: The head and neck; in Haagensen
CD, Feind CR, Herter FP, Slanetz CA Jr,
Weinberg LA (eds): The Lymphatics in Cancer.
Philadelphia, Saunders, 1972, pp 59–230.
224 ORL 2000;62:217–225
65 Lindberg R: Distribution of cervical lymph
node metastases from squamous cell carcino-
ma of the upper respiratory and digestive
tracts. Cancer 1972;29:1446–1449.
66 Feldman DE, Applebaum EL: The submandib-
ular triangle in radical neck dissection. Arch
Otolaryngol 1977;103:705–706.
67 Byers RM: Modified neck dissection. A study
of 967 cases from 1970–1980. Am J Surg 1985;
150:414–421.
68 Byers RM, Wolf PF, Ballantyne AJ: Rationale
for elective modified neck dissection. Head
Neck Surg 1988;10:160–167.
69 Candela FC, Shah J, Jaques DP, Shah JP: Pat-
terns of cervical node metastases from squa-
mous carcinoma of the larynx. Arch Otolaryn-
gol Head Neck Surg 1990;116:432–435.
70 Shah JP: Patterns of cervical lymph node me-
tastasis from squamous carcinoma of the upper
aerodigestive tract. Am J Surg 1990;160:405–
409.
71 Wenig BL, Applebaum EL: The submandibu-
lar triangle in squamous cell carcinoma of the
larynx and hypopharynx. Laryngoscope 1991;
101:516–518.
72 Redaelli de Zinis LO, Nicolai P, Barezzani
MG, Tomenzoli D, Antonelli AR: Incidenza e
distribuzione delle metastasi linfonodali nel
carcinoma laringeo sopraglottico: implicazioni
terapeutiche. Acta Otorhinolaryngol Ital 1994;
14:19–27.
73 Kowalski PL, Franco EL, de Andrade Sobrinho
J: Factors influencing regional lymph node me-
tastasis from laryngeal carcinoma. Ann Otol
Rhinol Laryngol 1995;104:442–447.
74 Li XM, Wei WI, Guo XF, Yuen PW, Lam LK:
Cervical lymph node metastatic patterns of
squamous carcinomas in the upper aerodiges-
tive tract. J Laryngol Otol 1996;110:937–941.
75 Nicolai P, Redaelli de Zinis LO, Ghizzardi D,
Tomenzoli D, Nasif N, Antonelli AR: The dis-
tribution of lymph node metastases in supra-
glottic squamous cell carcinoma: Therapeutic
implications (abstract). Br J Cancer 1998;77
(suppl 1):21.
76 Suarez O: El problema de las metastasis linfáti-
cas y alejadas del cáncer de laringe e hipofa-
ringe. Rev Otorrinolaringol 1963;23:83–99.
77 Bocca E, Pignataro O: A conservation tech-
nique in radical neck dissection. Ann Otol
1967;76:975–987.
78 Calearo CV, Teatini G: Functional neck dissec-
tion. Anatomical grounds, surgical technique,
clinical observations. Ann Otol Rhinol Laryn-
gol 1983;92:215–222.
79 Bocca E, Pignataro O, Oldini C, Cappa C:
Functional neck dissection: An evaluation and
review of 843 cases. Laryngoscope 1984;94:
942–945.
80 O’Brien CJ, Urist MM, Maddox WA: Modified
radical neck dissection. Terminology, tech-
nique, and indications. Am J Surg 1987;153:
310–316.
81 Gavilán J, Moñux A, Herranz J, Gavilán C:
Functional neck dissection: Surgical technique.
Oper Tech Otolaryngol Head Neck Surg 1993;
4:258–265.
82 de Campora E, Radici M, Camaioni A, Pianelli
C: Clinical experiences with surgical therapy of
cervical metastases from head and neck cancer.
Eur Arch Otorhinolaryngol 1994;251:335–
341.
83 Myers EN, Fagan JJ: Treatment of the N+ neck
in squamous cell carcinoma of the upper aero-
digestive tract. Otolaryngol Clin North Am
1998;31:671–686.
84 Talmi YP, Hoffman HT, Horowitz Z, McCul-
loch TM, Funk GF, Graham SM, Peleg M,
Yahalom R, Teicher S, Kronenberg J: Patterns
of metastases to the upper jugular lymph nodes
(the ‘submuscular recess’). Head Neck 1998;
20:682–686.
85 Ferlito A, Rinaldo A: Level I dissection for
laryngeal and hypopharyngeal cancer: Is it indi-
cated? J Laryngol Otol 1998;112:438–440.
86 Jesse RH, Ballantyne AJ, Larson D: Radical or
modified neck dissection: A therapeutic dilem-
ma. Am J Surg 1978;136:516–519.
87 Friedman M, Lim JW, Dickey W, Tanyeri H,
Kirshenbaum GL, Phadke DM, Caldarelli D:
Quantification of lymph nodes in selective
neck dissection. Laryngoscope 1999;109:368–
370.
88 Tu G: Upper neck (level II) dissection for N0
neck supraglottic carcinoma. Laryngoscope
1999;109:467–470.
89 Ambrosch P, Freudenberg L, Kron M, Steiner
W: Selective neck dissection in the manage-
ment of squamous cell carcinoma of the upper
aerodigestive tract. Eur Arch Otorhinolaryngol
1996;253:329–335.
90 Ferlito A, Rinaldo A: Selective lateral neck dis-
section for laryngeal cancer in the clinically
negative neck: Is it justified? J Laryngol Otol
1998;112:921–924.
91 Spiro RH, Gallo O, Shah JP: Selective jugular
node dissection in patients with squamous car-
cinoma of the larynx or pharynx. Am J Surg
1993;166:399–402.
92 Houck JR, Medina JE: Management of cervical
lymph nodes in squamous carcinomas of the
head and neck. Semin Surg Oncol 1995;11:
228–239.
93 Davidson J, Khan Y, Gilbert R, Birt BD, Ba-
logh J, MacKenzie R: Is selective neck dissec-
tion sufficient treatment for the N0/Np+ neck?
J Otolaryngol 1997;26:229–231.
94 Pellitteri PK, Robbins KT, Neuman T: Ex-
panded application of selective neck dissection
with regard to nodal status. Head Neck 1997;
19:260–265.
