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Dermatopathology

Tumours and inflammatory lesions of the anal

canal and perianal skin revisited: an update
and practical approach
Heather Dawson,1 Stefano Serra2
1
Department of Pathology, ABSTRACT forms a granular layer with subsequent keratinisa-
Pathology and Laboratory Tumours of the anal and perianal region are relatively tion distally. The appendages of the perianal skin
Medicine, Mount Sinai
Hospital, Toronto, Ontario,
rare, and clinically often interpreted as innocuous consist primarily of hair follicles, sebaceous glands
Canada lesions, leading to frequent delays in diagnosis and and apocrine glands. Here, there are well-
2
Department of Pathology, adequate treatment. Although squamous cell neoplasia developed papillae and prominent melanocytes.3
Laboratory Medicine Program, represents the most common entity encountered in this The particular location of a tumour is important
University Health Network and anatomically complex area, many conditions, both for planning treatment, as the lymphatic drainage of
University of Toronto, Toronto,
Ontario, Canada neoplastic and inflammatory, may occur. Adding to the the anatomical canal differs from that of the perianal
challenge of correct diagnosis and patient management, skin. Whereas the perianal skin drains mainly to the
Correspondence to recent years have seen major updates in the terminology inguinal lymph nodes, the lymphatics of the distal
Dr Stefano Serra, Department of squamous cell neoplasia, created to reflect advances anal canal communicate with those of the mid-canal
of Pathology, Laboratory
Medicine Program, University in our understanding of the role of human papilloma and proximal canal, draining to the internal iliac and
Health Network and University virus and unify previous terminologies used for different superior haemorrhoidal lymph nodes.4
of Toronto, Toronto, Ontario, sites in the anogenital tract. However, squamous cell According to the seventh edition of the
Canada M5G 2C4; neoplasia in the anal canal and perianal region may American Joint Committee on Cancer (AJCC)
stefano.serra@uhn.ca
differ in terms of histology, biological behaviour, staging cancer staging manual, carcinomas involving the
Received 3 April 2015 and treatment. The aim of this review is to present an anorectal junction should be classified as rectal
Accepted 11 April 2015 overview of neoplastic and non-neoplastic lesions that cancers if their epicentre is >2 cm proximal to the
may be seen in this area, an update on important dentate line and as anal cancers if the epicentre is
developments and terminology, potential pitfalls that ≤2 cm from the dentate line.5 Cancers arising in
may be encountered in routine pathology practice and a the hair-bearing perianal skin are classified and
practical approach on how to resolve these issues. staged as tumours of the skin.

TUMOURS AND TUMOUR-LIKE LESIONS

ANATOMY OF THE ANAL REGION The most common masses and lumps in the anal
The anus and perianal region make up an anatomic- and perianal region are non-neoplastic. However,
ally complex area, and terms used to define the anal as discussed below, a large proportion of malignant
canal use different anatomical landmarks, which tumours diagnosed in the anal region are inciden-
may be a source of confusion. Embryologically, the tally detected in resections from these clinically
anal canal is derived in its proximal end from the innocuous lesions.
hindgut, and distally from the ectodermal procto-
deum with the dentate line at the fusion point.1 The SQUAMOUS CELL NEOPLASIA:
term ‘surgical anal canal’ is used to describe the INTRAEPITHELIAL NEOPLASIA AND INVASIVE
functional unit extending from the distal intestinal SQUAMOUS CELL CARCINOMA
tract enclosed by the internal sphincter muscle to These are the most frequent lesions in the anal canal
the anal verge. The ‘anatomic anal canal’ is the and perianal skin, and human papilloma virus (HPV)
segment between the dentate line to the anal verge.2 has been established as a major etiological factor. It is
The mucosa of the anal canal encompasses the estimated that 90–93% of squamous cell carcinomas
anal transitional zone just above the dentate line (SCCs) arising in the anal canal are caused by HPV.6
and anoderm. The anoderm, which extends along a This figure differs for SCCs in the perianal skin,
length of about 2 cm, consists of pecten, the where 80% of cases in female patients but only 29%
smooth, non-hairy zone extending between the of cases in male patients may be attributable to HPV.7
dentate line, and merges into the hair-bearing peri- It is important to distinguish between SCCs in these
anal skin. The perianal skin is defined as the region two regions since they follow different biological
in a 5 cm radius from the anal verge. courses (table 1): primary SCCs of the perianal skin
Histologically, colorectal-type mucosa extends to tend to be well-differentiated and superficial, and
the anal transition zone (ATZ), located just above have high cure rates with wide local excision alone as
the dentate line. The surface and ducts of the anal opposed to anal canal lesions, which are often poorly
transitional zone are lined by lined by either transi- differentiated, non-keratinising and behave more
tional epithelium (which indeed bears resemblance aggressively.8 9
to urothelium) or squamous mucosa. The pecten is
To cite: Dawson H, Serra S. lined by non-keratinising squamous mucosa with TERMINOLOGY OF SQUAMOUS CELL LESIONS
J Clin Pathol 2015;68:971– short stromal papillae without skin appendages and As terminology for HPV-associated squamous
981. contains increased numbers of melanocytes and lesions in the lower anogenital tract has been
Dawson H, Serra S. J Clin Pathol 2015;68:971–981. doi:10.1136/jclinpath-2015-203056 971
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Dermatopathology

Table 1 Current terminology and summary of (peri) anal intraepithelial squamous cell lesions
Term Presentation Histology HPV associations Prognosis

