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CHAPTER 7
Although incidence rates are still low, there has been a signif-
icant increase in squamous cell carcinoma over the last 50
years. HIV infected homosexual men appear particularly at
risk. HPV DNA is detectable in most anal squamous cell car-
cinomas.
_________
1
{1, 66}. This classification applies only to carcinomas.
2
A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.
3
This includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through muscularis mucosae into
submucosa.
Definition appendages. There exists no generally 100,000 in women and between 0.3 and
Tumours that arise from or are predomi- accepted definition of its outer limit {62, 0.8 per 100,000 in men {1471}. Still a rel-
nantly located in the anal canal. The 66, 845}. The term anus refers to the dis- atively rare disease, anal SCC has shown
most frequent neoplams of this region tal external aperture of the alimentary a remarkable increase in incidence dur-
are human papilloma virus (HPV-)associ- tract. Anal margin tumours are classified ing the past half century {540, 600, 1213}.
ated squamous cell carcinomas and according to the WHO histological typing From being similar in the two sexes until
adenocarcinomas. of skin tumours {682}. approximately 1960 at 0.2 per 100,000,
annual age-adjusted incidence rates in
Topographic definition of anal canal Squamous cell carcinoma Denmark rose 2.5-fold in men and 5-fold
and anal margin in women during the period 1943-1994.
The anal canal is defined as the terminal Definition For both men and women, urban popula-
part of the large intestine, beginning at Squamous cell carcinoma (SCC) of the tions are at higher risk than rural popula-
the upper surface of the anorectal ring anal canal is a malignant epithelial neo- tions {540, 600, 1213}, and there are con-
and passing through the pelvic floor to plasm that is frequently associated with siderable racial differences in incidence.
end at the anus {68}. The most important chronic HPV infection. In the United States, blacks tend to have
macroscopic landmark in the mucosa is higher incidence rates than whites
the dentate (pectinate) line composed of ICD-O code 8070/3 {1213}, while Asians and Pacific Islanders
the anal valves and the bases of the anal appear to be at very low risk {70}.
columns. Histologically, the mucosa can Epidemiology Homosexual men appear to constitute a
be divided into three zones. The upper SCC of the anal canal and anal margin group at particular risk {368, 538, 140,
part is covered with colorectal type typically occurs among patients in their 96, 369, 540, 1213, 1690, 730}. In the
mucosa. The middle part is the anal tran- 6th or 7th decade of life {540}. However, United States, the incidence of anal SCC
sitional zone (ATZ), which is covered by a anal SCCs may occur in young adults, in homosexual men has been estimated
specialized epithelium with varying particularly in patients with cellular to be 11 to 34 times higher than in the
appearances; it extends from the dentate immune incompetence {1212}. Unselec- general male population and approxi-
line and on average 0.5-1.0 cm upwards ted, population-based studies show an mately as high as the incidence of cervi-
{490, 1929}. The lower part extends from approximate 2:1 female predominance cal cancer before the introduction of cer-
the dentate line and downwards to the among patients with anal SCC {540, 600, vical cytology screening {369, 1447}. HIV
anal verge and has formerly been called 1213}. infected homosexual men appear to be
the pecten. It is covered by squamous There are few published, histologically at particularly risk {1212, 1449, 598}.
epithelium, which may be partly kera- verified incidence rates of anal cancer Other sexual factors strongly associated
tinized, particularly in case of mucosal {540, 600, 1213}. Data from most popula- with anal SCC include number of sexual
prolapse. tion-based cancer registries worldwide partner, receptive anal intercourse, and
The perianal skin (the anal margin) is show age standardized incidence rates co-existence of sexually transmitted dis-
defined by the appearance of skin of anal SCC of between 0.5 and 1.0 per eases {368, 538, 730, 733}.