95 Pitman KT, Johnson JT, Myers EN: Effective-
ness of selective neck dissection for manage-
ment of the clinically negative neck. Arch Oto-
laryngol Head Neck Surg 1997;123:917–922.
96 Clayman GL, Frank DK: Selective neck dissec-
tion of anatomically appropriate levels is as
efficacious as modified radical neck dissection
for elective treatment of the clinically negative
neck in patients with squamous cell carcinoma
of the upper respiratory and digestive tracts.
Arch Otolaryngol Head Neck Surg 1998;124:
348–352.
Ferlito/Silver/Rinaldo/Smith
 97 Byers RM, Clayman GL, McGill D, Andrews
T, Kare RP, Roberts DB, Goepfert H: Se-
lective neck dissections for squamous carci-
noma of the upper aerodigestive tract: Pat-
terns of regional failure. Head Neck 1999;21:
499–505.
98 Brazilian Head and Neck Cancer Study
Group: End results of a prospective trial on
elective lateral neck dissection vs. type III
modified radical neck dissection in the man-
agement of supraglottic and transglottic carci-
nomas. Head Neck 1999;21:694–702.
99 Byers RM, Weber RS, Andrews T, McGill D,
Kare R, Wolf P: Frequency and therapeutic
implications of ‘skip metastases’ in the neck
from squamous carcinoma of the oral tongue.
Head Neck 1997;19:14–19.
100 Kerawala C, Martin IC: Extending the su-
praomohyoid neck dissection in squamous
cell carcinoma of the floor of mouth. Head
Neck 1998;20:434.
101 Ferlito A, Devaney KO, Rinaldo A, Devaney
SL, Carbone A: Micrometastases: Have they
an impact on prognosis? Ann Otol Rhinol
Laryngol 1999;108:1185–1189.
102 Crile G: Excision of cancer of the head and
neck with special reference to the plan of dis-
section based upon one hundred thirty-two
operations. JAMA 1906;47:1780–1786.
Surgical Treatment of the Neck
103 Martin H, Del Valle B, Ehrlich H, Cahan WB:
Neck dissection. Cancer 1951;4:441–499.
104 Skolnik EM, Yee KF, Friedman M, Golden
TA: The posterior triangle in radical neck sur-
gery. Arch Otolaryngol 1976;102:1–4.
105 Bhattacharyya N: The effects of more conser-
vative neck dissections and radiotherapy on
nodal yields from the neck. Arch Otolaryngol
Head Neck Surg 1998;124:412–416.
106 Davidson BJ, Kulkarny V, Delacure MD,
Shah JP: Posterior triangle metastases of
squamous cell carcinoma of the upper aerodi-
gestive tract. Am J Surg 1993;166:395–398.
107 Gallo O, Boddi V, Bottai GV, Parrella F, Fini
Storchi O: Treatment of the clinically nega-
tive neck in laryngeal cancer patients. Head
Neck 1996;18:566–572.
108 Ferlito A, Rinaldo A: Selective lateral neck
dissection for laryngeal cancer with limited
metastatic disease: Is it indicated? J Laryngol
Otol 1998;112:1031–1033.
109 International Union Against Cancer: Sobin
LH, Wittekind C (eds): TNM Classification
of Malignant Tumours, ed 5. New York, Wi-
ley-Liss, 1997.
ORL 2000;62:217–225
110 Traynor SJ, Cohen JI, Gary J, Andersen PE,
Everts EC: Selective neck dissection and the
management of the node-positive neck. Am J
Surg 1996;172:654–657.
111 Robbins KT, Medina JE, Wolfe GT, Levine
PA, Sessions RB, Pruet CW: Standardizing
neck dissection terminology. Official report
of the Academy’s Committee for head and
neck surgery and oncology. Arch Otolaryngol
Head Neck Surg 1991;117:601–605.
112 Suárez C, Rodrigo JP, Herranz J, Llorente JL,
Martı́nez JA: Supraglottic laryngectomy with
or without postoperative radiotherapy in su-
praglottic carcinomas. Ann Otol Rhinol Lar-
yngol 1995;104:358–363.
113 de Carvalho MB: Quantitative analysis of the
extent of extracapsular invasion and its prog-
nostic significance: A prospective study of
170 cases of carcinoma of the larynx and
hypopharynx. Head Neck 1998;20:16–21.
114 Robbins KT, Wong FSH, Kumar P, Hartsell
WF, Vieira F, Mullins B, Niell HB: Efficacy
of targeted chemoradiation and planned se-
lective neck dissection to control bulky nodal
disease in advanced head and neck cancer.
Arch Otolaryngol Head Neck Surg 1999;125:
670–675.
225
 ORL 2000;62:226–233

Nonsurgical Treatment of Advanced

Metastatic Cervical Disease in Cancer of
the Larynx
Guy J. Petruzzelli a Bahman Emami b
a Departments of Otolaryngology-Head and Neck Surgery and General Surgery, and Head and Neck Oncology

Program, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Ill., and
b Department of Radiation Oncology, Cardinal Bernardin Cancer Center, Loyola University Medical Center,

Maywood, Ill., USA

Key Words The development of advanced metastatic cervical ade-

Chemotherapy W Radiotherapy W Advanced cervical
metastases
Abstract
Historically, patients with advanced cervical adenopathy
(N2 or N3) have between a 20 and 30% chance of surviv-
ing their disease at 5 years from treatment. Despite
attempts at more aggressive surgical resection, includ-
ing resection and reconstruction of the carotid artery,
patients with advanced cervical adenopathy remain at
the highest risk for the development of local recurrences
and distant metastases. This chapter will review the cur-
rent limitations of surgical resectability for advanced
neck disease, discuss the evolution of combined chemo-
radiation therapy for these patients, and finally present
promising recent technological advances in radiation on-
cology which will have significant impact on the treat-
ment of these patients.
Copyright © 2000 S. Karger AG, Basel
nopathy (N2 or N3) remains a prognostic indictor connot-
ing the poorest outcome in patients with squamous cell
carcinomas of the head and neck. Historically, patients in
this category have between a 20 and 30% chance of sur-
viving their disease at 5 years from treatment [1]. Despite
attempts at more aggressive surgical resection, including
resection and reconstruction of the carotid artery, patients
with advanced cervical adenopathy remain at the highest
risk for the development of local recurrences and distant
metastases. This chapter will review the current limita-
tions of surgical resectability for advanced neck disease,
discuss the evolution of combined chemoradiation thera-
py for these patients, and finally present promising recent
technological advances in radiation oncology which will
have significant impact on the treatment of these pa-
tients.