ASIN (HSIL and Usually flat lesions of anal LSIL: atypia and mitoses confined to the lower LSIL: low-risk HPV, Rate of progression to invasive carcinoma
LSIL) canal third of the epithelium, and/or the presence of HSIL: high-risk HPV, varies depending on grade (LSIL<HSIL), high
koilocytes, most commonly 16 risk genotype, but also immune (HIV) status
HSIL: full-thickness nuclear atypia, mitoses and 18
Condyloma Exophytic papillomatous Papillomatous configuration with koilocytes Low-risk HPV, most Generally benign, risk of progression
acuminatum lesions in anal canal/ (LSIL) commonly 6 and 11 especially in HIV-positive patients
perianal skin
Bowenoid Small smooth papules HSIL High-risk HPV, most Excellent, very low rate of progression
papulosis <5 mm in perianal skin commonly 16 and 18
(PSIN-H)
Bowen’s disease Multiple large scaly HSIL High-risk HPV, most Progression to invasive SCC in up to 5%
(PSIN-H) plaques in perianal skin commonly 16 and 18
Verrucous SCC Large fleshy Very well differentiated squamous epithelium Low-risk HPV, most Generally good, large tumours may require
cauliflower-like mass in with broad pushing border (often only clue to commonly 6 and 11 extensive surgery. Distant metastases
perianal skin diagnosis), koilocytes may not be evident restricted to cases with overt atypia/invasive
component
SCC Mass at anal margin/ Often keratinising and tend to be well- or High-risk HPV, most High percentage (70–90%) of N0 tumours
(‘keratinising’) perianal skin moderately differentiated commonly 16 and 18 cured by radiation (anal canal tumours) or
wide excision (perianal skin)
SCC (‘basaloid’) Often flat or ulcerated in Non-keratinising, cellular, frequently invade and High-risk HPV, most Anal canal SCCs are more aggressive than
anal canal ulcerate rectal-type mucosa commonly 16 and 18 those arising in the perianal skin
ASIN, anal (squamous) intraepithelial neoplasia; HPV, human papilloma virus; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; PSIN,
perianal (squamous) intraepithelial neoplasia; SCC, squamous cell carcinoma.

variable in the past, the Lower Anogenital Terminology Project of patient groups that may be eligible for conservative treatment
(LAST) was initiated to recommend classifications that would and compare outcomes data.10 However, the value of one single
reflect current knowledge of HPV biology, the appropriate use such definition under the assumption that the aetiology and bio-
of biomarkers and facilitate clear communication across differ- logical behaviour of early squamous carcinomas in the lower
ent medical specialties.10 anogenital tract are analogous may be questioned. For instance,
Recommendations from the LAST Committee include unify- the exceptionally high prevalence of AIN and higher risk of pro-
ing the terminology for all sites of intraepithelial squamous cell gression to invasive SCC among HIV-positive individuals in
lesions in the lower anogenital tract. A two-tiered nomenclature comparison to other sites would suggest different screening,
(low-grade squamous intraepithelial lesion (LSIL)/high-grade treatment and follow-up strategies are needed for different
squamous intraepithelial lesion (HSIL)) is recommended for all at-risk patient groups,11 12 and SISCCA as defined above is cur-
dysplastic lesions, which may be further specified by the abbre- rently not part of management algorithms for SCC of the anal
viated appropriate location and the suffix ‘-IN’ (eg, ‘AIN’ or canal or perianal skin.13
‘ASIN’ in the case of anal (squamous) intraepithelial neoplasia Other terms frequently used for intraepithelial neoplasia in
or ‘PAIN’ or ‘PSIN’ for perianal (squamous) intraepithelial neo- the perianal region are Bowen’s disease and bowenoid papulosis,
plasia) (figure 1). the use of which has been discouraged by some because of
Morphological criteria used to define the presence of LSIL are
1. Proliferation of squamous or metaplastic squamous cells
with atypical nuclear features (increased nuclear size, irregu-
lar membranes, increased nuclear/cytoplasmic ratio).
Maturation begins in the middle third of the epithelium and
is normal in the upper third. Mitotic figures should be con-
fined to the lower third of the epithelium.
2. Diagnostic cytopathic effect of HPV (koilocytes). Koilocytes
are recognised by perinuclear clearing, irregular nuclear
membranes and are frequently binucleated.
HSIL is characterised by the same atypical nuclear features as
LSIL but with only little or no maturation in the middle and
superficial third of the epithelium. Here, mitotic figures may be
found within the full thickness of the epithelium.
The LAST group suggests the definition of superficially inva-
sive squamous cell carcinoma (SISCCA) in the anal canal and
the perianal region is an invasive squamous carcinoma that has
an invasive depth of ≤3 mm from the basement membrane and
a horizontal spread of ≤7 mm in maximal extent, and has been Figure 1 Squamous epithelium with severe high-grade dysplasia
completely resected (figure 2). This definition is arbitrary and (anal (squamous) intraepithelial neoplasia III). Cell dysmaturation
identical to superficial carcinomas in the lower anogenital tract. involves the full thickness of the epithelium. The nuclei show irregular
It was created to eliminate confusion in terms of defining early contours with slight variability in nuclear shape, nuclear chromatin is
invasive SCC among different sites to enable the identification disperse. Mitotic figures are seen in the upper half of the epithelium.
972 Dawson H, Serra S. J Clin Pathol 2015;68:971–981. doi:10.1136/jclinpath-2015-203056
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Dermatopathology

Table 2 Appropriate use of p16 for anal squamous intraepithelial

neoplasia10
Recommended
Reactive versus HSIL
Diagnosis of LSIL vs HSIL, equivocal Block positive staining supports HSIL
Disagreement of histological diagnosis
Not recommended
Diagnosis of negative or reactive on
histology
Diagnosis of LSIL on histology Staining may be difficult to interpret
Diagnosis of HSIL on histology
HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous
intraepithelial lesion.