Aetiology
Sexually transmittable human papillo-
maviruses (HPVs) are detected by PCR
in the majority of anal SCC {355, 367,
538, 704, 732, 1448}. One large study
showed that SCCs involving the anal
Anorectal ring canal are more often high-risk HPV posi-
Anal columns tive (92%) than lesions confined to the
Anal valves and sinuses Surgical anal canal perianal skin (64%) {536}, suggesting
that HPV-unrelated pathways may apply
Histological anal canal particularly to cancers of the perianal
DENTATE LINE
skin. A strong association with tobacco
Intersphincteric groove Anatomical anal canal
smoking has been established in women,
Anal verge, ‘anus’ but the role of smoking in men is less
clear {367, 539, 730, 733}. States of cel-
Fig. 7.01 Anatomy of the anal canal. Printed with permission from ref 490. lular immunosuppression are associated
ular, and a lymphocytic infiltrate may be gies, i.e. size of predominant neoplastic
pronounced or absent. None of these fea- cell, basaloid features, degree of keratin-
tures have been shown to have any prog- isation, adjacent squamous intraepithe-
nostic significance, but poor keratiniza- lial neoplasia, or presence of mucinous
tion, prominent basaloid features and microcysts.
small tumour cell size are related to infec- Apart from the verrucous carcinoma
tion with ‘high risk’ HPV {536}. The keratin mentioned below, only two rare histolog-
profile of anal SCC is complex and vari- ical subtypes seem to have a different
able {2112, 2113}. The usual immunoex- biological course, both having a less
pression pattern is shown in Table 7.01. favourable prognosis {1734}. One is
The second edition of the WHO classifi- characterized by areas with well formed
Fig. 7.06 Well differentiated squamous cell carci-
noma composed of large cells showing keratiniza- cation of SCC in the anal canal included acinar or cystic spaces containing mucin
tion. the large-cell keratinizing subtype, the that reacts with Alcian dyes or PAS after
large-cell non-keratinizing subtype, and diastase digestion. This is termed squa-
the basaloid subtype {845}. The value of mous cell carcinoma with mucinous
tumour cells may be facilitated by this classification of anal SCC has been microcysts. The other is characterized
immunostaining for high molecular weight questioned in recent years. Many by a rather uniform pattern of small
cytokeratins (CKs). tumours show more than one subtype. tumour cells with nuclear moulding, high
In 15-20% of cases, the lesion may infil- Thus in a study of 100 cases of anal car- mitotic rate, extensive apoptosis and dif-
trate the lower rectum and the neigh- cinomas, 99 showed some features of fuse infiltration in the surrounding stro-
bouring organs including the rectovagi- squamous differentiation (keratinisation, ma. This has been called small cell
nal septum, bladder, prostate and poste- stratification and prickles), 65 showed (anaplastic) carcinoma, but should not
rior urethra, sometimes with suppuration basaloid features (small cell change, pal- be confused with small cell carcinoma
and fistulas. The vulva is usually spared. isading, retraction artefact and central (poorly differentiated neuroendocrine
Lymphatic spread occurs in up to 40 per- eosinophilic necrosis) and 26 showed carcinoma).
cent of cases {165, 1174, 1621, 1719, focal evidence of ductal proliferation and
2033}. Tumours proximal to the pectinate occasionally positive staining for PAS
line drain into the pelvis along the middle after diastase digestion {2111}. Further-
rectal vessels to the pelvic side walls and more, the diagnostic reproducibility of
internal iliac chains and superiorly via the these subtypes is low {492}. This is prob-
superior rectal vessels to the periaortic ably the reason that the proportion of
nodes. Tumours distal to the dentate line basaloid carcinoma in larger series has
drain along cutaneous pathways to the varied from 10 to almost 70 %, and that
inguinal and the femoral nodal chains. no significant correlation between histo-
Inguinal nodes are involved in about logical subtype and prognosis has been
10-20% of cases {230, 575, 1174, 1650, established. In addition, the histological
1692}. Inguinal lymph nodes can be diagnosis is nowadays nearly always per-
involved bilaterally in a small number of formed on small biopsies, that may not be Fig. 7.08 Squamous cell carcinoma showing a
cases at time of presentation. Retrograde representative for the whole tumour {492}. combination of basaloid and squamous features.