© 2000 S. Karger AG, Basel Guy J. Petruzzelli, MD, PhD, FACS

ABC 0301–1569/00/0624–0226$17.50/0 Head and Neck Oncology Program, Cardinal Bernardin Cancer Center
Fax + 41 61 306 12 34 2160 S. First Ave, Bldg 112, Rm 270
E-Mail karger@karger.ch Accessible online at: Maywood, IL 60153 (USA)
www.karger.com www.karger.com/journals/orl Tel. +1 708 327 3315, Fax +1 708 327 3248, E-Mail gpetruz@wpo.it.luc.edu
 Limitations of Surgical Resectability
The surgical treatment of advanced neck disease in
patients with head and neck squamous cell carcinoma has
not changed dramatically since 1906 when Crile [2] pub-
lished his first series of patients treated with radical neck
dissection. Increased sophistication in the nonsurgical
and intraoperative care of these patients has led however
to significant reductions in operative mortality from the
originally reported 8% to less than 1% [1].
It remains an accepted principle that for neck dissec-
tion to be effective in controlling cervical metastases, eve-
ry attempt must be made to remove disease from the all-
node-bearing tissue [3]. Extracapsular extension into the
sternocleidomastoid muscle, jugular vein, or cranial nerve
XI mandates resection of these structures as well and con-
stitutes the traditional radical or comprehensive neck dis-
section. Involvement and resection of cranial nerves VII,
X, XII, the carotid artery, or extension of disease into the
mediastinum constitutes an extended radical neck dissec-
tion [4]. The utility of extended radical neck dissection in
controlling head and neck cancer remains extremely con-
troversial, and to date no studies have demonstrated
increases in survival. Contraindications to neck dissec-
tion include, involvement of the cervical spine, paraspinal
muscles, or clavicle, extracapsular extension into the deep
layer of the deep cervical fascia (i.e. ‘fixed node’), and the
presence of metastatic disease.
Computed tomography (CT) has been used extensively
in the staging of patients with head and neck carcinoma
and has a high negative predictive value [5]. However, in
patients presenting with advanced cervical adenopathy
the utility of the CT scan may be reduced. Righi et al. [6]
reported their experience with 29 patients in whom the
preoperative CT scan was interpreted by the neuroradio-
logists as either ‘suspicious’ (12) or ‘nonsuspicious’ (17)
for invasion of the prevertebral muscles by tumor. Their
results indicated the overall accuracy for CT scan in this
setting is poor with sensitivity and specificity at 50 and
61% respectively. The authors advocate neck exploration
in patients with potentially resectable tumors to deter-
mine fixation to prevertebral fascia (hence not surgically
resectability).
Resection of the carotid artery in patients with ad-
vanced cervical metastases remains controversial. Recon-
struction of the carotid artery may be considered in select-
ed patients with advanced head and neck cancer. At-
tempts at evaluating the safety of carotid resection in-
clude both anatomic and functional assessments of collat-
eral circulation by combinations of carotid arteriography,
Advanced Metastatic Disease
temporary balloon occlusion, measurement of carotid
stump pressures, xenon blood flow CT imaging, single-
photon emission tomography, somatosensory-evoked po-
tential testing, and serial neurological examinations. Al-
though potentially useful in risk stratification, no study
can clearly predict outcome for a given patient [7].
Many authors have reported case series detailing the
technical considerations and neurological sequelae in
patients with elective carotid resection with and without
reconstruction [8]. Meta-analysis estimates the rate of
major neurologic complications at approximately 17%.
Although significantly reducing local recurrence, carotid
resection has not been associated with an increase in
disease-free survival in patients with advanced head
and neck carcinoma [9]. Resection and reconstruction
of the carotid artery remain valuable additions to the
surgical armamentarium in treating patients with ad-
vanced head and neck cancer; improved local/regional
control and successful palliation are reasonable thera-
peutic goals.
Evolution of Combined Modality Treatment
Induction Chemotherapy
Beginning in the 1970s it became clear that patients
with locally advanced head and neck squamous cell carci-
noma treated with combined surgery and radiation thera-
py experienced improved local and region control of their
disease when compared to those treated with either single
modality [10, 11]. In 1973 the Radiation Therapy Oncolo-
gy Group (RTOG) initiated a clinical trial to determine
the optimal sequencing of radiation therapy and surgery
for the treatment of advanced head and neck squamous
cell carcinoma. The report of RTOG 73-03 in 1987 illus-
trated the clear superiority of postoperative radiation
over preoperative radiation therapy in patients with head
and neck squamous cell carcinoma. In that trial, 277
patients were stratified based on primary site and T and N
status. Patients were randomly assigned to receive 50 Gy
of preoperative radiotherapy (RT) followed by surgical
resection or surgical resection followed by 60 Gy. An
additional treatment arm of definitive RT to between 65
and 70 Gy was included for patients with oral cavity and
oropharyngeal tumors. Locoregional control in the sur-
gery-RT group was superior to that in the RT-surgery
group (65 vs. to 48% respectively). However, deaths due
to distant metastases were identical in all treatment
groups [12].
ORL 2000;62:226–233 227
 The development of distant metastases in the absence
of locoregional failure and the overall poor prognosis for
advanced disease heightened interest in developing new
treatment strategies involving systemic chemotherapy.
Through the 1970s, multiple drugs used as either single
agent or in combinations were used to treat head and neck
cancer in a variety of clinical situations. Clinical response
rates of 50–70% with 20–30% complete and up to 15%
pathological responses were reported [13]. In 1982, Kish
et al. [14] reported that using a combination of cisplatin
and 5-fluorouracil yielded response rates between 80 and
90% with 40% clinical and 30% pathological responses.
Other investigators have attempted to enhance the re-
sponse to chemotherapy by dose escalation, addition of
bleomycin or methotrexate, leucovorin rescue, and bio-
modulation of 5-fluorouracil with interferon-·-2B [15–
17]. These studies have been replicated by many investi-
gators and the combination of cisplatin and 5-fluorouracil
is now the most widely used chemotherapeutic regimen in
chemotherapy of naive head and neck squamous cell car-
cinoma [18].
