- Email: [email protected]
Polyps and polypoid lesions of the anus
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Polyps and polypoid lesions of the anus
working knowledge of the embryology and the basic anatomical compartments is essential for accurate reporting of anal specimens. The proximal portion of the anus is derived from the endodermal hindgut and the distal portion from the ectodermal proctodeum.3 The dentate (pectinate) line represents the point of fusion of these structures and also roughly corresponds to the mid point of the anal canal. It is an important landmark as the lymphatic’s proximal to the dentate line drain to the inferior mesenteric lymph nodes, whereas the distal drainage is to the internal iliac and inguinal nodes.2 The endodermal hindgut has a larger calibre than the proctodeum and as such the anus above the dentate line is thrown into folds to accommodate this discrepancy. These folds are recognized as the columns of Morgagni and the intervening anal crypts. Anatomically the anus begins at the level of the levator ani muscle and ends 5 cm external to the anal verge. The anus is then divided into three key regions namely; the anal transformation zone (ATZ), encompassing the 1e2 cm of mucosa proximal to the dentate line; the intra-anal compartment, extending from the dentate line to the anal verge and the perianal region which extends 5 cm external to the anal verge. The anal canal includes the transformation zone and the intra-anal compartment and is about 4 cm in length. Precise localization of anal pathology is of critical importance. In particular, the management of peri-anal lesions can be vastly different to intra-anal lesions. Confusion tends to occur when a lesion crosses an anatomical boundary. Currently, if a lesion cannot be completely visualized with gentle traction on the buttocks it is considered to be intra-anal. If a lesion can be completely visualized with gentle traction on the buttocks then it is considered to be peri-anal.4
Mark Bettington Ian Brown
Abstract Anal polyps are a relatively rare and neglected part of pathology practice. Similar to other parts of the gastrointestinal tract, anal polyps are predominantly epithelial in origin, but mesenchymal lesions do occur. The aetiology of anal polyps is diverse and includes infectious, reactive, developmental and neoplastic conditions. Thus an awareness of the clinical scenario can be very informative in difficult cases. Diagnostic pitfalls are perhaps more common than is generally realized and misdiagnosis can have important management and social implications. Herein, we discuss the most common and interesting anal polyps and polypoid lesions with a particular focus on diagnostic pitfalls. Careful attention to the clinical scenario and histological features, along with judicious use of immunohistochemistry will resolve most diagnostic dilemmas.
Keywords anus; diagnosis; human papilloma virus; pathology; polyps
Introduction Anal polyps are uncommon, accounting for significantly less than one percent of gastrointestinal (GI) polyps. As such they are a neglected part of pathological practice. Recently there has been a renewed interest in anal pathology, driven largely by the rise in human papilloma virus (HPV) related anal pathology. A byproduct of anal surveillance for HPV is the increasing identification of incidental anal lesions that then require pathological diagnosis. Usually these diagnoses are straightforward; however some entities create diagnostic dilemmas. This review focuses on the more common polyps and polyp-like lesions of the anus and particularly emphasizes areas where misdiagnosis occurs.
Anal histology The upper extent of the anus is composed of rectal type mucosa. This quickly changes to the ATZ, which represents the transition from glandular rectal type mucosa to squamous anal mucosa. The transition zone itself is lined by a metaplastic squamous epithelium that resembles urothelium. The ATZ ends at the dentate line to become non-keratinizing squamous mucosa. The squamous mucosa of the intra-anal compartment is devoid of adnexal structures and this allows distinction from the peri-anal skin that begins at the anal verge. Melanocytes are present in the squamous mucosa of the intra-anal compartment and in lesser numbers in the ATZ but are not normally present in rectal type mucosa.5 The anal ducts enter the anus via the anal crypts just proximal to the dentate line. The anal glands are lined by stratified columnar epithelium and are most often found in the submucosa of the anterior anus.
Anal embryology and anatomy The anus is an anatomically and embryologically complex region and a comprehensive discourse of these topics is beyond the scope of this review. We refer interested readers to excellent dedicated reviews of the subjects by Pandey and Dujovny et al.1,2 However, a
Mark Bettington BSc MBBS FRCPA The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Envoi Specialist Pathologists, Brisbane, QLD, Australia. Conflicts of interest: none.
Anal polyps For the purposes of this review we divide the discussion into; 1. ‘true’ anal polyps, that is, lesions that essentially always present as a discrete elevated lesion, and 2. ‘polypoid’ anal lesions, that is, lesions that can present as a polyp or polyp-like mass in some patients but can also present as non-discrete mass lesions. Table 1 represents a comprehensive list of entities that can theoretically present as an anal polyp, only the more relevant of these will be discussed.
Ian Brown BGEN MBBS FRCPA Envoi Specialist Pathologists, Brisbane, QLD, Australia; Department of Anatomical Pathology, Central Laboratory, Pathology Queensland, Brisbane, QLD, Australia. Conflicts of interest: none.
DIAGNOSTIC HISTOPATHOLOGY 20:1
38
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
arise from the anal papillae at the base of the columns of Morgagni. This occurs on a background of chronic injury and inflammation. In particular, fissures of the anal valves are frequent antecedents to FEPs, and thus they are common in patients with Crohn’s disease.
