Original Article

Mucosal Melanoma of the Nose and

Paranasal Sinuses, a Contemporary
Experience From The M. D. Anderson
Cancer Center
Mauricio A. Moreno, MD1; Dianna B. Roberts, PhD1; Michael E. Kupferman, MD1; Franco DeMonte, MD2;
Adel K. El-Naggar, MD, PhD3; Michelle Williams, MD3; David S. Rosenthal, MD4; and Ehab Y. Hanna, MD1

BACKGROUND: Sinonasal mucosal melanoma is a rare disease associated with a very poor prognosis. Because most
of the series extend retrospectively several decades, we sought to determine prognostic factors and outcomes with
recent treatment modalities. METHODS: A retrospective chart review of 58 patients treated for sinonasal melanoma
at a tertiary cancer center between 1993 and 2004. The patients were retrospectively staged according to the sino-
nasal American Joint Committee on Cancer (AJCC) staging system. Demographic, clinical and pathological parame-
ters were identified and correlated with outcomes. RESULTS: There were 35 males and 23 females with a median age
of 63 years; 56 patients were treated surgically and 33 received radiation therapy. According to Ballantyne’s clinical
staging system, 88% of the patients presented with stage I (local) disease. Classification by the AJCC staging classi-
fied yielded 27% of the patients with T1, 33% with T2, 21% with T3, and 19% with T4. T-stage and the degree of tumor
pigmentation were associated with a worse survival (P ¼ .0096 and P ¼ .018, respectively), while pseudopapillary
architecture was associated with a higher locoregional failure (P ¼ .0144). Postoperative radiation therapy improved
locoregional control when a total dose greater than 54 Gy was used (P ¼ .0215), but did not affect overall survival.
CONCLUSIONS: Tumor stage according to sinonasal AJCC staging system is an effective outcome predictor and
should be the staging system of choice. Postoperative radiation therapy improves locoregional control when a higher
dose and standard fractionations are used. Histological features such as pigmentation and pseudopapillary architec-
ture are associated with worse outcome. Cancer 2010;116:2215–23. V C 2010 American Cancer Society.

KEYWORDS: sinonasal melanoma, mucosal, radiation, treatment, outcomes.

Mucosal melanomas of the sinonasal tract are infrequent and account for less than 1% of all melanomas and up to 4% of
all sinonasal malignancies.1 The rarity of this tumor is because of its origin from melanocytes that have migrated as neuroecto-
dermal derivatives in the ectodermal mucosa.1 Melanomas originating from the respiratory mucosa and those originating from
the squamous mucosa have different clinical and histopathological features, but share a similar prognosis.2 Despite the finding
that a distinct staging system has been proposed for sinonasal melanomas,3 Ballantyne’s clinical staging system4 is still the most
widely used to the date. This system classifies tumors in 3 stages: stage I for localized lesions, stage II for cervical lymph node
metastasis, and stage III for distant metastasis. Unfortunately, because the vast majority of patients present with local disease
only (stage I),2 the prognostic value of this staging system is relatively limited. It is widely accepted that surgery with or without
postoperative radiation is the standard of care for treatment of patients with mucosal melanomas of the sinonasal tract. In recent
literature, the use of postoperative radiation has increased the rate of locoregional control, but has not improved survival.5-7
The 5-year overall survival ranges from 20%-35% among different series1 and has not changed significantly over the
last several decades. Given the rarity of this tumor, most series extend retrospectively several decades to gather an adequate

Corresponding author: Ehab Y. Hanna, MD, Department of Head and Neck Surgery, Unit 1445, The University of Texas M. D. Anderson Cancer Center, 1515
Holcombe Boulevard, Houston, TX 77030; Fax: (713) 794-4662; eyhanna@mdanderson.org
1
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2Department of Neurosurgery, The University of
Texas M. D. Anderson Cancer Center, Houston, Texas; 3Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 4Depart-
ment of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Dr. Mauricio A. Moreno’s current address: Department of Otolaryngology, Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock,
Arkansas.
DOI: 10.1002/cncr.24976, Received: July 15, 2009; Revised: August 18, 2009; Accepted: August 19, 2009, Published online March 2, 2010 in Wiley InterScience
(www.interscience.wiley.com)

Cancer May 1, 2010 2215

Original Article

Table 1. Description of the AJCC Staging System for Sinonasal Tumors

Nasal Cavity and Ethmoid Sinus

T1 Tumor restricted to one subsite, with or without bony invasion.
T2 Tumor invading 2 subsites in a single region or involving an adjacent region within
the nasoethmoidal complex, with or without bony invasion.
T3 Tumor invades the medial wall or floor of the orbit, maxillary sinus, palate, or cribiform plate.
T4a Tumor involves any of the following: anterior orbital contents, skin of nose or cheek, minimal
extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses.
T4b Tumor involves any of the following: orbital apex, dura, brain, middle cranial fossa, cranial
nerves, other than V2, nasopharynx, or clivus.