Figure 2 Microinvasive well-differentiated squamous cell carcinoma. carcinoma), large keratinising and large non-keratinising sub-
The epithelium shows high-grade dysplasia with keratinisation, focally types. However, low interobserver agreement may be the reason
small nests of neoplastic cells invade into the inflamed stroma. why no significant correlation between histological subtype and
Occasional foreign body granulomas are seen. prognosis has been established. In light of this and the fact that
biopsies may not be representative of the entire tumour and that
therapy is not influenced by histological subtype, the subclassifi-
potential confusion with cutaneous counterparts and the fact cation is no longer recognised by the WHO, and the generic
that since most cases are HPV-related they should be term SCC should be used.14 However, an additional comment
approached as such. Nevertheless, the WHO considers Bowen’s on histological features (such as degree of differentiation, basa-
disease to be synonymous with perianal squamous intraepithelial loid features, degree of keratinisation) is recommended.17
neoplasia (this term seemingly restricted to high-grade intrae-
pithelial neoplasia/squamous carcinoma in situ).14 Bowen’s CONDYLOMA ACUMINATUM
disease appears as large scaly plaques with irregular borders and These papillary squamous proliferations usually appear grossly
may be ulcerated.15 Bowenoid papulosis, on the other hand, as soft, polypoid, cauliflower-shaped excrescences and are
presents as small demarcated papules that usually spare the cuta- caused by HPV infection, usually by the low-risk genotypes 6
neous appendages. Although both entities are forms of HSIL and 11.18 Lesions within this spectrum demonstrate low-grade
and cannot be distinguished by histology alone, the clinico- cytopathic features of HPV and are designated as LSIL (figures 3
pathological differentiation is important to make, as bowenoid and 4). It must be noted that interobserver agreement of koilo-
papulosis is much less likely to progress to invasive SCC.16 cytic features is fair at best, with reported kappa vales ranging
from 0.4 to 0.53.19 Since condyloma acuminata are usually asso-
ciated with low-risk HPV and harbour a very low risk of pro-
THE APPROPRIATE USE OF BIOMARKERS IN THE gressing to SCC, their clinical significance as a precancerous
ASSESSMENT OF SQUAMOUS LESIONS OF THE ANAL lesion may be questioned. However, some condylomata, espe-
CANAL AND PERIANAL SKIN cially those located in the anal canal, may show aggressive
In general, the grade of the lesion should be determined on behaviour, and it is thought that this subset may harbour high-
H&E. However, some lesions may fall into a category that would risk HPV types (especially HPV type 16),20 or a mixture of
have been called AIN2 using the former three-tier classification, low-risk and high-risk types. Foci of high-grade dysplasia are
thus corresponding to an equivocal lesion falling between LSIL
(morphological changes of HPV infection) and HSIL ( precancer-
ous). Also in some instances the differential diagnosis is that of
benign mimickers of precancer (such as regenerative epithelial
atypia, immature epithelium, tangential cutting) versus true
HSIL. In these cases, the use of p16 immunohistochemistry
(IHC) is recommended to resolve this issue. Strong and diffuse
block-positive (nuclear and cytoplasmic) immunoreactivity of
p16 supports the classification of HSIL, whereas negative or
patchy non-block staining strongly favours LSIL or a
non-HPV-related lesion. There is no role for the use of p16 as a
routine marker in cases of morphological LSIL, HSIL or in nega-
tive cases (table 2). Ki-67 immunostaining has also been sug-
gested as a biomarker and parallels the level of dysplasia
(suprabasal staining in LSIL, full-thickness staining in HSIL), but
there is no sufficient evidence to warrant its routine use in prac-
tice.10 Although routinely performed in some institutions, there
are currently no widely accepted guidelines on HPV genotyping
assays on specimens with intraepithelial neoplasia or SCC. Figure 3 Condyloma acuminatum exhibit a striking papillary
SCC of the anal canal has been previously further divided architecture. Papillae of different sizes and shapes are lined by
into subtypes, namely basaloid (also referred to as cloacogenic acanthotic squamous epithelium and have a fibrovascular stroma.
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Dermatopathology

may be challenging to determine whether superficial invasion is

present on biopsy material. The most helpful diagnostic features
are small nests of atypical squamous cells without basal layers or
basal membrane, with or without stromal desmoplasia (not
always present).
Tumours of the perianal skin are usually treated by wide local
resection (with or without adjuvant chemoradiation).13 In these
cases, the diagnosis of invasive SCC will already have been
established, and the pathologist’s role is to assign the correct
pathological stage. In addition, pathologists may be asked to
evaluate the margins of the resection by frozen section.
The differential diagnosis of squamous dysplasia in the anal
region encompasses a plethora of conditions such as epithelial
hyperplasia, reparative/reactive epithelial changes and atrophy.
In these situations, p16 IHC may be used. Also, HSIL may dem-
onstrate cytoplasmic vacuoles that can mimic extramammary
Figure 4 Condyloma acuminatum. The epithelium is hyperkeratotic Paget’s disease.19 A pitfall when examining anal canal mucosa is
with superficial parakeratosis. Occasionally the nuclei are misinterpreting anal transitional mucosa as dysplasia. By nature,
hyperchromatic with irregular nuclear membranes. Orderly maturation cells in the ATZ are crowded, smaller than normal squamous
with sporadic mitotic figures in the basal layer and hypergranulosis are cells and have a higher nuclear/cytoplasmic ratio. However,
present. unlike AIN, nuclei of the ATZ are uniform in shape and size.1