Close examination of the literature reveals that the
majority of studies reporting a favorable response of head
and neck squamous cell carcinoma to chemotherapy can
be criticized due to small sample size, retrospective na-
ture, single institution, or excessively heterogeneous pa-
tient populations. There is however conclusive data re-
garding the lack of survival advantage provided by induc-
tion chemotherapy.
In 1978, under the direction of the National Institutes
of Health, a randomized, prospective multi-institutional
study was undertaken to determine the role of neoadju-
vant (induction) chemotherapy in the treatment of stage
III and IV head and neck squamous cell cancer. The Head
and Neck Contracts Program randomly assigned 462
patients to receive one of three treatments: (1) surgery fol-
lowed by radiation therapy (standard therapy); (2) induc-
tion chemotherapy consisting of a single course of bleo-
mycin and cisplatin followed by standard therapy, or
(3) induction chemotherapy and standard therapy fol-
lowed by six cycles of monthly cisplatin (maintenance
chemotherapy). Results from this study did not demon-
strate any differences in improved survival, improved
disease-free survival, or alterations in relapse patterns
between any of the three treatment groups. Interestingly,
what the study did show was the reduction in the frequen-
cy of distant metastases and the increased time to first
distant failure in patients receiving maintenance chemo-
therapy compared to either the control or the induction
groups [19].
228 ORL 2000;62:226–233
Similar results were reported by the Head and Neck
Intergroup Study 0034 in 1992. In this multi-institutional
trial, patients received primary surgery followed by either
standard radiation therapy or interval chemotherapy con-
sisting of three cycles of cisplatin and 5-fluorouracil fol-
lowed by radiation therapy. The dose of radiation in both
groups was dependent on risk stratification defined by the
pathological status of the lymph nodes and the surgical
margins. As in the Head and Neck Contracts Program, no
significant differences in time to local recurrence, survival
or disease-free survival were observed. Overall survival at
4 years was 44 and 48% respectively for the surgery 1 RT
and surgery 1 chemotherapy 1 RT groups. However, like
the Head and Neck Contracts Program, the incidence of
distant metastases was significantly lower in the group
which received systemic chemotherapy prior to the initia-
tion of radiation therapy [20].
In addition to prolonged survival and reductions in the
development of distant metastases, organ preservation
has continued to be a goal in head and neck cancer treat-
ment. Two large and noteworthy trials have examined the
role of induction chemotherapy in organ preservation
strategies of the larynx (Veterans Administration – VA
Larynx Trial) and the hypopharynx (European Organiza-
tion for the Research and Treatment of Cancer –
EROTC). Begun in 1985, the VA Larynx Trial random-
ized 332 patients with stage II or IV cancer of the larynx to
either standard therapy (total laryngectomy and postoper-
ative radiation therapy) or neoadjuvant chemotherapy
consisting of three courses of cisplatin and 5-fluorouracil
followed by definitive radiation therapy (66–70 Gy). An
86% response rate with 31% complete response was
reported following two cycles of chemotherapy. Fifty-nine
(36%) patients in the chemotherapy arm required salvage
total laryngectomy. Overall survival was the same in both
treatment groups. Significant differences were again ob-
served in that patients receiving chemotherapy had an
increased incidence of local failure but fewer distant
metastases. Larynx preservation without compromise of
survival was achieved in 64% of patients in the induction
chemotherapy arm [21]. In the patients treated with pri-
mary surgery, neck dissection and radiation therapy, met-
astatic adenopathy in three or more nodes and positive
nodes in the posterior triangle (zone 5) were independent
predictors of distant failure and ultimate reduced survival
[22].
The EROTC trial consisted of 194 randomized pa-
tients who received either conventional surgery (total
laryngectomy-partial pharyngectomy) with postoperative
radiation therapy or three cycles of cisplatin and 5-fluo-
Petruzzelli/Emami
rouracil followed by definitive radiation therapy to 70 Gy.
As in the VA Larynx Study, an interval endoscopy and
biopsy was performed after the second cycle of chemo-
therapy and nonresponders were then offered convention-
al treatment. Of the 97 patients receiving induction che-
motherapy, a complete response was observed in 54% at
the primary site and 51% (31 of 61 patients) with cervical
metastases. There were no differences in survival between
patients treated in the two arms and larynx preservation
without compromise of survival was observed in 42% of
patients. There were significantly fewer distant failures in
the induction chemotherapy arm than the surgery arm (25
vs. 36%, p = 0.034) [23].
The activity of cisplatin-based regimens in the treat-
ment of advanced head and neck cancer has been demon-
strated by both randomized and nonrandomized trials.
The rate of both locoregional and distant failure can be
reduced by the addition of chemotherapy; however, a sur-
vival advantage has yet to be shown. Potential concerns
regarding the use of neoadjuvant chemotherapy remain:
(1) reduction in the efficacy of local therapies (surgery and
radiation) due to proliferation of chemotherapy-resistant
clones during induction cycles; (2) failure to comply with
consolidation therapy (surgery and/or radiation) in pa-
tients who initially respond to chemotherapy thus result-
ing in tumor repopulation and a ‘missed opportunity for
cure’, and (3) increased cost, duration, morbidity and
mortality associated with treatment [13].
Concurrent Chemoradiotherapy
The ability of certain drugs to enhance the toxicity of
ionizing radiation has been known for many years. Mi-
tomycin, 5-fluorouracil, hydroxyurea, cisplatin, carbo-
platin, and recently paclitaxel have all demonstrated in
vivo radiosensitization [24, 25]. By concurrently admin-
istering a radiosensitizing drug with ionizing radiation,
both enhancement of the locoregional radiotherapeutic
effect and the elimination of micometastatic distant dis-
ease can be expected. The four mechanisms underlying
this synergistic response were articulated by Steel and
Peckham [26] in 1979: (1) spatial cooperation: simulta-
neously treating the tumor at both locoregional and pre-
sumed micometastatic sites; (2) toxicity independence:
toxicities of the two modalities are different (i.e. local
effects of radiation versus myelosuppression of chemo-
therapy), although they may be additive (i.e. increased
severity of mucositis); (3) protection of normal tissues:
potential selective cytoprotective mechanisms of certain
agents, and (4) radiation enhancement or sensitization:
cytotoxic effects of chemotherapy further reduce the
Advanced Metastatic Disease
ability of tumor cells to repair radiation-induced cellular
damage.