Maxillary Sinus
T1 Tumor limited to the maxillary sinus mucosa without bony destruction.
T2 Tumor causing bone destruction including erosion into the hard palate and/or middle nasal
meatus, except extension to posterior maxillary wall and pterygoid plates.
T3 Tumor invades any of the following: bone of the posterior wall of the maxillary sinus,
subcutaneous tissues, floor or medial wall of the orbit, pterygoid fossa, ethmoid sinuses.
T4a Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa,
cribiform plate, sphenoid or frontal sinuses.
T4b Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa,
cranial nerves other than V2, nasopharynx, or clivus.

AJCC indicates American Joint Committee on Cancer.

number of patients. Unfortunately, survival analysis
under these circumstances may fail to reflect the advances
in diagnosis and treatment that might have occurred in
recent decades. We limited our retrospective review to 15
years to capture contemporary data that more accurately
reflect the current status of this disease.
MATERIALS AND METHODS
After the institutional review board approved the study, a
query of the database of the head and neck department
identified 58 consecutive patients treated for sinonasal
mucosal melanoma at The University of Texas M.D.
Anderson Cancer Center between January 1993 and
December of 2004. Histological confirmation of the
lesion was required for all the cases. This was achieved by
documenting the presence of melanin or melanoma-asso-
ciated markers by the pathologist.
Clinical information retrieved included demo-
graphic data, presenting symptoms, subsite of origin, stag-
ing, surgical treatment, adjuvant therapy, and outcome.
The available pathology specimens were reviewed by one
experienced head and neck pathologist (MW) to identify
histopathological features that have been related to out-
come in the medical literature.3,8,9 These variables are as
follows: level of pigmentation,0-3 percentage of necrosis,
number of mitosis per 10 high-power fields (HPFs),
inflammation,1-3 presence of bony, perineural or lympho-
vascular invasion, presence of ulceration, cell morphology
and tumor architecture.
All patients were retrospectively staged according to
Ballantyne’s clinical staging system and to the American
Joint Committee on Cancer (AJCC) staging system for
sinonasal tumors,10 which is summarized in Table 1. All
the available clinical information, such as clinical presen-
tation, endoscopic description of the tumor, radiological
data, and intraoperative findings, were used for staging
purposes. This information was also used to determine
the point of origin of the tumor.
For patients who underwent radiation therapy, the
radiation technique, fractionation schedule, and dosime-
try data were retrieved. Acute and late toxicities to the
skin, mucous membranes, eyes, ears, salivary glands,
brain, and temporomandibular joints (TMJ) were docu-
mented and graded according to the Radiation Therapy
Oncology Group/European Organization for Research &
Treatment of Cancer (RTOG/EORTC) scoring system.
Correlations between parameters and endpoints
were assessed by Pearson chi-square test or 2-tailed Fisher
exact test. Curves describing overall survival, disease-spe-
cific survival, and disease-free intervals were calculated
with the Kaplan-Meier method. Differences between the
actuarial curves were tested by the log-rank test and assess-
ment of prognostic factors by the Cox proportional haz-
ard regression model. Data for variables resulting in
correlations for which statistical significance (P<.05)
were noted were also tested for statistical power. The sta-
tistical analysis was performed with the assistance of the
Statistica Version 8.0 statistical software application (Stat-
Soft, Tulsa, Okla; www.statsoft.com).

2216 Cancer May 1, 2010

 Sinonasal Mucosal Melanoma/Moreno et al

Table 2. Subsite of Origin and Site-Specific Overall Survival

Subsite of Origin No. (%) 5-Year OS

Lateral nasal wall 25 (43.1) 16%
Septum 14 (24.2) 50%a
Maxillary sinus 11 (19) 27.3%
Ethmoid sinus 5 (8.6) 20%
Sphenoid sinus 1 (1.7) N/A
Nasopharynx 1 (1.7) N/A
Nasal vestibule 1 (1.7) N/A

OS indicates overall survival.

a
Fisher exact test (septum vs other origin) P ¼ .0433.