lymphatic drainage occurs in advanced Therefore, it is recommended that the
cases when the lymphatics are obstruct- generic term ‘squamous carcinoma’ be
ed by malignant spread {1621, 1719}. used for these tumours, accompanied by Squamous cell carcinoma of anal margin
a comment describing those histopatho- The distinction between anal canal and
Histopathology logical features that may possibly affect anal margin SCC may be difficult, as
Squamous cell carcinoma of anal canal the prognosis or reflect different aetiolo- tumours often involve both areas at the
Anal SCC may show a single predomi- time of diagnosis. This may account for
nant line of differentiation, but most exhib- the varying data on prognosis, but this is
it a mixture of areas with different histo- generally better for anal margin SCC
N
logical features. One pattern is that of than for anal canal SCC, in particular if
large, pale eosinophilic cells and kera- local resection is possible {392, 530,
tinization of either lamellar or single cell 1484}. Anal margin SCC is often of the
type. Another is that of small cells with large cell variant {536, 1484}.
palisading of the nuclei in the periphery
of tumour cell islands. The latter often Verrucous carcinoma
contain necrotic eosinophilic centres. In the anogenital area, this tumour is also
Intermediate stages between these two called giant (malignant) condyloma or
extremes are often present. Differentia- Buschke-Lowenstein tumour. It has a
tion into tubular or spindle cell configura- Fig. 7.07 Squamous cell carcinoma composed of cauliflower-like appearance, is larger
tion may be found. The invasive margin basaloid cells. Central necrosis (N) of tumour nests than the usual condyloma with a diame-
can vary from well circumscribed to irreg- is typical. ter up to 12 cm, and fails to respond to
Intraepithelial neoplasia
Precancerous anal intraepithelial neopla-
sia (AIN) in the anal transition zone (ATZ)
and the squamous zone, has also been
A termed dysplasia, carcinoma in-situ and
B
anal squamous intraepithelial lesion
Fig. 7.09 Squamous cell carcinoma of anus. A Combination of basaloid features and keratinization. B Large
(ASIL) {494, 1449}. The corresponding
cells, poorly differentiated.
lesions in the perianal skin are commonly
referred to as Bowen disease. This termi-
conservative treatment. In contrast to an 33 published anorectal cases, 42 per nology is complicated by the fact that the
ordinary condyloma, it is characterized cent have shown malignant transforma- precancerous changes are not always
by a combination of exophytic and endo- tion {133}. The presence of severe cyto- restricted to one area. Leukoplakia is a
phytic growth. Histologically, it shows logical changes, unequivocal invasion or clinical term and should not be used as a
acanthosis and papillomatosis with metastases should lead to the diagnosis histological diagnosis.
orderly arrangement of the epithelial lay- of SCC and to the appropriate therapy. Anal intraepithelial neoplasia (squamous
ers and an intact but often irregular base cell dysplasia in the anal canal). Most
with blunt downward projections and ker- Grading cases of AIN are incidental findings in
atin-filled cysts. The endophytic growth Poor prognosis has been related to poor minor surgical specimens for benign con-
is accompanied by destruction of the differentiation {165}, especially if this was ditions. When macroscopically detected,
underlying tissues. Cytologically, the defined only by the degree of dissocia- AIN may present as an eczematoid or
epithelial cells appear benign. Large tion of tumour cells {599}. However, such papillomatous area, or as papules or
nuclei with prominent nucleoli may be differences may be related to tumour plaques. The latter may be irregular,
present, but dysplasia is usually minimal stage in multivariate analysis {1734}. raised, scaly, white, pigmented or erythe-
and mitoses are restricted to the basal Grading on biopsies is not recommend- matous and occasionally fissured. Indur-
layers {162}. ed, as these may not be representative ation or ulceration may indicate invasion.