In general, chemoradiotherapy has been delivered in
one of several schedules: (1) sequential RT following
induction (neoadjuvant) chemotherapy (see previous
section); (2) standard dose radiation with single-agent
chemotherapy used as a radiosensitizer [27, 28]; (3) rap-
idly alternating cycles of chemotherapy and radiation
and suspending one while delivering the other [29], and
(4) concurrent full-dose chemoradiotherapy with plan-
ned treatment breaks in the radiation (i.e. split-course
radiation therapy) [30–32]. A fifth method has been
described to enhance the local responses which involves
concurrent chemoradiation using high-dose selective in-
tra-arterial chemotherapy with systemic neutralization
[33]. It is beyond the scope of this review to detail the
results of these multiple studies. We shall therefore focus
our attention on the question of the ability of chemora-
diation to control advanced cervical metastases (N2 or
N3). This data is derived from trials in which patients
received primary chemoradiation and underwent either
planned or salvage neck dissection as part of their treat-
ment.
The VA Larynx Study has been previously cited as an
example of one organ preservation strategy utilizing in-
duction chemotherapy followed by definitive RT. In this
study, 46 of the 166 patients receiving chemoradiation
had N2 or N3 disease at the time treatment began.
Patients who were less than complete responders to che-
moradiation underwent a salvage neck dissection. In pa-
tients demonstrating less than a complete response in the
neck, overall death rate was increased and the survival
time was decreased. Neck dissection following chemora-
diation did not affect outcome as indicated by the 20–
30% survival demonstrated following neck dissection in
partial responders [34].
Treatment of the neck in patients receiving concurrent
chemoradiation has been reported by Lavertu and Adel-
stein [35–37] from the Cleveland Clinic. In their study,
100 patients were treated in a phase III randomized trial
and received either definitive radiotherapy (68–72 Gy) or
chemoradiation (cisplatin, 5-fluorouracil concurrently
with identical RT). In 47 early-stage patients (N0/N1)
there were 43 complete responders. Six neck dissections
were performed in these patients, which revealed no via-
ble tumor; there were no recurrences in these 6 patients.
Three of the remaining 41 patients had progression of dis-
ease and 4 of the final 38 patients developed recurrences
at the original primary site. Fifty-three patients had
advanced (N2/N3) cervical disease, 35 of which under-
ORL 2000;62:226–233 229
went neck dissection. Of the 18 complete responders
undergoing neck dissection, 4 had viable tumor in the
specimen, while in the 17 less than complete responders, 8
had viable tumor. As in the VA Larynx Study, a complete
response in the neck was associated with increased dis-
ease-free survival. Although addition of neck dissection
reduces the risk of local recurrence, it does not increase
overall survival. Based on this, the authors recommended
neck dissection for all N2/N3 patients regardless of the
therapeutic response in the neck.
In an attempt to overcome cisplatin resistance and
enhance the locoregional effects of concurrent chemora-
diotherapy, Robbins et al. [38, 39] and Weisman et al. [40,
41] have reported separate institutional experiences with
simultaneous RT and intra-arterial cisplatin. This proto-
col involves selective intra-arterial administration of
high-dose cisplatin (150 mg/m2) with concurrent RT (1.8–
2 Gy standard external beam !35 fractions) and sys-
temic neutralization of cisplatin by intravenous infusion
of sodium thiosulfate.
In a recent report of this protocol in patients with N2
or N3 disease, Robbins et al. [39] demonstrated a com-
plete clinical response in 33 of 56 evaluable patients. Of
the 16 patients with complete response undergoing neck
dissection, none had pathologically demonstrable tumor
and there were no recurrences. Twenty-one of the patients
in this study had less than a complete response and 18
underwent neck dissection. Fourteen patients had viable
tumor in the neck dissection specimens and there was 1
local recurrence following neck dissection. Two of the 3
partial responders who did not have neck dissection died
of locally uncontrolled disease.
In a similar study, Weisman et al. [41] treated 22
patients presenting with N2/N3 disease with high-dose
intra-arterial cisplatin and concurrent RT. Six of 20 eva-
luable patients underwent neck dissection after having a
fine needle aspiration biopsy (FNAB) of a persistent neck
mass. Neck dissections for 2 patients demonstrated viable
cancer, 1 of which was positive and 1 was ‘suggestive’ of
persistent carcinoma on FNAB. Local control at 2 years
was reported in 20 of 22 patients. These authors also
advocate planned neck dissection following chemoradio-
therapy in patients with advanced nodal disease based on
posttreatment FNAB at 8 weeks.
230 ORL 2000;62:226–233
Advances in Radiation Oncology
In addition to advances in timing, dose escalation and
biological modulation of chemotherapeutic agents, sever-
al dramatic advances have been made in the field of radia-
tion oncology. The development of remote afterloading
brachytherapy, high linear energy transfer (particle-beam)
techniques, chemosensitizing drugs, intraoperative RT,
altered fractionation, radioprotection agents, and radia-
tion-targeted gene therapy are all being tested in the clini-
cal arena [42]. However, the most important of these
advances in head and neck radiation oncology is the
development of three-dimensional (3D) conformal radia-
tion therapy.
The effectiveness of radiation therapy in controlling a
given tumor volume is determined by the dose delivered
to that volume. The dose delivered is limited by the toler-
ance of adjacent normal uninvolved tissues. Specifically
of concern in the head and neck are the optic apparatus,
carotid artery, brain and spinal cord, and salivary glands.
Increasing the dose (total dose and dose per fraction) and
the size of the target field increases the probability of col-
lateral damage to normal structures. 3D conformal radia-
tion therapy (3D-CRT) was developed to more efficiently
target the 3D volume at greatest risk which minimizes the
damage to adjacent uninvolved tissue; by more precisely
targeting the treatment volume, dose escalation and in-
creased locoregional control can be achieved without
placing adjacent normal structures at significantly higher
risk [43].
Substantial computational power and imaging support
are required for the two components of 3D-CRT, 3D
treatment planning and 3D dose delivery. The high doses
delivered to exact 3D volumes require extreme accuracy
in constructing target volumes and precision in dose
delivery [44].