PAGET’S DISEASE
also more frequent in larger lesions that harbour high-risk HPV Perianal Paget’s disease is a rare occurrence, accounting for
and may be seen in up to 15% of condylomata <5 cm in size.19 <1% of all anal diseases and 6.5% of all cases of Paget’s
As all anal condylomata may potentially contain areas of dyspla- disease.24 Clinically, patients present with nonspecific symptoms
sia, they should be submitted in toto.19 including exfoliative, exsudative, verrucous or hypopigmented
patches accompanied by pruritus or burning sensations,25 the
GIANT CONDYLOMA OF BUSCHKE AND LÖWENSTEIN persistence of which may lead to biopsy and the correct diagno-
Giant condyloma of Buschke and Löwenstein and verrucous sis. The rate of associated malignancies ranges from 33% to
SCC are currently regarded as the same entity and the latter 86%,26 which is higher than Paget’s in other sites.27 This can be
term should be used.14 Grossly, these lesions look like large con- attributed to the fact that Paget’s disease in the anal region pre-
dylomas (with a diameter of up to 12 cm), but unlike ordinary sents as two entities: either as a primary anogenital extramam-
condylomas, verrucous carcinomas are characterised by both mary Paget’s disease, which affects areas bearing apocrine
exophytic and deep growth.21 Generally, patients with these glands, or secondary. In female patients, this is often an exten-
tumours fare well and are usually cured if the lesion is amenable sion from vulvar lesions. Secondary Paget’s disease is most com-
to complete surgical excision, especially since the clinical course monly due to primary colorectal carcinoma with intraepithelial
is that of local destructive invasion. Patients with advanced tumour extension (with either simultaneous or, more rarely,
tumours may present with involvement of the perianal skin, metachronous presentation), but may also be associated with
perirectal tissue and the ischiorectal fossa. Histologically, verru- remote carcinomas of the gastrointestinal (GI) tract, breast and
cous carcinomas are well-differentiated entities that may lack the of the urethra.27 28 This distinction is an important one to make
classic viral cytopathic features of HPV, even when the virus is as primary Paget’s disease is not associated with internal malig-
present (a subset of verrucous carcinoma harbour HPV; most nancies but may become locally invasive as an apocrine carcin-
commonly types 6 and 11). They may be extremely well differ- oma.29 Immunohistochemical stains may be useful to sort this
entiated with low-grade cytological atypia at most, and the out as secondary Paget cells arising from colorectal adenocarcin-
endophytic invading component shows a broad and pushing oma will usually be positive for CK20, CDX227 30 (and some-
border rather than an infiltrative invasive front. The possibility times also CK7), whereas primary (or local) Paget cells typically
of verrucous carcinoma must be entertained in all condyloma show a CK7+/CK20-/GCDFP-15+ profile (table 3).
resections, and often clinical correlation and thorough sampling The key morphological finding is that of Paget’s cells, charac-
will be key in establishing the correct diagnosis. Distant metasta- terised by abundant cytoplasm with vesicular nuclei and
ses do not appear to occur in this entity, provided areas of frank
invasion or overt atypia are not present,22 in which case the
term invasive SCC should be used with a comment to convey
Table 3 Immunohistochemical profiles of anal tumours with
this risk.19
intraepithelial (pagetoid) spread

THE ROLE OF THE PATHOLOGIST IN (PERI) ANAL CK7 CK20 CDX2 GCDFP-15 S100 p63
SQUAMOUS NEOPLASIA Primary Paget + − − + − −
As the treatment for anal SCC is primarily chemoradiation,13 Secondary Paget −/+ + + − − −
the pathologist’s role is more or less confined to establishing the (colorectal cancer)
diagnosis of invasive SCC on biopsy or cytology material. Anal gland + − − − − −
Surveillance programmes are increasingly using cytology as a adenocarcinoma
screening tool for anal intraepithelial neoplasia,23 and the Squamous cell carcinoma − − − − − +
Bethesda classification, which harmonises with the LAST ter- Melanoma − − − − + −
minology, should be used.10 As in other anatomical locations, it
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Dermatopathology

prominent nucleoli (classic type A cells) (figure 5A–D) or MALIGNANT MELANOMAS

mucin-containing signet ring-like cells (type B cells). The pres- The anorectum is the third most common site for primary
ence of intraepithelial gland formation with dirty necrosis has mucosal malignant melanomas (after head/neck and female
also been described within the context of secondary Paget’s genital tract).38 Diagnosis may be delayed as around 25% are
(due to colorectal adenocarcinoma).27 amelanotic39 and frequently present as polypoid lesions,40
which may initially be mistaken for haemorrhoids (especially
since the most frequent symptom is bleeding).41 42 In a recently
BASAL CELL CARCINOMA reported case series, 46 of 79 (58%) patients with malignant
In the (peri) anal region, basal cell carcinomas (BCCs) are uncom- anorectal melanoma were initially misdiagnosed with a benign
mon, comprising 0.2% of all anorectal neoplasms. The most fre- lesion.43 Therefore, it is not rare for patients to present with
quent site is close to the anal orifice, but very few cases extending locally advanced and metastatic disease (40%).42 Although anal,
into the anal canal have been reported.31 32 BCCs are a rare occur- anorectal and rectal melanomas differ in terms of presentation
rence in areas of non-sun-exposed skin, and other factors contrib- and patterns of recurrence, there appears to be no significant
uting to carcinogenesis in this region have been proposed, such as difference in terms of survival according to anatomical location
prior radiotherapy or chronic skin irritation.33 34 There appears to within the anorectum, and all patients face a dismal prognosis
be no association with HPV.35–37 The clinical course is fairly indo- with 5-year overall survival estimated to be at 20%, despite the
lent, without any metastatic lesions occurring in a large series of use of multiple treatment modalities including surgery, radio-
patients with BCC in the perianal and genital region (n=51, 30 therapy and systemic therapy.42
patients with 5 years’ follow-up).37 Histologically, BCCs are most In contrast to cutaneous malignant melanomas and mucosal
frequently of nodular type and the main differential diagnosis is melanomas of the head and neck, there is no pathological staging
that of basaloid SCC, which occurs far more frequently in this system for mucosal anorectal melanomas. Staging is performed
location, especially when found in the anal canal. Distinguishing according to clinical spread (stage I: clinically localised disease;
between these two entities may be challenging on biopsy material stage II: regional nodal involvement; stage III: distant metastatic
as some features (basaloid morphology with peripheral palisading) disease). The seventh edition of the Union for International
may overlap.32 37 The presence of intraepithelial squamous cell Cancer Control/AJCC classification system includes melanomas of
neoplasia is useful and strongly favours basaloid SCC as there is no the anal margin and perianal skin as cutaneous melanomas.5 44
well-defined precursor lesion in BCC. On the other hand, promin- Histologically, melanomas of the anorectum show the same
ent retraction artefact and lack of atypical mitotic figures are more morphological variability as elsewhere in the body, and the
in keeping with BCC. IHC may be used to help distinguish majority of cases demonstrate several morphologies.40
between these entities as BCCs are characterised by diffuse positiv- Histological features including lymphoma-like, spindle cell and
ity for BCL2 and BerEp4, and basaloid SCCs are usually positive pleomorphic cell types could be confused with lymphoma and or
for p16 and SOX2.32 sarcoma, but this is usually sorted out by immunohistochemical