Figure 1. The Kaplan-Meier curve for overall survival is shown.

RESULTS
There were 35 males and 23 females in the series and the
median age at presentation was 63.4 years (age range, 38
years to 93 years). The most common symptoms at pre-
sentation were epistaxis (72.4%) and nasal obstruction
(53.5%). The mean follow-up for the series was 34
months with an overall 2-year and 5-year survival of
58.4% and 38.7%, respectively (Fig. 1). The 2-year dis-
ease-free survival was 32.8%, while 5-year disease-free sur-
vival was 18.4%. The presence of melanosis of the nasal
mucosa was observed in 4 patients, but it was not corre-
lated with overall survival (P ¼ .3916).
Table 2 shows the site-specific 5-year overall sur-
vival; melanomas originating from the nasal septum had a
higher overall survival rate than those originating in other
sites (P ¼ .0433). Early stages (T1/T2) accounted for
92.8% in the septal melanoma group versus 46.4% in all
other subsites (P ¼ .0060). No statistically significant dif-
ference was found in margin status between septal and
nonseptal melanoma (P ¼ .7093).

Staging
Staging according to Ballantyne’s clinical staging system
yielded 51 (87.9%) patients with stage I disease, 4 (6.9%)
patients with stage II disease, and 3 (5.2%) patients with
Figure 2. Patient distribution according to Ballantyne’s clini-
stage III disease. All 3 patients who presented with distant cal staging system4 and American Joint Committee on Can-
disease died within 2 years of presentation, while all 4 cer staging system for sinonasal tumors.10
patients who presented with nodal metastasis (N þ) died
within 5 years of presentation.
Staging according to the AJCC sinonasal system patients with T4 (Fig. 2). Two-year overall survival was
yielded 16 (27.6%) patients with T1, 19 (32.8%) patients 68.8% for T1, 66.7% for T2, 33.4% for T3, and 18.2%
with T2, 12 (20.7%) patients with T3, and 11 (19%) for T4 (Fig. 3); these differences were statistically

Cancer May 1, 2010 2217

Original Article
Figure 3. The Kaplan-Meier curve for overall survival accord-
ing to tumor size in American Joint Committee on Cancer
sinonasal classification is presented.
significant (P ¼ .0183). Differences in 5-year survival
between these groups did not reach statistical significance
(P ¼ .2067), except when combining T1/T2 versus T3/
T4 (P ¼ .0096).
Surgery
Fifty-six patients underwent surgery as the primary treat-
ment modality. In these cases, the procedures were as fol-
lows: medial maxillectomy in 22 patients (39.3%),
extended maxillectomy in 13 patients (23.2%), septec-
tomy in 9 patients (16.1%), total maxillectomy in 6
patients (10.7%), and craniofacial resection in 6 patients
(10.7%). In 10 of these cases, an endoscopically assisted
approach was used. Patients who had an endoscopically
assisted procedure had a higher 2-year overall survival
when compared with those who had an open procedure
(64.3% vs 35.7%; P ¼ .0262).
On pathologic review, 12 patients had a microscopi-
cally positive or close margin (within 1 mm of section
cut), based on the review of the operative and pathology
report. Patients with negative margins had a better 2-year
survival (63.9% vs 41.7%) and 5-year survival (43.8% vs
25%), although this difference did not reach statistical sig-
nificance (P ¼ .1534 and P ¼ .2169, respectively). Local
recurrence developed in 41.7% of the patients with posi-
tive margins versus 19.6% of those with negative margins
(P ¼ .2657).
Radiation Therapy
External beam radiation therapy was used in 33 patients
(56.9%). This was used as the definitive therapy in 2
2218
Figure 4. The Kaplan-Meier curve for overall survival accord-
ing to development of late mucositis is shown.
patients who declined surgery and as postoperative adju-
vant therapy in the remaining 31 cases. Total radiation
dose (RT dose) ranged from 30 to 66 Gy, with an average
of 50.9 Gy. The radiation technique was three-dimen-
sional conformal in 25 patients, 3-field radiation in 5
patients, and intensity-modulated radiation therapy in 3
patients. Conventional fractionation was used in 23 cases
(RT dose range: 50 to 66 Gy), while hypofractionation
was used in 10 cases (RT dose range: 30 to 38 Gy). The
neck was treated in 16 patients, including 4 cases of bilat-
eral treatment. Twenty-three patients developed acute
skin toxicity (grade 3 in 1 case; grade 2 in 12 cases; grade 1
in 10 cases), 28 patients developed acute mucosal toxicity
(grade 3 in 5 cases; grade 2 in 15 cases; grade 1 in 8 cases),
5 patients had acute ocular toxicity (grade 2 in 4 cases;
grade 1 in 1 case), 4 cases had acute salivary toxicity (2
cases of grade 2 and grade 1, respectively), and there were
no cases of acute ear, brain, or TMJ toxicity. Mucosal tox-
icity was the most common form of late toxicity and was
observed in 7 patients (grade 2 in 2 cases; grade 1 in 5
cases). The development of late mucositis appeared to be
related to overall survival but did not reach statistical sig-
nificance (P ¼ .1027) as shown in Figure 4.
Radiation therapy did not improve overall survival
(P ¼ .2018) independently of the total dose, technique,
or fractionation schedule used. However, disease-free sur-
vival analysis demonstrated that patients who were treated
with a total dose of 54 Gy or more had a lower rate of
locoregional recurrence when compared with those who
had 30-50 Gy of total dose (P ¼ .02,144), as is shown in
Figure 5. The use of standard a fractionation schedule was
also associated with a lower locoregional failure rate than
Cancer May 1, 2010
 Sinonasal Mucosal Melanoma/Moreno et al