All entities that can potentially present as an anal polyp Entity
Neoplastic Epithelial Squamous cell carcinoma Adenocarcinoma Adenoma Neuroendocrine carcinoma Basal cell carcinoma Adnexal type tumours Mesenchymal Neurofibroma Granular cell tumour Lipoma Fibrolipoma Lymphangioma Kaposi sarcoma Angiosarcoma Aggressive angiomyxoma Leiomyoma/sarcoma Fibrohistiocytic Inflammatory fibroid tumour Gastrointestinal stromal tumour Melanoma Haematolymphoid Non-neoplastic lesions Fibroepithelial polyp Inflammatory cloacogenic polyp Haemorrhoids Endometriosis Heterotopia (prostate, breast, gastric) Amyloid Infectious HPV (condyloma accuminatum) Treponema pallidum (condyloma lata), Granulomatous (Mycobacterium tuberculosis, Enterobius) Cysts Epidermoid, dermoid, tailgut, median raphe, anal gland, duplication
Presentation Presentation in the anus as a polyp
þþþ þ þþ þ þ þ
þþ þ þþþþ þ þþþ þþ
þ þ þ þ þ þ þ þ þ þ þ þ
þþ þþþ þþ þþ þþþ þ þ þþ þþþ þ þþ þþ
þþ þ
þþ þ
þþþþ þþþ
þþþþ þþþþ
þ þ þ
þþ þ þþþ
þ
þ
þþþ þ
þþþ þ
þ
þ
þþ
þþ
Clinical findings: the majority of FEPs come to clinical attention because of local irritation related to incontinence and discharge. Rarely they can bleed secondary to trauma. They may be attached to the surrounding mucosa by either a narrow pedicle or a broad base. Pathological features: FEPs are variable in size and are soft and fleshy when in situ. They are lined by non-keratinizing squamous epithelium. Because they are subjected to recurrent trauma, areas of hyper and parakeratosis are universal and ulceration will sometimes be present. Serum lakes are often seen in the superficial layers of the epithelium and are useful diagnostically, as this feature is rare in condylomata. The stroma is variable; in most it is myxoid with abundant ectatic vessels, however over time it becomes pauci-cellular and collagenized.6 The myxoid appearance is more prominent in subepithelial regions. At the base of FEPs, vessel walls may exhibit hyaline change, but no true vasculitis. Bi or multinucleate atypical stromal cells can be identified in many cases. CD34 is characteristically expressed in these cells and they are reactive for desmin in one third of cases, but are of no significance. Most cases contain some smooth muscle that is usually continuous with the underlying muscularis mucosa. An infiltrate of Mast cells is often present but unless ulcerated or arising in a setting of Crohn’s disease, significant inflammation is not seen. FEPs sometimes arrive with a clinical query of Crohn’s disease. The only histological feature useful in this distinction are granulomas, which are reported in 30% of patients with Crohn’s disease but never in patients without (Figure 1).7 Diagnostic pitfalls: despite the general lack of interest surrounding FEPs, problems with diagnosis are surprisingly common. In particular, over-diagnosis of reactive epithelial changes as HPV-induced koilocytosis is a recurring issue. In response to injury, the superficial squamous cells of FEPs can develop voluminous clear cytoplasm, accompanied in some cases by centrally placed nuclei. This can be erroneously interpreted as koilocytosis, leading to the diagnosis of condyloma acuminatum. This is not a trivial mistake, as it may result in inappropriate follow-up and treatment and can also have significant social implications. In one series, 40% of polyps diagnosed as condyloma acuminata of the anus were actually FEPs.8 Attention to the architectural and cytological features helps avoid this misdiagnosis. FEPs do not have the verrucous pattern of a condyloma acuminatum and lack the genuine HPV-induced nuclear changes, such as binucleation, chromatin margination, nuclear indentation and central clearing. True HPV effect in FEPs is exceedingly rare and probably only occurs in the setting of HPV in the adjacent anal epithelium. In unresolved cases, immunohistochemistry can be applied. Ki67 staining will typically be negative in the upper two thirds of the epithelium in FEPs, whereas condyloma will usually show some positive staining in the upper layers. P16 is generally not helpful as it will usually be negative in both lesions.
þ Rarely; þþ sometimes; þþþ usually; þþþþ essentially always.
Table 1
True anal polyps Fibroepithelial polyp The fibroepithelial polyp (anal tag, hypertrophied anal papilla) is the most common anal polyp. They are non-neoplastic and typically
DIAGNOSTIC HISTOPATHOLOGY 20:1
39
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
glandular and squamous mucosa should be evident at least focally, but glandular mucosa predominates in most. At low power the polyps maintain a regular architecture, with even spacing of the crypts and without cribriform or complex growth patterns. Cystically dilated glands are frequent and diamondshaped crypts are a fairly characteristic feature. It is also common to see nests of displaced glands in the submucosa.9 Generally, these are easily recognized as benign by their rounded contour, accompanying lamina propria and the narrow gap in the muscularis mucosa. This contrasts with the irregular infiltration of malignant glands surrounded by desmoplastic stroma. The surface may show areas of erosion or ulceration. In some cases this can take on the ‘volcano-like’ pattern of injury more typically associated with Clostridium difficile toxin. This pattern of injury can of course be seen in any type of ischaemic mucosal injury and is not restricted to C. difficile. The lamina propria shows various degrees of fibromuscular consolidation and lymphoplasmacytic and histiocytic inflammation. In areas of erosion and ulceration an acute inflammatory component will also be present. The cytology of ICPs is typically bland. Goblet cells are preserved and there is obvious maturation from the crypt bases to the luminal surface. Mitoses are regular and mostly confined to the basal aspects of the crypts.