Unlike traditional two-dimensional treatment plans
drawn from plain films, 3D treatment planning is per-
formed on CT databases. Close attention to detail is paid
to delineating tumor volumes and normal structures
based on imaging, physical examination and evaluation of
surgical pathology specimens. Although 3D-CRT is CT-
based, the fusion of magnetic resonance image (MRI) data
into the treatment planning systems significantly in-
creases the accuracy of the target volume and prevents
maginal or gross misses in certain head and neck tumors
(e.g. nasopharynx). The end result of the treatment plan is
a 3D reconstruction of target volumes and adjacent nor-
mal anatomy which can be viewed as the entire plan or
from the perspective on an individual beam. The mathe-
Petruzzelli/Emami
matical relationships between the doses delivered to the carcinoma) were treated with IMRT-based simultaneous
tumor and specified adjacent tissues can be interpolated modulated accelerated radiation therapy (SMART). Pa-
into a dose volume histogram [43, 44]. At our institution tients were treated over 5 weeks to a total dose of 60 Gy to
every effort is made to coordinate the delineation of target the primary and 50 Gy to the secondary targets. Overall
volumes with both the surgical and radiation oncologists. toxicity was acceptable with the majority of patients
The delivery of ionizing radiation to complex 3D tar- (80%) completing treatment in 40 days without treatment
gets while sparing normal uninvolved tissues requires the break. Nine patients reported symptomatic xerostomia
use of multiple coplanar and non-coplanar beams. Inte- during treatment and no patient had higher than grade 2
gral to the precise delivery of these beams is the multileaf salivary toxicity. Nineteen of 20 patients had a complete
collimator (MLC) [45]. This device is placed at the beam response at the completion of radiation therapy. Review
exit of the linear accelerator and can create multiple irreg- of the dosimetry reveals significant sparing of the mandi-
ular shaped fields under computer control within seconds, ble, contralateral parotid glands, and spinal cord. Total
thus providing the capability for multiple treatment fields allowable Medicare charges for treatment were less than
in a single therapy session. Use of the MLC has elimi- those for either conventional or accelerated fractionation
nated the need for traditional cumbersome, heavy and RT.
less optimal cerrobend blocks for beam shaping. Other In summary, the nonsurgical treatment of advanced
3D-CRT delivery accessories, such as enhanced dynamic (N2/N3) metastatic disease continues to evolve. Com-
wedges, asymmetric jaws, etc., have significantly im- bined chemoradiation therapy appears to offer higher
proved the capability of highly precise dose delivery [46]. response rates than single modality radiation in advanced
The more advanced version of 3D-CRT is intensity- metastatic disease. Patients in whom chemoradiation is
modulated radiation therapy (IMRT). The principal dif- not effective in eradicating cervical metastases will still
ference between 3D-CRT and IMRT is that in the former, need to be offered neck dissection as salvage; as less than
the dose is determined by the radiation oncologist and a complete responders will need some surgical treatment of
plan is created by a team of dosimetrists/radiation onco- the primary site. While nonsurgical treatments do not
logists (trial and error as well as experience) to achieve the appear to influence survival positively or negatively, no
conformity of the prescribed dose to the target volume in data has clearly demonstrated their contribution a superi-
three dimensions. Whereas in IMRT the dose is specified or quality of life in comparison to surgical treatments.
by the radiation oncologist (both to target volumes as well
as normal tissues) and the specialized computer, through
millions of iterations will create the best plan to achieve
the goal of conformity. In 3D-CRT, the intensity of the
individual beams are usually not modulated and are of
similar intensity whereas in IMRT the individual beam
intensities are modulated (both in planning and delivery)
by the computer to achieve the desired goal. Utilization of
IMRT eliminated the use of traditional accessories, such
as wedges and tissue compensators [44, 46].
In a recent report by Eisbruch et al. [47] on utilization
of 3D-CRT in treatment of 15 patients with unresectable
head and neck cancer, the authors have significantly
reduced the dose to the salivary glands without compro-
mising the coverage of tumor target volumes, thus elimi-
nating one of the most debilitating long-term complica-
tions of head and neck RT, namely xerostomia. Similarly,
the significant potential of 3D-CRT in sparing unin-
volved normal structures, such as the mandible, spinal
cord, etc., has been shown by other authors [48].
An initial experience with IMRT has recently been
reported by Butler et al. [49]. Twenty patients with head
and neck carcinoma (including 3 cases of nasopharyngeal

Advanced Metastatic Disease ORL 2000;62:226–233 231

 References
1 Suen JY, Stern SJ: Cancer of the neck; in Myers
EN, Suen JY (eds): Cancer of the Head and
Neck, ed 3. Philadelphia, Saunders, 1996, pp
462–484.
2 Crile G: Excision of cancer of the head and
neck. JAMA 1906;47:1780–1788.
3 Myers EN, Fagan JJ: Treatment of the N+ neck
in squamous cell carcinoma of the upper aero-
digestive tract. Otolaryngol Clin North Am
1998;31:671–686.
4 Robbins KT, Medina JE, Wolfe GT, Levine
PA, Sessions RB, Pruet CW: Standardizing
neck dissection terminology. Official report of
the Academy’s Committee for Head and Neck
Surgery and Oncology. Arch Otolaryngol Head
Neck Surg 1991;117:601–605.
5 Madison MT, Remley KB, Latchaw RE, Mit-
chell SL: Radiologic diagnosis and staging of
head and neck squamous cell carcinoma. Oto-
laryngol Clin North Am 1998;31:727–754.
6 Righi PD, Kelley DJ, Ernst R, Deutsch MD,
Gaskill-Shipley M, Wilson KM, Gluckman JL:
Evaluation of prevertebral muscle invasion by
squamous cell carcinoma. Can computed to-
mography replace open neck exploration? Arch
Otolaryngol Head Neck Surg 1996;122:660–
663.
7 De Vries EJ, Sekhar LN, Horton JA, Eibling
DE, Janecka IP, Schramm VL Jr, Yonas H: A
new method to predict safe resection of the
internal carotid artery. Laryngoscope 1990;
100:85–88.
8 Katsuno S, Ishiyama T, Sakaguchi M, Take-
mae H: Carotid resection and reconstruction
for advanced cervical cancer. Laryngoscope
1997;107:661–664.
9 Snyderman CH, D’Amico F: Outcome of carot-
id artery resection for neoplastic disease: A
meta-analysis. Am J Otolaryngol 1992;13:373–
380.