Some verrucous carcinomas contain for the tumour as a whole. Histologically, AIN is characterized by
HPV, the most common types being 6 varying degrees of loss of stratification
and 11. They are regarded as an inter- Precursor lesions and benign tumours and nuclear polarity, nuclear pleomor-
mediate state between the ordinary Chronic HPV infection phism and hyperchromatism, and in-
condyloma and SCC, and the clinical Warts in the perianal skin and lower anal creased mitotic activity with presence of
course is typically that of local destruc- canal (condyloma acuminatum) show the mitoses high in the epithelium. The sur-
tive invasion without metastases. Among same histology as their genital counter- face may or may not be keratinized, and
koilocytic changes may be present.
AIN has been graded into I, II or III, or
into mild, moderate and severe dysplasia
{494}. Reproducibility studies have
shown considerable observer variation
{254}. A two grade system (low- and
high-grade) may be more appropriate.
Squamous dysplasia at the anal margin -
Bowen disease. Clinically, this presents
as a white or red area in the perianal skin
that may be in continuity with dysplastic
lesions in the anal canal. HPV DNA is
sometimes identified, including types 16
and 18, among others. Histologically it
shows full thickness dysplasia of the
squamous and sometimes the piloseba-
ceous epithelium, with disorderly matura-
tion, mitoses at all levels and dyskerato-
sis. Occasionally, atypical keratinocytes
may resemble Paget cells, but are nega-
tive for low molecular weight CKs and for
mucin. In pigmented Bowen disease the
Fig. 7.10 Mucinous carcinoma of anus. Tumour extends to anal sphincter. neoplastic cells are invariably negative
B
Fig. 7.17 A, B Inflammatory cloacogenic polyp.
Dilated elongated hyperplastic glands showing
Fig. 7.15 Low-grade squamous intraepithelial neo- Fig. 7.16 High-grade squamous intraepithelial neo- regenerative atypia. Surface erosion is a constant
plasia with koilocytosis. plasia with hyperkeratosis. feature.
associated Paget disease of the anus from ordinary colorectal type adenocar- mucin composition {491} and keratin
(see below). Tumour spread and staging cinoma, and do not seem to represent a expression {2113}.
largely correspond to anal SCC. special entity except for their low loca- Adenocarcinoma within anorectal fistula.
tion. Adenocarcinoma in the anal transi- These tumours develop in pre-existing
Histopathology tional zone (ATZ) may develop after anal sinuses or in fistulae {74}. Some are
Adenocarcinoma arising in anal mucosa restorative proctocolectomy for ulcera- associated with Crohn disease {992}.
Most adenocarcinomas found in the anal tive colitis {1711}. Others may contain epithelioid granulo-
canal represent downward spread from Extramucosal (perianal) adenocarcinoma mas, often related to foci of inflammation
an adenocarcinoma in the rectum or Approximately two hundred cases of or extravasated mucin but without other
arise in colorectal type mucosa above extramucosal adenocarcinoma have signs of inflammatory bowel disease
the dentate line. Macroscopically and been reported, the largest series unfortu- {863}.
histologically, they are indistinguishable nately with insufficient histological data Rarely, the tumours may be related to fis-
{9}. A minimum criterion for the diagnosis tulae lined by normal rectal mucosa
is an overlying non-neoplastic mucosa, including muscularis mucosae, most
which may be ulcerated. Recent reports likely representing adenocarcinomas
indicate that about two thirds of these arising in congenital duplications {863}.
tumours manifest in men with a mean age Histologically, carcinomas arising in fistu-
about 60 years. Reliable data for the lae usually are of the mucinous type, but
prognosis for such patients have not tubular adenocarcinomas and squamous
been identified. Difficulties in establishing neoplasia can also be found {992, 2173}.