Figure 1 A fibroepithelial polyp with large numbers of granulomas in a patient with Crohn’s disease.
When stromal oedema is prominent, FEP may be confused with superficial angiomyxoma or aggressive angiomyxoma. Common expression of CD34 (and desmin in the case of aggressive angiomyxoma) can further confuse the issue. Careful attention to the clinical setting, lack of an infiltrative border and presence of multinucleate cells aids separation of FEP from aggressive angiomyxoma, while absence of a lobulated architecture, epithelial inclusions and neutrophil infiltration is against superficial angiomyxoma.
Diagnostic pitfalls: over-interpretation of reactive epithelial changes as neoplastic is the most common pitfall. This invariably occurs adjacent to areas of erosion and ulceration, thus caution is warranted when assessing the cytology in these areas. Paying attention to the preserved architecture at low power is helpful. Also, the reactive epithelium will merge gradually with the surrounding, obviously benign epithelium, rather than having an abrupt transition as in true dysplasia. The presence of maturation and a high nuclear to cytoplasmic ratio are also useful clues to the reactive nature. In difficult cases immunohistochemistry can be helpful. Reactive lesions are typically negative for p53 and Bcatenin.10 Dysplasia will often show the opposite pattern. When the staining is equivocal, reliance on the histological appearance is appropriate. Similar to the above, over-interpretation of displaced glands in the submucosa can be misinterpreted as invasive malignancy. This usually occurs in small biopsies where the overall benign architecture of the displaced glands cannot be appreciated. Recognition of the benign cytology along with accompanying lamina propria is helpful, remembering that the lamina propria often shows fibromuscular consolidation. Immunohistochemistry as above can also be applied. In contrast to the above, ICPs can rarely harbour genuine neoplastic elements. These can be glandular or squamous in origin.10,11 Adenomatous elements can be recognized by loss of the normal architectural pattern, with crowding and effacement of crypts. The dysplastic glands have a top-down arrangement, with the most atypical and mitotically active cells at the luminal surface. Immunohistochemistry will be opposite to the benign mucosa described above. Squamous dysplasia shares the same aetiology and nomenclature as for anal intraepithelial neoplasia (AIN), discussed further below. Reactive squamous metaplasia can closely mimic high-grade squamous dysplasia. In these instances immunohistochemistry for p16 can be very useful, with block positive staining strongly favouring high-grade dysplasia.
Treatment: management depends on the clinical scenario but treatment of any underlying inflammatory condition is warranted. If they become overly irritating, simple excision at the base is curative, although there is a risk of post-operative complications, such as infection and incontinence. Inflammatory cloacogenic polyp Lobert and Appleman first described the inflammatory cloacogenic polyp (ICP) in 1981.9 They arise in the setting of chronic injury, probably secondary to mucosal prolapse. They are more frequent in the developed world, possibly due to low-fibre diets. They have a close aetiological and histological relationship to the mucosal prolapse syndrome and the two entities may represent spectrums of the same disease. In contrast to the mucosal prolapse syndrome, ICPs present as a distinct polypoid mass, rather than a flat erythematous or ulcerated area. ICPs are relatively uncommon lesions, representing less than one percent of lower gastrointestinal tract polyps. Clinical and endoscopic findings: ICPs occur in middle aged to elderly patients of both sexes. They can present with episodic per rectal bleeding or mucoid discharge but are frequently asymptomatic. The polyps are usually palpable at the extent of digital examination. Early lesions are more often anterior, but advanced lesions can be circumferential. At endoscopy they appear as broad based masses of the ATZ. Erythema and foci of ulceration can easily give an endoscopic impression of malignancy. Pathological features: specimens received by pathology are typically either biopsy fragments or polypectomy specimens. Grossly they appear as erythematous and often oedematous masses. Histopathological assessment demonstrates the nonneoplastic nature of these polyps. Components of both
DIAGNOSTIC HISTOPATHOLOGY 20:1
40
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Diagnostic pitfalls: diagnostic issues are rare. While misdiagnosis of FEPs as condyloma acuminata is relatively common, the converse is unusual. Ensuring that foci of high-grade dysplasia are identified is important, as this will impact patient management. Finally exclusion of a verrucous carcinoma is required. In the anus they are also known as the BuschkeeLowenstein tumour or as giant condylomata (Figure 2A). Although these lesions are also associated with the low risk HPV genotypes 6 and 11, they are locally destructive tumours. The invasive front is broad based and the cytology is indistinguishable from a typical condyloma, making diagnosis on biopsy specimens difficult or impossible (Figure 2B). In excision specimens, clinical and macroscopic evidence of local invasion are helpful in making the correct diagnosis. Thorough sampling is essential as foci of overt squamous cell carcinoma may arise in these tumours. Identifying such foci is important, as pure verrucous carcinomas have very limited or no metastatic potential.