10 Vikram B, Strong EW, Shah JP, Spiro R: Fail-
ure in the neck following multimodality treat-
ment for advanced head and neck cancer. Head
Neck Surg 1984;6:724–729.
11 Vikram B, Strong EW, Shah JP, Spiro R: Fail-
ure at distant sites following multimodality
treatment for advanced head and neck cancer.
Head Neck Surg 1984;6:730–733.
12 Kramer S, Gelber RD, Snow JB, Marcial VA,
Lowry LD, Davis LW, Chandler R: Combined
radiation therapy and surgery in the manage-
ment of advanced head and neck cancer: Final
report of Study 73-03 of the Radiation Therapy
Oncology Group. Head Neck Surg 1987;10:19–
30.
13 Stupp R, Weichselbaum RR, Vokes EE: Con-
bined modality therapy of head and neck can-
cer. Semin Oncol 1994;21:349–358.
14 Kish J, Krelichman A, Jacobs J, Hoschner J,
Kinzie J, Loh J, Weaver A, Al Sarraf M: Clini-
cal trial of cisplatin and 5-FU infusion as initial
treatment for advanced squamous cell carcino-
ma of the head and neck. Cancer Treat Rep
1982;66:471–474.
232 ORL 2000;62:226–233
15 Browman GP, Cronin L: Standard chemother-
apy in squamous cell head and neck cancer:
what we have learned from randomized trials.
Semin Oncol 1994;21:311–319.
16 Vokes EE, Schilsky RL, Weichselbaum RR,
Guaspari A, Guarnieri CM, Whaling SM,
Panje WR: Cisplatin, 5-fluorouracil, and high-
dose oral leucovorin for advanced head and
neck cancer. Cancer 1989;63(suppl):1048–
1053.
17 Vokes EE, Ratain MJ, Mick R, McEvilly JM,
Haraf D, Kozloff M, Hamasaki V, Weichsel-
baum RR, Panje WR, Wenig B, et al: Cisplatin,
fluorouracil, and leucovorin augmented by in-
terferon ·-2b in head and neck cancer: A clini-
cal and pharmacologic analysis. J Clin Oncol
1993;11:360–368.
18 Harari PM: Why has induction chemotherapy
for advanced head and neck cancer become a
United States community standard of practice?
J Clin Oncol 1997;15:2050–2055.
19 Endicott JN, Jensen R, Lyman G, et al: Adju-
vant chemotherapy for advanced head and
neck squamous carcinoma. Cancer 1987;60:
301–311.
20 Laramore GE, Scott CB, Al Sarraf M, Haselow
RE, Ervin TJ, Wheeler R, Jacobs JR, Schuller
DE, Gahbauer RA, Schwade JG, et al: Adju-
vant chemotherapy for resectable squamous
cell carcinomas of the head and neck: Report
on Intergroup Study 0034. Int J Radiat Oncol
Biol Phys 1992;23:705–713.
21 The Department of Veterans Affairs Laryngeal
Cancer Study Group: Induction chemotherapy
plus radiation compared with surgery plus ra-
diation in patients with advanced laryngeal
cancer. N Engl J Med 1991;324:1685–1690.
22 Moe K, Wolf GT, Fisher SG, Hong WK: Re-
gional metastases in patients with advanced
laryngeal cancer. Arch Otolaryngol Head Neck
Surg 1996;122:644–648.
23 Lefebvre JL, Chevalier D, Luboinski B, Kirk-
patrick A, Collette L, Sahmoud T: Larynx pres-
ervation in pyriform sinus cancer: Preliminary
results of a European organization for research
and treatment of cancer phase III trail. J Natl
Cancer Inst 1996;13:890–899.
24 Vokes EE, Weichselbaum RR: Concomitant
chemoradiotherapy: Rationale and clinical ex-
perience in patients with solid tumors. J Clin
Oncol 1990;8:911–934.
25 Vokes EE: Interactions of chemotherapy and
radiation. Semin Oncol 1993;20:70–79.
26 Steel GG, Peckham MJ: Exploitable mecha-
nisms in combined radiotherapy-chemothera-
py: The concept of additivity. Int J Radiat
Oncol Biol Phys 1979;5:85–91.
27 Gasparini G, Recher G, Testolin A, Dal Fior S,
Panizzoni GA, Cristoferi V, Squaquara R, Poz-
za F: Synchronous radiotherapy and chemo-
therapy with cisplatin in the management of
locally advanced or recurrent head and neck
cancer. Am J Clin Oncol 1992;15:242–249.
28 Gasparini G, Pozza F, Recher G, Panizzoni
GA, Cristoferi V, Squaquara R, Dal Fior S:
Simultaneous cis-platinum and radiotherapy in
inoperable or locally advanced squamous cell
carcinoma of the head and neck. Oncology
1991;48:270–276.
29 Merlano M, Vitale V, Rosso R, Benasso M,
Corvò R, Cavallari M, Sanguineti G, Bacigalu-
po A, Badellino F, Margarino G, et al: Treat-
ment of advanced squamous-cell carcinoma of
the head and neck with alternating chemother-
apy and radiotherapy. N Engl J Med 1992;327:
1115–1121.
30 Vokes EE, Panje WR, Weichselbaum RR,
Schilsky RL, Moran WJ, Awan AM, Guarnieri
CM: Concomitant hydroxyurea, 5-fluorouracil,
and radiation therapy for recurrent head and
neck cancer: Early results. Otolaryngol Head
Neck Surg 1988;4:295–298.
31 Keane TJ, Cummings BJ, O’Sullivan B, Panye
D, Rawlinson E, MacKenzie R, Danjoux C,
Hodson I: A randomized trial of radiation ther-
apy compared to split-course radiation therapy
combined with mitomycin C and 5-fluoroura-
cil as initial treatment for advanced laryngeal
and hypopharyngeal squamous carcinoma. Int
J Radiat Oncol Biol Phys 1993;25:613–618.
32 Weissler MC, Melin S, Sailer SL, Qaqish BF,
Rosenman JG, Pillsbury HC III: Simultaneous
chemoradiation in the treatment of advanced
head and neck cancer. Arch Otolaryngol Head
Neck Surg 1992;118:806–810.