Figure 5. The Kaplan-Meier curve for locoregional disease- Figure 6. The Kaplan-Meier curve for overall survival stratified
free survival stratified by radiation dose in presented. by level of melanotic pigmentation is shown.

pigment was a highly significant outcome predictor (0%

Table 3. Summary of Histopathological Features
vs 47.6% 5-year survival; P ¼ .0183). Even more, the level
Histopathological Feature No. % Pa of pigmentation of the lesion was correlated with a worse
Architecture clinical outcome, as shown in Figure 6. The presence of
Polypoid 11 31.4 .2554 10 or more mitosis per HPF appeared to be an outcome
Discohesive 22 62.9 .483
predictor that reached borderline statistical significance (P
Pseudopapillary 13 37.1 .4324
¼ .0619). All except 1 of the 20 patients who had >10
Cell morphology
Pagetoid 10 28.6 .6539
mitoses per HPF died of disease or presented with locore-
Epithelioid 9 25.7 .6568 gional recurrence. In contrast, all the patients who had a
Spindled 8 22.9 .1606 complete response to biochemotherapy were among those
Rhabdoid 8 22.9 .1606
with 10 mitoses per HPF or less. As is shown on Figure 7,
Undifferentiated (small cell) 16 45.7 .1498
Pleomorphic 3 8.6 .2069 the presence of a pseudopapillary architecture was associ-
Ulceration 21 60.0 .2554 ated with a higher rate of locoregional failure (P ¼ .0144)
Bony invasion 7 20.0 .6568
but did not affect survival (P ¼ .4909).
PNI/lymphovascular inv. 2 5.7 .4827
Inflammation (1-3) 8 22.9 .1388
Necrosis (any %) 14 40.0 .7041 Recurrence
Pigmentation 10 28.6 .0192
A total of 18 patients presented with locoregional recur-
Mitosis per 10HPF (>10) 20 58.9 .0619
rence; this was local in 14 cases, cervical in 2 cases, and
PNI indicates perineural invasion.
a
synchronic local and cervical in 2 cases. The time for re-
Fisher test comparing 5-year overall survival.
currence presentation ranged from 0.9 to 67 months,
with an average of 19.8 months. Twenty-two patients
hypofractionation (54.6% vs 100% locoregional failure;
developed a distant metastasis with an average time for
P ¼ .0102).
presentation of 12.3 months (range 2.1 to 60 months).
Systemic Therapy The first identified location for the metastatic disease was
Fourteen patients (24.1%) had chemotherapy and 21 the lung in 10 patients, the brain in 6 patients, the liver in
patients (36.2%) had immunotherapy as part of the initial 5 patients, the bone in 2 patients, the bowel and pancreas
treatment; neither of these affected 5-year overall survival in 1 patient, respectively. In 3 of these cases, more than
(P ¼ .5275 and P ¼ .5438, respectively). 1 site was involved at the time of the diagnosis.
The development of locoregional recurrence was
Histological features not a significant predictor of survival (26.7% vs 47.1% 5-
The histopathological findings of the 34 available speci- year survival; P ¼ .1367), while distant failure was a statis-
mens are summarized in Table 3. The presence of melanin tically significant outcome predictor (50% vs 14.3% 5-