Careful assessment for invasive malignancy is of course warranted when true neoplastic elements are seen. Overall, it is worth remembering that true neoplasia in ICPs is very unusual and as such careful exclusion of a non-neoplastic mimic should be conducted prior to making such a diagnosis. Treatment: management depends on the clinical setting and the nature of the polyp. Asymptomatic cases can be observed with dietary and lifestyle advice to minimize further mucosal prolapse. If symptomatic and not responding to other measures, local resection is typically performed. This can be either endoscopic or transanal depending on size and local preference. In rare cases of severe, treatment refractory disease, proctectomy may be offered. Condyloma acuminatum Condyloma acuminata (anal warts) are common anal polyps that arise in the setting of HPV infection. Infection is typically, but not invariably, with a low risk genotype. Receptive anal intercourse, immunosuppression and other lower anogenital tract HPV infection are key risk factors for HPV-related anal pathology.12
Treatment: treatment options depend on size, location and local preference. A range of topical treatments are available, or else simple excision can be performed.12 Importantly, none of the treatments will eradicate the HPV infection and as such, ongoing surveillance is warranted. Peri-anal condylomata are the most
Clinical features: condylomata are frequently multiple and can occur in all compartments of the anus but most often present around the anal verge. They are variable in size, ranging from a few millimetres to several centimetres. Patients typically present due to local irritation or with concern relating to the growth. Examination of the entire lower anogenital tract is warranted in these patients to exclude synchronous disease at other sites. Pathological features: grossly, they are pale, fleshy, exophytic lesions. They often occur in clusters and are quite friable. Histologically they have a verrucous growth pattern and because they are prone to trauma, the surface frequently shows parakeratosis and a granular layer. At high power the epithelium is normally bland but koilocytes are usually readily identified. Mitoses rarely extend above the basal third of the epithelium. However, in around 15% of cases, condylomata harbour highgrade dysplasia and this usually indicates co-infection with a high risk HPV genotype(s).13 In our experience, condylomata with high-grade dysplasia tend to occur at the ATZ. Invasive squamous cell carcinoma is rare but must be excluded. Terminology surrounding condylomata continues to be controversial. It is now accepted that all HPV driven lesions require a designation regarding degree of dysplasia. Similar to the cervix, the competing terminologies are low-grade and high-grade squamous intraepithelial lesion (LSIL and HSIL) versus anal intraepithelial neoplasia (AIN) grades 1e3. LSIL corresponds to either koilocytosis or AIN 1 and HSIL corresponds to AIN 2&3. Many authorities now consider AIN 2 to be an indeterminate diagnosis requiring further workup with p16 immunohisto chemistry.14 P16 positive AIN 2 is diagnosed as HSIL, whereas p16 negative AIN 2 is downgraded to LSIL. In concordance with the recommendations of the recent lower anogenital squamous terminology (LAST) project paper15 we prefer the SIL terminology, as it is biologically more meaningful. LSIL correlates with low-risk HPV genotypes and carries a negligible risk of malignant progression; in contrast HSIL correlates with high-risk genotypes and has a significant risk of malignant progression. In practice, we report both terminologies. The majority of condylomata, particularly of the anal verge or peri-anal region are low-grade.
DIAGNOSTIC HISTOPATHOLOGY 20:1
Figure 2 (a) Cut section of a verrucous carcinoma showing the broad based nature of the invasive front and (b) the corresponding histological section.
41
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
easily managed, as the risk of complications is minimal. Intra-anal lesions are more problematic, particularly for surgeons, as postoperative scarring can result in anal stenosis. High-resolution anoscopy may be performed to detect synchronous flat AIN, particularly if high-grade dysplasia has been diagnosed elsewhere. Colorectal adenoma Conventional adenomas sometimes occur in the rectal type mucosa of the proximal anus. In particular we find that traditional serrated adenomas have a propensity to arise at this site. The diagnosis of these polyps is no different to elsewhere in the colorectum. Some patients with previous proctocolectomy will develop conventional adenomas in the strip of rectal mucosa left after surgery. This is of particular relevance to surveillance of patients after prophylactic proctocolectomy for a polyposis syndrome. We have also encountered conventional adenomas in the remnant rectal cuff of mucosa following proctocolectomy for ulcerative colitis. Condyloma lata The condyloma lata is now a very rare anal polyp and represents a cutaneous manifestation of secondary syphilis. Patients typically present with a painless, flat-topped polypoid lesion (Figure 3A). In many instances the diagnosis is not suspected clinically, making pathological diagnosis extremely challenging. The lesions show psoriasiform epidermal hyperplasia overlying a heavy mixed inflammatory infiltrate rich in plasma cell, lymphocytes and histiocytes (Figure 3B). A peri-vascular distribution may be evident and in occasional cases obliterative endarteritis and granulomas may be seen. The diagnosis is confirmed by the demonstration of spirochaetes in the lesion. The spirochaetes are typically present in large numbers and are located in the squamous epithelium. A silver stain, such as a Warthin-Starry is usually adequate to identify the spirochaetes (Figure 3C), but more recently an immunohistochemical stain for Treponema pallidum has become available and has a better specificity.
Polyp-like lesions of the anal tract Figure 3 (a) Low power view of a condyloma lata showing the flat-topped nature of these polyps with psoriasiform hyperplasia of the epidermis and heavy dermal inflammatory infiltrate. (b) High power of the heavy lymphoplasmacytic and histiocytic inflammation. (c) High power of the WarthineStarry stain showing large numbers of spirochaetes in the epidermis.