33 Robbins KT, Storniolo AM, Hryniuk WM,
Howell SB: ‘Decadose’ effects of cisplatin on
squamous cell carcinoma of the upper aerodi-
gestive tract. II. Clinical studies. Laryngoscope
1996;106:37–42.
34 Wolf GT, Fisher SG: Effectiveness of salvage
neck dissection for advanced regional metas-
tases when induction chemotherapy and radia-
tion are used for organ preservation. Laryngo-
scope 1992;102:934–939.
35 Adelstein DJ, Saxton JP, Lavertu P, Tuason L,
Wood BG, Wanamaker JR, Eliachar I, Strome
M, Van Kirk MA: A phase III randomized trial
comparing concurrent chemotherapy and ra-
diotherapy with radiotherapy alone in resecta-
ble stage III and IV squamous cell head and
neck cancer: Preliminary results. Head Neck
1997;19:567–575.
36 Lavertu P, Adelstein DJ, Saxton JP, Secic M,
Wanamaker JR, Eliachar I, Wood BG, Strome
M: Management of the neck in a randomized
trial comparing concurrent chemotherapy and
radiotherapy with radiotherapy alone in resect-
able stage III and IV squamous cell head and
neck cancer. Head Neck 1997;19:559–566.
37 Lavertu P, Adelstein DJ, Saxton JP, Secic M,
Eliachar I, Strome M, Larto MA, Wood BG:
Aggressive concurrent chemoradiotherapy for
squamous cell head and neck cancer: an 8-year
single-institution experience. Arch Otolaryngol
Head Neck Surg 1999;125:142–148.
Petruzzelli/Emami
38 Robbins KT, Fontanesi J, Wong FS, Vicario D,
Seagren S, Kumar P, Weisman R, Pellitteri P,
Thomas JR, Flick P, Palmer R, Weir A III,
Kerber C, Murry T, Ferguson R, Los G, Orloff
L, Howell SB: A novel organ preservation pro-
tocol for advanced carcinoma of the larynx and
pharynx. Arch Otolaryngol Head Neck Surg
1996;122:853–857.
39 Robbins KT, Wong FS, Kumar P, Hartsell WF,
Vieira F, Mullins B, Niell HB: Efficacy of tar-
geted chemoradiation and planned selective
neck dissection to control bulky nodal disease
in advanced head and neck cancer. Arch Otola-
ryngol Head Neck Surg 1999;125:670–675.
40 Weisman RA, Robbins KT: Management of
the neck in patients with head and neck cancer
treated by concurrent chemotherapy and radia-
tion. Otolaryngol Clin North Am 1998;31:773–
784.
41 Weisman RA, Christen RD, Jones VE, Kerber
CW, Seagren SL, Orloff LA, Glassmeyer SL,
Howell SB, Robbins KT: Observations on con-
trol of N2 and N3 neck disease in squamous
cell carcinoma of the head and neck by intra-
arterial chemoradiation. Laryngoscope 1998;
108:800–805.
Advanced Metastatic Disease
42 Hellman S, Weichselbaum RR: Radiation on-
cology. JAMA 1996;275:1852–1853.
43 Fu KF: Future direction in radiation therapy;
in Harrison LB, Sessions RB, Hong WK (eds):
Head and Neck Cancer: A Multidisciplinary
Approach. Philadelphia, Lippincott-Raven,
1999, pp 999–1014.
44 Teh BS, Woo SY, Butler EB: Intensity-modu-
lated radiation therapy (IMRT): A new promis-
ing technology in radiation oncology. Oncolo-
gist 1999;4:433–442.
45 Brewster L, Mohan R, Mageras G, Burman C,
Leibel S, Fuks Z: Three-dimensional conformal
treatment planning with multileaf collimators.
Int J Radiat Oncol Biol Phys 1995;33:1081–
1089.
ORL 2000;62:226–233
46 Emami B, Graham MV, Michalski JM, Perez
C: Three-dimensional conformal radiation
therapy: Clinical aspects; in Perez CA, Brady
LW (eds): Principles and Practice of Radiation
Oncology, ed 3. Philadelphia, Lippincott-Ra-
ven, 1998, pp 371–386.
47 Eisbruch A, Marsh LH, Martel MK, Ship JA,
Ten Haken R, Pu AT, Fraass BA, Lichter AS:
Comprehensive irradiation of head and neck
cancer using conformal multisegmental fields:
Assessment of target coverage and noninvolved
tissue sparing. Int J Radiat Oncol Biol Phys
1998;41:559–568.
48 Emami B: Oral cavity; in Perez CA, Brady LW
(eds): Principles and Practice of Radiation On-
cology, ed 3. Philadelphia, Lippincott-Raven,
1998, pp 1047–1068.
49 Butler EB, Teh BS, Grant WH III, Uhl BM,
Kuppersmith RB, Chiu JK, Donovan DT, Woo
SY: Smart (simultaneous modulated acceler-
ated radiation therapy) boost: A new acceler-
ated fractionation schedule for the treatment of
head and neck cancer with intensity modulated
radiotherapy. Int J Radiat Oncol Biol Phys
1999;45:21–32.
233
 Author Index Vol. 62, No. 4, 2000
Alexiou, C. 199
Arnold, W. 177, 199
Curtin, H.D. 186
Devaney, K.O. 204
Devaney, S.L. 204
Emami, B. 226
Ferlito, A. 177, 204, 212, 217
Kau, R.J. 199
Subject Index Vol. 62, No. 4, 2000
Advanced cervical metastases 226
Angiogenesis 178
Cancer invasion 178
Cervical node metastases 204
Chemotherapy 226
Classification 212
Computed tomography 186, 199
Head and neck cancer 212
– – – neoplasms 186
Laryngeal cancer 199
Larynx 217
© 2000 S. Karger AG, Basel
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
Mancuso, A.A. 186
Mondin, V. 212
Petruzzelli, G.J. 178, 226
Rinaldo, A. 204, 212, 217
Silver, C.E. 217
Smith, R.V. 217
Som, P.M. 186, 212
Stimmer, H. 199
Lymph node(s) 186, 217
– – metastases 178, 199
Lymphatic metastasis 186
Magnetic resonance imaging 199
Metastasis 217
Neck dissection 212, 217
Pathology 204
Positron emission tomography 199
Radiotherapy 226
Specimen processing 204
Ultrasound 199