Figure 5 Extramammary Paget disease. Nests and single atypical epithelial cells within the epidermis show pagetoid upward spread to the
keratinous layer (Fig 5 A). Hale colloidal iron for mucin is positive within the cytoplasm of these atypical cells (Fig 5 B). Immunohistochemical stains
show the atypical cells to be positive for CK18 (Fig 5 C), and negative for CK5 (Fig 5 D).
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Table 4 Poorly differentiated anal tumours: an (immuno-) histochemical approach

Tumour Mucin stains Melanocytic CK7/20 Neuroendocrine CD45/CD20 CK5/6, p63 Pankeratin

SCC − − (+)/− − − +/+ +

Adenocarcinoma + − +/− (anal gland) May be seen in a proportion − −/− +
−/+ (rectal-type) of tumours, MANEC
NEC − − −/(+) (dot-like: + (include chromogranin as − −/− +
Merkel, diffuse: MANEC) potential serum follow-up marker)
Undifferentiated carcinoma − − − − − − +
Melanoma − + − − − −/− −
Lymphoma − − − − + − −
SCC, squamous cell carcinoma; MANEC, mixed adenoneurocarcinoma.

work-up (table 4). An in situ component with junctional nests and only variable immunoreactivity for CK7 (if any), whereas
and intraepithelial spread is frequently found (60%) and particu- most anal-type adenocarcinomas will show an inverse staining
larly helpful in suggesting mucosal origin.40 pattern (CK20–, CK7+).
An important potential pitfall to keep in mind is that a signifi- The WHO reserves the term ‘undifferentiated carcinoma’ for
cant proportion (up to 60%) of anorectal melanomas may be malignant epithelial tumours that have no further morphological,
positive for CD117,41 45 much higher than melanomas of other (immuno-)histochemical or ultrastructural differentiation.14
primary sites. Although IHC has been shown not to correlate
with mutational status and therefore cannot be used as a surro- NEUROENDOCRINE TUMOURS
gate,46 functional KIT mutations appear to be far more frequent The presence of neuroendocrine cells in the anal canal opens
in primary anorectal melanomas in comparison to those meta- the possibility of neuroendocrine tumours in this location.52 53
static to the GI tract (35.5% vs 3.8%, p=0.004).45 Indeed, KIT Indeed, although rare neuroendocrine tumours of the anus do
driver mutations are much more prevalent in mucosal melano- occur (comprising 1.2% of all anal tumours in the Surveillance,
mas compared with cutaneous melanomas, where BRAF muta- Epidemiology, and End Results database54), these are conven-
tions, suggested to be due to UV-associated damage,47 are the tionally classified as rectal tumours according to the WHO and
most frequent driver mutation ( present in at least 60% of graded according to the 2010 WHO classification.14 Due to
cases). their rarity, not much is known about these tumours and how to
Although KIT mutations are relatively common among ano- manage them. Well-differentiated neuroendocrine tumours (G1
rectal melanomas, response to imatinib is presumably fair at or G2) appear to fare similarly to stage-matched SCCs, whereas
best, with reported durable responses in 16% of patients with neuroendocrine carcinomas (G3, both small and large cell)
KIT-mutated mucosal melanomas and a median time to progres- behave far more aggressively.54 Morphologically, well-
sion of 12 weeks in a phase II study,48 and most melanoma differentiated tumours show a typical nested appearance as else-
patients that respond initially develop resistance via secondary where in the GI tract, while neuroendocrine carcinomas are
mutations.49 characterised by brisk mitotic activity, apoptosis and necrosis.
Immunohistochemical markers to establish neuroendocrine dif-
ADENOCARCINOMA ferentiation include chromogranin A (which should always be
Adenocarcinomas of the anal canal can be classified as two main performed as it can be used as a serum marker of disease pro-
groups, arising either from the mucosal surface or extramucosal gression if secreted by the tumour), synaptophysin and less spe-
adenocarcinomas, namely those from anal glands and those cific neuroendocrine markers NSE and CD56.
arising in the lining of fistulous tracts.14 However, if considering In some cases, the differential diagnosis is that of poorly dif-
primary anal adenocarcinomas to arise within the histological ferentiated adenocarcinoma versus neuroendocrine carcinoma.
mucosa of the anal canal, namely the anal transitional zone or Some neuroendocrine carcinomas show focal glandular differ-
pecten, it becomes clear that this entity is indeed quite rare. entiation or diffuse CK20 positivity (interpreted by some
Many studies examining ‘anal adenocarcinomas’ have included authors as glandular differentiation).55 The WHO suggests the
tumours arising from the most distal colorectal mucosa, which arbitrarily set category ‘mixed adenoneurocarcinoma’ for cases
is covered by the sphincter muscles and therefore part of the with morphological evidence of at least 30% of each neuroen-
surgical anus, but considered to represent rectal-type adenocar- docrine and adenocarcinoma component.14 However, poorly
cinomas. In fact, many tumours coded as anal adenocarcinomas differentiated carcinomas with a glandular component may not
in the US national database were lesions overlapping the rectum routinely be investigated for neuroendocrine markers. Indeed,
and anus and therefore probably misclassified.50 Due to their a significant proportion of poorly differentiated adenocarcin-
rarity, the natural history of anal adenocarcinoma is poorly char- omas do show immunohistochemical positivity for neuroendo-
acterised and distinguishing among different subtypes is more of crine markers (23/44),56 and such mixed tumours are linked
academic interest. However, it has been observed that tumours with poorer prognosis than those without neuroendocrine
with haphazardly arranged small glands in the perianal stroma differentiation.56 57
with scant mucin and without a surface mucosal component are A few cases of Merkel cell carcinoma in the anal canal have
most likely of anal gland origin, whereas adenocarcinomas been described in the literature.58 59 Typically occurring on