Cancer May 1, 2010 2219

Original Article
Figure 7. The Kaplan-Meier curve for locoregional disease-
free survival stratified by presence of pseudopapillary archi-
tecture is presented.
year survival; P ¼ .0139). This difference is shown in
Figure 8.
DISCUSSION
Sinonasal mucosal melanoma is an uncommon disease
that has been consistently associated with poor outcome.1
Given the rarity of this disease, most of the published
series are retrospective studies that extend back several
decades to gather an adequate number of patients.1-3,6,8,11
In contrast, the present study is a contemporary series that
attempts to provide a better representation of clinical sce-
narios that head and neck oncologists may face when
treating these patients. Limiting the study period to the
last 15 years allows us to evaluate and compare the poten-
tial impact of current diagnostic and treatment modalities
that were not available 2 or more decades ago.
There are clinical and histopathological differences
between melanomas originating from the sinonasal respi-
ratory mucosa and those that originate from the oral squa-
mous mucosa. Sinonasal melanomas have been described
to have a lower rate of N(þ) disease at presentation,12 are
thicker, and more commonly present ulceration, necrosis,
perineural invasion, polypoid morphology, and a pseudo-
papillary growth pattern.2,13 Despite these well-docu-
mented differences, the prognosis is comparable to
melanomas originating from squamous oral cavity
mucosa.2,13
Location
The lateral nasal wall and nasal septum are the most com-
mon points of origin of mucosal melanomas of the sino-
2220
Figure 8. The Kaplan-Meier curve for overall survival stratified
by development of distal metastasis is shown.
nasal tract,3; in this series, melanomas arising from the
lateral nasal wall accounted for almost half of the total
number of patients. We found that melanomas arising
from the septum had a more favorable prognosis than
those arising from other subsites (Table 2); similar find-
ings have been reported by other authors.8,14-16 Our data
suggest that the advantage in survival is probably related
the lower T classification of septal melanomas versus other
subsites of origin. In the literature, this is usually attrib-
uted to earlier symptomatology for tumors arising from
the nasal cavity versus those arising from paranasal
sinuses.
Melanosis of the sinonasal mucosa has been consid-
ered as the equivalent of radial phase growth of cutaneous
melanomas by some authors17 and has been associated
with a better disease-specific distant metastasis free sur-
vival.12 We found melanosis in 6.8% of the patients,
which is consistent with 7% that has been described in a
large series.3 In the present study, we found no relation-
ship between melanosis and with disease-free or overall
survival.
Staging
On the basis of the review of 115 cases, Thompson et al3
proposed a specific staging system for melanomas of the
sinonasal tract and nasopharynx. This system has the
advantages of being site and histology-specific, but despite
these characteristics, it has not been widely used in the
medical literature. Variations of the AJCC TNM staging
system and other classification systems have been pro-
posed by other authors.14,18 In 1970, Ballantyne intro-
duced a clinical staging system for cutaneous and mucosal
Cancer May 1, 2010