Melanoma The anus is a leading site for mucosal malignant melanoma. They arise from the native anal melanocytes and pass through an in situ phase the same as for cutaneous melanoma. Also in parallel with the their cutaneous counterparts, most anal melanomas go through a nodular phase of invasive growth and this is the point when they may present as an anal polyp or be confused with a haemorrhoid. The prognosis for anal melanoma is poor, with a five-year survival of around 20%.16
mixed pattern and tumour giant cells are fairly common. They are usually thick (mean 8.9 mm)16 and mitotically active at diagnosis and pigment is generally obvious. By immunohistochemistry the tumours stain for the usual melanoma markers, of S100, Melan-A and HMB45. Mucosal melanoma has a higher rate of CD117 immunohistochemical expression (27e40%)17,18 than cutaneous melanoma and this can create confusion with a gastrointestinal stromal tumour (GIST) if unwary. Conversely, only about 5% of mucosal melanomas harbour BRAF mutations.17,18
Clinical presentation: because they are not usually visible, anal melanomas present late compared to cutaneous melanoma. They come to attention once local symptoms such as PR bleeding, pain or obstruction develop. Pathological features: the gross appearance depends on the size at diagnosis, but they can present as a black polypoid nodule, although up to 20% are amelanotic. The histological appearances are similar to cutaneous melanomas. The tumours can display an epithelioid, spindled or
DIAGNOSTIC HISTOPATHOLOGY 20:1
Diagnostic pitfalls: the diagnosis of anal melanoma is not difficult provided adequate tissue is received. In poorly differentiated
42
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Unlike other sites, leiomyosarcoma is probably more common in the anus than leiomyoma. Both tend to present as a polyp, with leiomyosarcoma having a particular tendency to bulge into the lumen.20 The histology is the same as for smooth muscle neoplasms elsewhere. Immunohistochemical expression of smooth muscle markers and absence of staining for CD117 separate of these very rare neoplasms from the more common GIST, as discussed above.
cases without an in situ component, immunohistochemistry will usually be required, but will easily differentiate melanoma from the usual differential diagnoses of poorly differentiated adenocarcinoma, poorly differentiated squamous cell carcinoma, neuroendocrine carcinomas and high-grade lymphomas. GIST can occasionally be confused with spindle cell predominant malignant melanoma, particularly if the melanoma is CD117 positive. Recognition of pigment or an in situ component, are morphological clues to the correct diagnosis and application of appropriate immunohistochemistry will ensure the correct diagnosis.
Basal cell carcinoma Basal cell carcinoma (BCC) of the anus is very rare, accounting for less than 0.2% of anal tumours.21 It presents similarly to lesions on the sun-exposed skin as a raised nodule often with central ulceration. Anal BCCs are restricted to the perianal region, although if neglected can involve the anal canal. The major clinical and pathological dilemma is distinction of the very favourable BCC from the much more aggressive basaloid SCC. Anal BCCs are histologically analogous to BCCs at sun-exposed locations and will not be further elaborated here. Most important is the distinction from basaloid SCC. In the recent study of Patil et al, retraction artifact and lack of atypical mitoses are histological features that favour a BCC.21 In contrast, an in situ component confirms a basaloid SCC. By immunohistochemistry a BerEP4 and Bcl2 positive and p16 negative immunoprofile is very likely to represent BCC.21 p16 is the most helpful of these markers.
Treatment: there is a tendency towards wide local excision rather than abdominoperineal resection, as survival rates for both groups are similar,19 but in some advanced cases, local control cannot be achieved without radical surgery. Postoperative treatment options are limited and typically reserved for patients with either lymph node involvement or widespread metastasis. As mentioned, mucosal melanomas are more frequently CD117 positive and this predicts response to treatment with tyrosine kinase inhibitors such as imatinib. BRAF mutation is rare in mucosal melanoma and as such vemurafinib is rarely indicated. Gastrointestinal stromal tumour GISTs are the most common mesenchymal tumour of the gastrointestinal tract. They most often develop in the wall of the stomach or small bowel, with oesophagus and anus being the least common sites. That said, anal GISTs are well recognized and can be diagnostically troublesome when they occur in this unusual location.
Hidradenoma papilliferum Hidradenoma papilliferum (papillary hidradenoma) are derived from either ectopic breast tissue or apocrine adnexal glands. They are more frequently associated with the lower female genital tract but can occur in many locations, including the perianal region. They present as either a cutaneous nodule or as an ulcerating lesion. Hidradenoma papilliferum are well circumscribed and rarely larger than 20 mm. They are benign and local excision is curative. Histologically, hidradenoma papilliferum is characterized by a papillary growth pattern. The papillary fronds are lined by a double-layered epithelium analogous to the normal breast.
Clinical presentation: anal GISTs usually present as a mural nodule. In some instances there will be ulceration of the overlying mucosa. They may also present as a pelvic mass or as a lesion of the posterior vaginal wall, which can be particularly problematic for diagnosis. Pathological features: macroscopically they appear as circumscribed mural based lesions. The cut surface can be either soft or firm and is usually off-white. Areas of haemorrhage are common, particularly in larger lesions. The microscopic appearance is the same as for GISTs occurring elsewhere in the GI tract. Spindled cell morphology dominates (65%) and most of the remainder are mixed spindled and epithelioid.20
Granular cell tumour Granular cell tumours are derived from a neuroectodermal precursor and rarely involve the anus, but when they do they present as an anal polyp (Figure 3A and B). The histological appearance of the tumours is the same as elsewhere, being composed of large cells with abundant eosinophilic, granular cytoplasm. The overlying epithelium often shows pseudoepitheliomatous hyperplasia and should not be confused with SCC. The tumour cells are positive with the periodic acid Schiff stain and with the S100 immunohistochemical stain.