arising from fistula tracts are most often of mucinous type.51 sun-exposed skin and therefore an unexpected finding in this
IHC can help distinguish between colorectal-type adenocarcin- location, these tumours show small cell morphology, and charac-
omas and those arising from anal glands, as tumours arising teristic ‘dot-like’ CK20 positivity in contrast to diffuse cytoplas-
from rectal mucosa typically show positivity for CK20, CDX2 mic staining seen in adenocarcinomas.55
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GASTROINTESTINAL STROMAL TUMOURS AND frequent and contribute to mucosal regeneration with hyperpla-
MESENCHYMAL TUMOURS sia and frequent serration of colorectal mucosa and ‘diamond’-
The anal canal is a rare site for gastrointestinal stromal tumour shaped crypts.69 Such regenerative changes may be so striking as
(GIST), comprising around 3–5% of all GISTs.60 61 They to cause confusion with adenomatous dysplasia71 or in the case
usually present as a mural nodule, and more rarely as a pelvic of proctitis cystica profunda, with invasive mucinous adenocar-
mass. The appearance and immunohistochemical profile of anal cinoma.72 To make matters more difficult, adenomas may also
GISTs is as is elsewhere in the GI tract and should not be a diag- undergo mucosal prolapse change. The use of p53 and Ki67
nostic problem if included in the differential diagnosis.62 immunostains highlighting areas of dysplasia in difficult cases
Virtually any mesenchymal tumour can present in the anus, and has been recommended.71
these are probably not different from identical tumours in other
locations. Hidradenoma papilliferum
These benign apocrine sweat gland tumours occur virtually
BENIGN TUMOURS AND TUMOUR-LIKE LESIONS exclusively in the female anogenital region and represent the
Fibroepithelial polyps most common adnexal tumour occurring in the perianal area.73
These soft fleshy polyps, also referred to as anal tags or hyper- Macroscopically, they present as subcutaneous nodules with a
trophied anal papilla, are the most common anal polyps and smooth to tan surface.74 Histologically, these tumours are iden-
arise from the anal papillae at the base of the columns of tical to their vulvar counterparts, with numerous papillary folds
Morgagni.63 Histologically, the epithelium is virtually always projecting into cystic spaces lined by a double layer of cells con-
hyper-keratotic and parakeratotic and serum lakes are often sisting of a luminal layer of tall columnar cells with apocrine-
found. type decapitation secretion and an outer layer of myoepithelial
Despite their frequency and benign clinical behaviour, some cells.75 Most tumours show immunoreactivity for oestrogen and
diagnostic pitfalls must be considered. For instance, multinu- progesterone receptor.73 It appears the vast majority of these
cleated stromal cells are seen in a large proportion of fibroe- apocrine tumours are benign and cured by local excision, inva-
pithelial polyps. Usually relatively small and innocuous, these sive apocrine adenocarcinoma having been described in a case
may be large and atypical in appearance like prominent nucleoli, report.75
but without mitotic figures, and these cells may be mistaken as
malignant by the unwary.63 Granular cell tumour
The epithelial component is also prone to misinterpretation. Arising from Schwann cells, granular cell tumours are relatively
For instance, in a recent case review, 40% polyps diagnosed as common benign tumours arising from Schwann cells and can
condyloma acuminata were reclassified as fibroepithelial polyps occur in many anatomical locations. In a case series of 75 granu-
with reactive epithelial change.64 Such reactive epithelial lar cell tumours in the GI tract, 16 (21%) occurred in the peri-
changes may frequently be mistaken for koilocytosis as superfi- anal region. The most common presentation is an incidental,
cial squamous cells can acquire abundant clear cytoplasm with asymptomatic, solitary mass.76 Histologically, granular cell
centrally placed nuclei. However, unlike true koilocytes, these tumours have a distinctive appearance with large polygonal cells
changes are usually widespread and may be accompanied by with small nuclei and abundant PAS-positive granular eosino-
serum lakes. philic cytoplasm. Immunohistochemically, tumour cells stain for
the lysosomal marker CD68 and S100.77 The most common
pitfall to be aware of is that many granular cell tumours, espe-
Haemorrhoids cially those in the perianal region, elicit an extensive pseudoe-
These are perhaps the most common tumour-like lesions in the pitheliomatous reaction of the overlying squamous epithelium,
anus and arise from abnormal dilatation of the venous plexus. which may even be misdiagnosed as SCC.76
This may be caused by elevated intra-abdominal pressure of any
sort (straining at defecation, constipation, diarrhoea, during Perianal cysts
pregnancy). They may be external (originating distal to the A wide variety of developmental and acquired cysts may affect
dentate line and covered with squamous mucosa) or internal the perianal region, including anal duplications, anal duct cysts,
(originating proximal to the dentate line and covered by ATZ or median raphe cysts, (epi)dermoid cysts, teratoma or tailgut cysts.
colorectal-type mucosa). Surgical treatment is offered after Many of these entities are more prevalent in childhood, but
symptomatic and conservative treatments fail.65 The main issue adults may be affected.78 As clinical presentation may be highly
is to ensure that all surgical specimens are examined histologi- variable, initial misdiagnoses are common. They may present as
cally, to exclude incidental findings such as intraepithelial neo- a polyp79 or undergo secondary infection with abscess or for-
plasia or more serious conditions such as anal melanoma and mation of a fistula tract.78 80 Most lesions are benign and cured
carcinoma, which may masquerade as haemorrhoids.66 67 by surgical removal, but malignant transformation can occur.78