melanomas of the head and neck.4 This is a simple system
that comprises 3 stages: stage I for local disease, stage II
for regional disease, and stage III for distant disease. The
prognostic value of this system has been validated in the
literature: clinical stage at presentation has been a predic-
tor of overall survival12,19 and disease free survival.19,20 In
the present series, clinical stage at presentation did affect
overall survival but it could not be validated as an inde-
pendent prognostic factor, mostly because the low per-
centage of patients who presented with stage II or III
(12% combined).
According to Ballantyne’s clinical staging system,
76%-95% of patients with mucosal melanomas of the
sinonasal tract present with stage I disease,12,14,21,22
and in the present series, this reached up to 88%.
Unfortunately, establishing a prognosis based on a
specific system is difficult when the majority of
patients fall in a single category. To address this prob-
lem, Prasad et el9 has proposed a microstaging system
based on histopathological features such as depth of
invasion and tumor architecture.
In the present series, we sought to evaluate the prog-
nostic value of the current AJCC sinonasal staging sys-
tem10 in patients with sinonasal melanoma. This staging
system has the advantage of being well known by onco-
logic surgeons and other specialists routinely involved in
the care of head and neck cancer patients. Because sino-
nasal melanomas are frequently polypoid, a detailed
description of the site of origin by endoscopic assessment
and careful examination of the intraoperative findings are
of paramount importance. We found that this staging sys-
tem provides an even distribution of the tumor stages
(Fig. 2) and accurately reflects stage-specific prognostic
information (Fig. 3). Other authors have also described
the prognostic value of this staging system in smaller se-
ries.7,16 On the basis of these findings, we believe that the
current AJCC sinonasal staging system should be the pri-
mary staging system for patients with mucosal melanomas
of the sinonasal tract.
Surgery
Complete tumor excision is widely accepted as the standard
of care for treatment of patients with mucosal melanomas
of the sinonasal tract. The anatomical complexity of the
sinonasal passages and proximity to vital structures makes a
complete resection difficult in most cases. Even more, radi-
cal procedures do not appear to be justified when there is
evidence suggesting that >50% of the patients who achieve
local control with surgery will ultimately develop distant
Cancer May 1, 2010
Sinonasal Mucosal Melanoma/Moreno et al
metastasis.1 In this context, the surgeon’s experience and
thorough knowledge of the anatomy are key to achieve a
successful oncologic resection with a minimum cosmetic
and functional impact. In our series, all except 2 patients
underwent surgery with curative intent; the type of surgery
and surgical approach were based on the location and
extension of the tumor. Patients who underwent endo-
scopic resection had better survival in this series. This is
probably reflecting a selection bias as this approach was
more commonly used for lesser volume and more localized
disease. No other differences in outcome where found
when different surgical techniques were analyzed.
Surgical margins were described as microscopically
positive or close (within 1 mm) in 20% of patients. We
observed that patients with negative margins had better
2-year and 5-year survival rates, although statistical analy-
sis did not reach statistical significance. Bachar et al11 has
reported similar findings where margin status did not
affect overall survival. In contrast, Penel et al23 has
reported recently that margin status affects overall sur-
vival. A lower local disease, disease-free survival for
patients with positive margins was also documented in the
present series, although no statistical significance was
achieved. We consider that the potential benefits of nega-
tive margins in terms of local control and overall outcome
may be concealed by the development of distant metasta-
sis in a significant number of patients with a profound
negative impact on survival (Fig. 8).
Radiation Therapy
In the last 20 years, there are only 5 series with at least 15
patients treated with radiation therapy in the postopera-
tive setting.5,7,12,19,25 The available evidence from these
studies suggests that the use of adjuvant radiation therapy
improves locoregional control, although there is no evi-
dence of benefit in overall survival.26 Some authors report
the use of postoperative radiation more commonly in
sinonasal versus oral cavity melanomas,12 probably
because of the inherent difficulty of obtaining negative
margins in the nasal cavity. To date, there is no consensus
regarding the indications for postoperative radiation ther-
apy, although most authors agree regarding its use in
patients with positive and close margins, especially as
these have been recently identified as negative prognostic
factors.23 In the current study, the use of postoperative
radiation improved locoregional control but only when a
total dose greater than 54 Gy was used (Fig. 5). A similar
outcome was observed when a standard fractionation
schedule was used versus hypofractionation. It is difficult
2221
Original Article
to determine whether the lack of improvement for the
group that received a lower dose was determined by total
RT dose, hypofractionation, or a combination of both. In
contrast with these findings, other authors have reported
that hypofractionation might improve local control and
overall survival in head and neck mucosal melanomas.6,20