Diagnostic pitfalls: anal GISTs are usually only misdiagnosed if they do not enter the differential diagnosis of the reporting pathologist. Spindle cell GIST may be misdiagnosed as a sarcoma; in particular leiomyosarcoma as around 30% will express SMA. Bland lesions may be misdiagnosed as a leiomyoma. Awareness is the key to diagnosis. GIST must enter the differential diagnosis of any spindle cell lesion of the anus. Immunohistochemistry makes diagnosis straightforward. In the rare CD117 negative cases, DOG1 will usually be definitive.
Lymphangioma Lymphangiomas of the anal canal are rare and usually inconsequential lesions. They may represent developmental or acquired lesions and can present incidentally, with PR bleeding or as a mass.22 Macroscopically they are soft and fleshy. Microscopically they are composed of dilated, thin-walled vascular spaces, immediately underlying the squamous epithelium. The epithelium frequently shows acanthosis and hyperkeratosis, presumably secondary to irritation.22 The diagnosis is typically straightforward. Dilated lymphatic vessels are common in FEP
Other mesenchymal lesions Essentially any mesenchymal lesion can present in the anus. Smooth muscle tumours are the most likely to present as a polyp.
DIAGNOSTIC HISTOPATHOLOGY 20:1
43
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Figure 4 (a) Low power view of a tailgut cyst giving rise to an adenocarcinoma. (b) A higher power view showing adenocarcinoma adjacent to residual tailgut cyst epithelium. 2 Pandey P. Anal anatomy and normal histology. Sex Health 2012 Dec; 9: 513e6. 3 Balachandra B, Marcus V, Jass JR. Poorly differentiated tumours of the anal canal: a diagnostic strategy for the surgical pathologist. Histopathology 2007 Jan; 50: 163e74. 4 Welton ML, Sharkey FE, Kahlenberg MS. The etiology and epidemiology of anal cancer. Surg Oncol Clin N Am 2004 Apr; 13: 263e75. 5 Clemmensen OJ, Fenger C. Melanocytes in the anal canal epithelium. Histopathology 1991 Mar; 18: 237e41. 6 Groisman GM, Polak-Charcon S. Fibroepithelial polyps of the anus: a histologic, immunohistochemical, and ultrastructural study, including comparison with the normal anal subepithelial layer. Am J Surg Pathol 1998 Jan; 22: 70e6. 7 Bonheur JL, Braunstein J, Korelitz BI, et al. Anal skin tags in inflammatory bowel disease: new observations and a clinical review. Inflamm Bowel Dis 2008 Sep; 14: 1236e9. 8 Pirog EC, Quint KD, Yantiss RK. P16/CDKN2A and Ki-67 enhance the detection of anal intraepithelial neoplasia and condyloma and correlate with human papillomavirus detection by polymerase chain reaction. Am J Surg Pathol 2010 Oct; 34: 1449e55. 9 Lobert PF, Appelman HD. Inflammatory cloacogenic polyp. A unique inflammatory lesion of the anal transitional zone. Am J Surg Pathol 1981 Dec; 5: 761e6. 10 Parfitt JR, Shepherd NA. Polypoid mucosal prolapse complicating low rectal adenomas: beware the inflammatory cloacogenic polyp!. Histopathology 2008 Jul; 53: 91e6. 11 Jaworski RC, Biankin SA, Baird PJ. Squamous cell carcinoma in situ arising in inflammatory cloacogenic polyps: report of two cases with PCR analysis for HPV DNA. Pathology 2001 Aug; 33: 312e4. 12 Lee PK, Wilkins KB. Condyloma and other infections including human immunodeficiency virus. Surg Clin North Am 2010 Feb; 90: 99e112. Table of Contents. 13 Longacre TA, Kong CS, Welton ML. Diagnostic problems in anal pathology. Adv Anat Pathol 2008 Sep; 15: 263e78. 14 Palefsky JM, Darragh TM. Classification of anal squamous intraepithelial lesions: 2-Tiered terminology and the quest to reduce the incidence of anal cancer among at-risk individuals. Pathol Case Rev 2013 July/August; 18: 200e8.
but the presence of other stromal and vascular elements points to the correct diagnosis. Heterotopias A range of heterotopias can occur in the anus. Probably the most common is gastric heterotopia, followed by prostate and breast. Some cases will be incidental findings, others will present with anal discharge, PR bleeding or pruritus ani. Gastric heterotopia of oxyntic type can result in peptic ulceration.23 Endoscopically they appear as a sessile polyp. Associated anorectal developmental anomalies, in particular duplications, are not uncommon.23 The diagnosis tends to be straightforward, with the heterotopic islands nicely recapitulating the organ of origin. Cysts A range of developmental and acquired cysts can occur in the anal region. They include anal duplications, tailgut, epidermoid, dermoid, median raphe and anal duct cysts.24 All are benign but have at least a theoretical risk of malignant transformation (Figure 4A & B). They may present as an incidental polyp or nodule or can become infected and painful in which case they are often mistaken for an abscess. In some instances developmental cysts are associated with other anorectal abnormalities. When solitary, surgical excision is curative.