Inflammatory cloacogenic polyps INFLAMMATORY DISORDERS

These polyps, usually located on the anterior wall of the anal Fistulas and abscesses
canal, arise from the transitional zone of the anus in the setting Although anal fistulas and abscesses occur in the setting of Crohn’s
of chronic injury and are one of the many manifestations of disease, most cases are actually idiopathic. Cryptoglandular infec-
mucosal prolapse, along with inflammatory cap polyps, colitis tion provides a pathway from the anal canal to the perineal soft
cystica profunda or solitary rectal ulcer syndrome.68–70 tissues and appears to be the most likely cause.81 The acute phase
Histological features include thickening of the muscularis will present as an abscess, whereas fistula tracts tend to form in
mucosae with extension of muscle strands into the lamina more chronic stages.82 For management purposes, anal fistulas can
propria and the presence of elastin fibres in the mucosa. The be classified as simple or complex and divided into five types
surface epithelium is composed of a combination of colorectal, based on the involvement of the anal sphincter muscles: submuco-
transitional and squamous mucosa. Ischaemic changes are sal/superficial, intersphincteric, transsphincteric, suprasphincteric
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and extrasphincteric.83 The surgical technique will vary according

to anatomical presentation and is usually curative for patients with
idiopathic fistulas.
Resection specimens show acute and chronic inflammation,
fibrosis and granulation tissue, and foreign body-type granu-
lomas are often seen. These must be distinguished from the
tight, epithelioid granulomas seen in Crohn’s disease and not
interpreted as such. Although most cases will be idiopathic, the
differential aetiologies of infection or inflammatory bowel
disease should be entertained, meriting careful review of patient
history and, if appropriate, special stains for microorganisms
(see below).

Hidradenitis suppurativa
This condition, also known as acne inversa, affects areas with
apocrine sweat glands (axillary, perianal, inguinal and mammary
region). Originally believed to be an infectious disease of the Figure 6 Crohn’s disease of the anal canal. Epithelioid granuloma
apocrine glands, its aetiology is still under debate. Recent formed by epithelioid macrophages and a multinucleated giant cell,
studies have suggested a follicular origin in apocrine gland- surrounded by a rim of lymphocytes.
bearing areas of the body, beginning with follicular plugging
and subsequent occlusion and rupture of the pilosebaceous unit.
inguinale and tuberculosis, all of which may masquerade as
Environmental factors, such as smoking, obesity, hormonal
Crohn’s disease clinically.92–94
status, obesity and genetic susceptibility, have been suggested to
play a role.84 85 The diagnosis is usually based on its typical clin-
Common infectious disorders of the anal canal
ical presentation with multifocal lesion distribution, sinus for-
The anal region is subject to a variety of infections, and indivi-
mation (which may be mistaken for perianal fistulas), multiple
duals that engage in anal sexual intercourse are at highest risk,
open comedones, painful nodules and odorous discharge.86 If
as the most common pathogens are sexually transmitted and
biopsied or resected, common histological findings are poral
often coexist with HIV. The last decade has seen resurgence of
occlusion, folliculitis, abscesses, scarring and formation of sinus
many of the infectious diseases discussed here, along with
tracts. Apocrine glands and apocrinitis may be present but are
HIV.95 Symptoms are highly variable, the most common presen-
not always found, supporting the notion that apocrine gland
tation being the frequent urge to defecate, but may mimic
involvement is a secondary manifestation.87
inflammatory bowel disease or be completely absent.95–97