At this point, the optimal RT dose and fractionation
schedule for mucosal melanomas of the sinonasal tract
remains undetermined.26 In cutaneous melanoma, there
is evidence suggesting that hypofractionation schemes
may improve tumor response rate and decrease treatment
toxicity,27 but prospective randomized trials have failed to
support these findings.28
In this series, the use of postoperative radiation did
not improve overall survival regardless of RT dose of frac-
tioning schedule. However, we observed that the develop-
ment of late mucositis was a significant prognostic factor
for overall survival (Fig. 4). One plausible interpretation
is to consider mucositis as a surrogate for a higher radia-
tion dose that has been more effectively delivered to the
target lesion.
Histopathological Features
In cutaneous head and neck melanoma, adequate deter-
mination of histopathological prognostic factors has pro-
ven to be essential for accurate risk stratification and to
provide a rationale for treatment. For mucosal head and
neck melanomas this task is much more complex because
the depth of invasion, the single most important prognos-
tic factor in cutaneous melanomas, cannot be used given
the lack of histological landmarks analogous to papillary
and reticular dermis. Prasad et al9 has reported that cell
morphology, a pseudopapillary or sarcomatoid architec-
ture, and tumor invasion into skeletal muscle, bone, or
cartilage are prognostic factors for disease-specific sur-
vival. On the basis of these findings, he proposed a micro-
staging system that considers depth of invasion relative to
the lamina propria and deeper structures such as bone and
skeletal muscle. Multiple cell morphologies have been
described for head and neck mucosal melanoma including
epithelioid, spindle, pleomorphic, rhabdoid pagetoid,
and undifferentiated (small) cells. Thompson et al3
reported that the presence of undifferentiated cells was
associated with poor survival. Similar findings were
reported by Prasad,9 who also described that undifferenti-
ated cells accounted for 25% of mucosal melanomas. Un-
differentiated cells were found in 45.7% of the patients in
the present study, higher than what has been reported in
previous series. In this series, no particular cell morphol-
2222
ogy proved to be a significant outcome predictor; similar
findings were reported by Dauer et al8 in a recent series.
We found that the presence of a pseudopapillary
architecture was associated with a higher rate of locore-
gional failure (P ¼ .0144) (Fig. 7), but this did not reflect
in overall outcome. Pseudopapillary and sarcomatoid
architectures have been previously reported to decrease
overall survival in other series.9
The presence of melanotic pigmentation was the
only histopathological prognostic factor in this series (P ¼
.0183), and the level of pigmentation appeared to corre-
late with decreased survival (Fig. 6). In the literature, it is
generally suggested that amelanotic melanomas have a
worse prognosis,3 but the presence or absence of melanin
has not been related to disease-free or overall survival in
recent series.3,8,12,19
The presence of more than 10 mitotic figures per
HPF has been described as an independent prognostic fac-
tor for sinonasal mucosal melanoma.3,29 In the present
study, this variable reached borderline statistical signifi-
cance (P ¼ .0619); however, the finding that all patients
who presented with more than 10 mitotic figures per
HPF either died of the disease or recurred suggest that this
may be indeed a valuable prognostic indicator.
The rare nature of sinonasal melanomas precludes
large-scale multivariate analysis of patient outcomes.
Although prospective randomized studies in a large popu-
lation are difficult to perform for this rare tumor type, col-
laborative multi-institutional efforts may provide more
valuable data even for retrospective analyses, and should
be pursued for future studies.
Conclusions
Mucosal melanomas of the sinonasal tract are rare but dis-
tinct tumors that present most commonly in elderly patients
and are associated with a poor prognosis. In the present
study, we have demonstrated the prognostic value of the
AJCC sinonasal classification system. We believe that this
staging system has the advantages of being widely known
and used and provides accurate prognostic information. In
contrast, Ballantyne’s clinical staging system offers limited
prognostic information for the vast majority of patients. His-
tology and site-specific staging systems have been described
for mucosal melanomas of the sinonasal tract, but the rarity
of this disease renders them impractical and they have not
been widely adopted in the literature.
Surgery continues to be the mainstay of treatment for
these patients and the role of radiation therapy appears to be
reserved for adjuvant therapy or for palliative cases. Along
Cancer May 1, 2010

with the present study, there is mounting evidence support-
ing the use of postoperative radiation therapy in mucosal
melanomas of the sinonasal tract, although the optimal radi-
ation dose and fractionation regimes are still undetermined.
The development of distant metastasis is probably
the single most relevant clinical outcome indicator in mu-
cosal melanomas of the sinonasal tract. Locoregional fail-
ure has been considered to precede the development of
distant metastasis in all the patients. In the present report,
as well as other recent series, the development of locore-
gional recurrence did not affect overall survival.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
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