the correct diagnosis may delay proper Adenocarcinoma of anal glands. Only a
treatment. few cases have been reported in which
Extramucosal adenocarcinoma seem to convincing evidence for origin in an anal
fall into two groups, based on their asso- gland has been demonstrated by conti-
ciation with either fistulae or remnants of nuity between anal gland epithelium and
anal glands. At present, no laboratory tumour {118, 650, 1472, 2087, 2131}.
methods can distinguish between these With a single exception {650}, these
two. patients have had no history of previous
The epithelium of persistent anal fistulae or concomitant fistula. The tumours were
is most often of the same type as found all characterized by a combination of
in the anal glands and ATZ {1117}, and ductular and mucinous areas. Pagetoid
the epithelium in these two locations spread was present in at least one case
Fig. 7.18 Adenocarcinoma arising in a fistula. show the same profile with regard to {2131}.
A B
Fig. 7.21 Secondary Paget disease of the anus. A The underlying adenocarcinoma is present beneath the Fig. 7.22 Malignant melanoma of anus with typical
squamous epithelium. High molecular weight keratin immunostain is largely restricted to normal squamous polypoid appearance.
epithelium. B Low molecular weight keratins 8 and 13 immunostaining of tumour cells.
Malignant melanoma haematogenously to the liver and thence {902}, fibrosarcoma, neurilemmoma and
Anal melanoma is rare. It is a disease of to other organs. Metastases are frequent neurofibroma {571}, granular cell tumour
adults with a wide age range; most at time of presentation, and the progno- (myoblastoma) {862}, spindle cell lipoma
patients are white {339, 182}. Presen- sis is poor; the 5-year survival is less than and aggressive angiomyxoma {503} and
tation is usually with mass and rectal 10% {339, 157}. The chances of long- extraspinal ependymoma in a newborn
bleeding, but tenesmus, pain and term survival are increased if the lesion is {2074}. HIV infected persons may, in
change in bowel habit also occur {339}. small. addition to the increased risk of squa-
Macroscopy. Lesions may be sessile or mous neoplasia, develop Kaposi sarco-
polypoid. Pigmentation of the lesion is Mesenchymal and neurogenic ma in the perianal area {113}.
often appreciated. Satellite nodules may tumours
occur. These are all rare and the exact point of Malignant lymphoma
Histopathology. The features resemble origin may be difficult to establish. Primary lymphomas of the anorectal
those of cutaneous melanomas. The Recent reports on tumours in the anorec- region are rare in the general population,
majority shows a junctional component tal and perianal area include haeman- but much more common in patients with
adjacent to the invasive tumour, and this gioma, lymphangioma {372}, haeman- AIDS, particularly homosexual men. All
finding is evidence that the lesion is pri- giopericytoma {478}, leiomyoma, malig- are of B-cell type, the most common
mary rather than metastatic. The tumour nant fibrous histiocytoma and leio- types being large cell immunoblastic or
cells express S-100 and HMB-45. myosarcoma {1110}, rhabdomyoma in a pleomorphic {687, 786}. Langerhans cell
Prognosis. Anal melanomas spread by newborn {1014}, and rhabdomyosarco- histiocytosis has been described in chil-
lymphatics to regional nodes, and ma in childhood {1560} and adulthood dren {617, 874} and an adult {329}.
A B C
Fig. 7.23 Malignant melanoma of anus. A Polypoid growth is frequent. B Scattered tumour cells contain melanin. C Epitheloid melanoma cells with prominent nucleoli.
Table 7.01
Anal tumours, immunoreactivity profile (exceptions occur, especially among CK and mucin)1
CK CK CK
8+18 7/20 5+14 Mucin CEA Vim Special
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1
Chrom = Chromogranin A PSA = Prostate specific antigen
CK = Cytokeratin PSAP = Prostate specific acid phosphatase
CRC = Colorectal carcinoma Synap = Synaptophysin
GCDFP = Gross cystic disease fluid protein Vim = Vimentin