Inflammatory bowel disease Gonorrhoea

Involvement of the ( peri-)anal region is common in patients suf- The Gram-negative diplococcus Neisseria gonorrhoea is the cause
fering from Crohn’s disease, and manifestations occur in the of this condition, which constitutes around 30% of infectious
form of anal fissures, ulcers, abscesses and fibroepithelial proctitis. Rectal gonorrhoea is often latent, and when suspected,
polyps.88 89 At least 50% of patients with Crohn’s disease will bacterial culture is the diagnostic method of choice, as about 20%
develop anal or perianal disease at some point,88 90 for which of culture-positive patients have no endoscopic abnormality98 and
the risk increases with site of involvement, and up to 90% of normal biopsy specimens are seen in >50% of patients with con-
patients with rectal involvement will also have involvement of firmed disease.99 Inflammation affects the rectal type mucosa at
the anal canal.91 Anal involvement in patients with ulcerative the proximal end of the anal canal and histological alterations
colitis tends to be restricted to rectal mucosa in the proximal include a mild increase in plasma cells and lymphocytes, and only
anal canal92 without involvement of the ATZ. Unfortunately, all 5–10% of patients show features as seen in acute infectious colitis,
of the above-mentioned conditions are by no means confined to with preservation of crypt architecture and accumulation of neu-
Crohn’s disease and occur frequently in the non-colitic popula- trophils in the lamina propria.100 101
tion. The pathologist must be aware of this limitation when
examining specimens for ‘query Crohn’s’ as the morphology of Chlamydia and lymphogranuloma venereum
specimens may not differ between the two patient groups. Chlamydia trachomatis (serovars D–K) target the rectal mucosa,
Epithelioid granulomas close to the anal mucosa support whereas serovars L1, L2 and L3 cause the systemic disease lym-
the diagnosis of Crohn’s disease but are not always present phogranuloma venereum. Chlamydial proctitis is asymptomatic
(figure 6). Numerous lymphoid aggregates similar to the trans- in 2/3 of cases, and when symptoms do appear, they are gener-
mural lymphoid aggregates as seen in the large and small bowel ally mild and include pruritus, mucoid discharge and perianal
are even more suggestive of Crohn’s disease.1 The pain.102 The diagnosis is made by rectal swab culture. Both
co-occurrence of several abnormalities is also typical of Crohn’s endoscopically and histologically, the main differential diagnosis
disease.88 Therefore, just as for other sites of the GI tract, the of chlamydial proctitis for pathologists to be aware of is that of
diagnosis of Crohn’s disease should take into consideration all inflammatory bowel disease, as marked architectural distortion
available clinical, endoscopic and radiological findings. as a regenerative phenomenon can be seen along with epithe-
When encountered with granulomatous inflammation in anal lioid granulomas and marked lymphoid hyperplasia.103 104
lesions, it is important to keep differential diagnoses in mind, Lymphogranuloma venereum takes on a more serious multistage
which include foreign body reaction in fistulas occurring in the clinical course with suppurative inguinal lymphadenopathy, and
non-colitic patient (frequent) but also sarcoidosis and infectious systemic features including fever, arthralgia, myalgia and finally,
diseases such as lymphogranuloma venereum granuloma strictures and fistula formation.97 105
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Syphilis combination with endarteritis, may lead to the correct diagnosis if

In the anal region, syphilis affects the squamous epithelium of the recognised. Secondary lesions (condyloma lata) have less character-
perianal area and the anal verge. Primary lesions (chancres) are istic features and can mimic a variety of dermatological conditions
suspected clinically and diagnosed without biopsy,106 so cases seen including lymphoma (earning its name as the ‘great mim-
by pathologists are usually not straightforward. In this disease icker’).107 108 Dark field microscopy of exudates and Warthin–
stage, the presence of abundant plasma cells, especially in Starry histochemical stains may be false positive due to commensal
spirochetes found in the physiological flora of the colorectum.
During the past few years, immunohistochemical antibodies spe-
cific to Treponema pallidum have become available and should be
the stain of choice for histological specimens.109 110

Herpes simplex
As in other sites, herpes simplex virus (HSV) infections are asso-
ciated with small vesicles that ulcerate. HSV2 is far more common
than HSV1, but symptoms and pathology are identical.111 112 In
the case of anorectal herpes infection, an HIV test should be per-
formed given the association between the two diseases.112 As is
the case with syphilis, the virus affects the squamous epithelium of
the perianal mucosa. If suspected clinically, the diagnosis may be
made with culture of vesicle fluid or PCR-based assays. On hist-
ology, typical viropathic changes (Cowdry type A inclusions, multi-
nucleation, ground-glass chromatin) are best found in the
epithelium at the edge of an ulcer. If needed, the presence of the
virus may be confirmed by immunohistochemical stains for HSV1
and HSV2 (figure 7A–C).

SUMMARY
Tumours of the anal canal and perianal region are rare and fre-
quently clinically misdiagnosed. As biopsy will often lead to the
correct diagnosis, pathologists play an important role in subse-
quent management of lesions in this area. Tumours are also fre-
quently found in clinically innocuous lesions, and it must be
ensured that all resected specimens are examined histologically.
Although squamous cell neoplasia, which has recently under-
gone a terminological ‘makeover’, is by far the most frequent
lesion in this area, it is important to be aware of certain pitfalls
and other entities that may be encountered as they will other-
wise be wrongly diagnosed or missed completely. This applies
not only to tumours but also to inflammatory conditions that
may be prone to misinterpretation. Knowledge and awareness
of the most common diagnostic pitfalls as outlined in this
review and an approach to resolving difficult issues should help
to avoid such errors.

Take home messages

▸ The pathology of the anal canal includes neoplastic and

inflammatory conditions.
▸ LAST Committee recommends the use of a two-tiered system
to classify squamous dysplastic lesions of the anal and
perianal region.
▸ Immunohistochemistry for p16 may be helpful in
distinguishing dysplastic changes from benign mimickers of
precancers.
Figure 7 Herpes simplex virus (HSV) infection in a patient treated ▸ Adenocarcinomas of the anal canal may arise from both the
with neoadjuvant therapy for rectal adenocarcinoma. The mucosal colonic mucosal surface or extramucosal structures including
surface is ulcerated with granulation tissue and embedded squamous anal glands and lining of fistlous tracts. Immunohistochemistry
epithelial cells with ballooning degeneration, multinucleation, may be helpful to distinguish these different conditions.
ground-glass nuclei with marginated chromatin and eosinophilic ▸ Inflammatory conditions mainly include inflammatory bowel
nuclear inclusions (Cowdry type A inclusions) (A, B). The squamous disease and infectious etiologies.
cells infected are immunoreactive for HSV (C).

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Handling editor Cheok Soon Lee 28 McCarter MD, Quan SH, Busam K, et al. Long-term outcome of perianal Paget’s
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Dawson H, Serra S. J Clin Pathol 2015;68:971–981. doi:10.1136/jclinpath-2015-203056 981

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