Conclusions Anal polyps continue to be a neglected part of pathology practice and knowledge of the basic embryology, anatomy and histology of the anus tends to be fairly poor amongst pathology trainees and specialists alike. Although anal polyps are relatively uncommon, issues with misdiagnosis are frequent and can have significant management implications. Knowledge of the common diagnostic pitfalls will assist in avoiding such errors. A
REFERENCES 1 Dujovny N, Quiros RM, Saclarides TJ. Anorectal anatomy and embryology. Surg Oncol Clin N Am 2004 Apr; 13: 277e93.
DIAGNOSTIC HISTOPATHOLOGY 20:1
44
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
15 Darragh TM, Colgan TJ, Cox JT, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012 Oct; 136: 1266e97. 16 Bello DM, Smyth E, Perez D, et al. Anal versus rectal melanoma: does site of origin predict outcome? Dis Colon Rectum 2013 Feb; 56: 150e7. 17 Omholt K, Grafstrom E, Kanter-Lewensohn L, et al. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res 2011 Jun 15; 17: 3933e42. 18 Ni S, Huang D, Chen X, et al. c-kit gene mutation and CD117 expression in human anorectal melanomas. Hum Pathol 2012 Jun; 43: 801e7. 19 Kiran RP, Rottoli M, Pokala N, et al. Long-term outcomes after local excision and radical surgery for anal melanoma: data from a population database. Dis Colon Rectum 2010 Apr; 53: 402e8. 20 Miettinen M, Furlong M, Sarlomo-Rikala M, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 2001 Sep; 25: 1121e33.
DIAGNOSTIC HISTOPATHOLOGY 20:1
21 Patil DT, Goldblum JR, Billings SD. Clinicopathological analysis of basal cell carcinoma of the anal region and its distinction from basaloid squamous cell carcinoma. Mod Pathol 2013 Oct; 26: 1382e9. 22 Val-Bernal JF, Mayorga M, Diego C, et al. Pedunculated polypoid lymphangioma of the anal canal. Pathol Int 2008 Jul; 58: 442e4. 23 Steele SR, Mullenix PS, Martin MJ, et al. Heterotopic gastric mucosa of the anus: a case report and review of the literature. Am Surg 2004 Aug; 70: 715e9. 24 Johnson KN, Young-Fadok TM, Carpentieri D, et al. Case report: misdiagnosis of tailgut cyst presenting as recurrent perianal fistula with pelvic abscess. J Pediatr Surg 2013 Feb; 48: e33e6.
Practice points C
C
C
45
Basic knowledge of the normal anal anatomy and histology is critical to reporting anal lesions Over diagnosis of fibroepithelial polyps as condyloma acuminata is common Implementation of the lower anogenital squamous terminology should be encouraged
Ó 2013 Elsevier Ltd. All rights reserved.
Polyps and polypoid lesions of the anus
working knowledge of the embryology and the basic anatomical compartments is essential for accurate reporting of anal specimens. The proximal portion of the anus is derived from the endodermal hindgut and the distal portion from the ectodermal proctodeum.3 The dentate (pectinate) line represents the point of fusion of these structures and also roughly corresponds to the mid point of the anal canal. It is an important landmark as the lymphatic’s proximal to the dentate line drain to the inferior mesenteric lymph nodes, whereas the distal drainage is to the internal iliac and inguinal nodes.2 The endodermal hindgut has a larger calibre than the proctodeum and as such the anus above the dentate line is thrown into folds to accommodate this discrepancy. These folds are recognized as the columns of Morgagni and the intervening anal crypts. Anatomically the anus begins at the level of the levator ani muscle and ends 5 cm external to the anal verge. The anus is then divided into three key regions namely; the anal transformation zone (ATZ), encompassing the 1e2 cm of mucosa proximal to the dentate line; the intra-anal compartment, extending from the dentate line to the anal verge and the perianal region which extends 5 cm external to the anal verge. The anal canal includes the transformation zone and the intra-anal compartment and is about 4 cm in length. Precise localization of anal pathology is of critical importance. In particular, the management of peri-anal lesions can be vastly different to intra-anal lesions. Confusion tends to occur when a lesion crosses an anatomical boundary. Currently, if a lesion cannot be completely visualized with gentle traction on the buttocks it is considered to be intra-anal. If a lesion can be completely visualized with gentle traction on the buttocks then it is considered to be peri-anal.4
Mark Bettington Ian Brown
Abstract Anal polyps are a relatively rare and neglected part of pathology practice. Similar to other parts of the gastrointestinal tract, anal polyps are predominantly epithelial in origin, but mesenchymal lesions do occur. The aetiology of anal polyps is diverse and includes infectious, reactive, developmental and neoplastic conditions. Thus an awareness of the clinical scenario can be very informative in difficult cases. Diagnostic pitfalls are perhaps more common than is generally realized and misdiagnosis can have important management and social implications. Herein, we discuss the most common and interesting anal polyps and polypoid lesions with a particular focus on diagnostic pitfalls. Careful attention to the clinical scenario and histological features, along with judicious use of immunohistochemistry will resolve most diagnostic dilemmas.
Keywords anus; diagnosis; human papilloma virus; pathology; polyps
Introduction Anal polyps are uncommon, accounting for significantly less than one percent of gastrointestinal (GI) polyps. As such they are a neglected part of pathological practice. Recently there has been a renewed interest in anal pathology, driven largely by the rise in human papilloma virus (HPV) related anal pathology. A byproduct of anal surveillance for HPV is the increasing identification of incidental anal lesions that then require pathological diagnosis. Usually these diagnoses are straightforward; however some entities create diagnostic dilemmas. This review focuses on the more common polyps and polyp-like lesions of the anus and particularly emphasizes areas where misdiagnosis occurs.
Anal histology The upper extent of the anus is composed of rectal type mucosa. This quickly changes to the ATZ, which represents the transition from glandular rectal type mucosa to squamous anal mucosa. The transition zone itself is lined by a metaplastic squamous epithelium that resembles urothelium. The ATZ ends at the dentate line to become non-keratinizing squamous mucosa. The squamous mucosa of the intra-anal compartment is devoid of adnexal structures and this allows distinction from the peri-anal skin that begins at the anal verge. Melanocytes are present in the squamous mucosa of the intra-anal compartment and in lesser numbers in the ATZ but are not normally present in rectal type mucosa.5 The anal ducts enter the anus via the anal crypts just proximal to the dentate line. The anal glands are lined by stratified columnar epithelium and are most often found in the submucosa of the anterior anus.
Anal embryology and anatomy The anus is an anatomically and embryologically complex region and a comprehensive discourse of these topics is beyond the scope of this review. We refer interested readers to excellent dedicated reviews of the subjects by Pandey and Dujovny et al.1,2 However, a
Mark Bettington BSc MBBS FRCPA The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, The University of Queensland, Brisbane, QLD, Australia; Envoi Specialist Pathologists, Brisbane, QLD, Australia. Conflicts of interest: none.
Anal polyps For the purposes of this review we divide the discussion into; 1. ‘true’ anal polyps, that is, lesions that essentially always present as a discrete elevated lesion, and 2. ‘polypoid’ anal lesions, that is, lesions that can present as a polyp or polyp-like mass in some patients but can also present as non-discrete mass lesions. Table 1 represents a comprehensive list of entities that can theoretically present as an anal polyp, only the more relevant of these will be discussed.
Ian Brown BGEN MBBS FRCPA Envoi Specialist Pathologists, Brisbane, QLD, Australia; Department of Anatomical Pathology, Central Laboratory, Pathology Queensland, Brisbane, QLD, Australia. Conflicts of interest: none.
DIAGNOSTIC HISTOPATHOLOGY 20:1
38
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
arise from the anal papillae at the base of the columns of Morgagni. This occurs on a background of chronic injury and inflammation. In particular, fissures of the anal valves are frequent antecedents to FEPs, and thus they are common in patients with Crohn’s disease.
All entities that can potentially present as an anal polyp Entity
Neoplastic Epithelial Squamous cell carcinoma Adenocarcinoma Adenoma Neuroendocrine carcinoma Basal cell carcinoma Adnexal type tumours Mesenchymal Neurofibroma Granular cell tumour Lipoma Fibrolipoma Lymphangioma Kaposi sarcoma Angiosarcoma Aggressive angiomyxoma Leiomyoma/sarcoma Fibrohistiocytic Inflammatory fibroid tumour Gastrointestinal stromal tumour Melanoma Haematolymphoid Non-neoplastic lesions Fibroepithelial polyp Inflammatory cloacogenic polyp Haemorrhoids Endometriosis Heterotopia (prostate, breast, gastric) Amyloid Infectious HPV (condyloma accuminatum) Treponema pallidum (condyloma lata), Granulomatous (Mycobacterium tuberculosis, Enterobius) Cysts Epidermoid, dermoid, tailgut, median raphe, anal gland, duplication
Presentation Presentation in the anus as a polyp
þþþ þ þþ þ þ þ
þþ þ þþþþ þ þþþ þþ
þ þ þ þ þ þ þ þ þ þ þ þ
þþ þþþ þþ þþ þþþ þ þ þþ þþþ þ þþ þþ
þþ þ
þþ þ
þþþþ þþþ
þþþþ þþþþ
þ þ þ
þþ þ þþþ
þ
þ
þþþ þ
þþþ þ
þ
þ
þþ
þþ
Clinical findings: the majority of FEPs come to clinical attention because of local irritation related to incontinence and discharge. Rarely they can bleed secondary to trauma. They may be attached to the surrounding mucosa by either a narrow pedicle or a broad base. Pathological features: FEPs are variable in size and are soft and fleshy when in situ. They are lined by non-keratinizing squamous epithelium. Because they are subjected to recurrent trauma, areas of hyper and parakeratosis are universal and ulceration will sometimes be present. Serum lakes are often seen in the superficial layers of the epithelium and are useful diagnostically, as this feature is rare in condylomata. The stroma is variable; in most it is myxoid with abundant ectatic vessels, however over time it becomes pauci-cellular and collagenized.6 The myxoid appearance is more prominent in subepithelial regions. At the base of FEPs, vessel walls may exhibit hyaline change, but no true vasculitis. Bi or multinucleate atypical stromal cells can be identified in many cases. CD34 is characteristically expressed in these cells and they are reactive for desmin in one third of cases, but are of no significance. Most cases contain some smooth muscle that is usually continuous with the underlying muscularis mucosa. An infiltrate of Mast cells is often present but unless ulcerated or arising in a setting of Crohn’s disease, significant inflammation is not seen. FEPs sometimes arrive with a clinical query of Crohn’s disease. The only histological feature useful in this distinction are granulomas, which are reported in 30% of patients with Crohn’s disease but never in patients without (Figure 1).7 Diagnostic pitfalls: despite the general lack of interest surrounding FEPs, problems with diagnosis are surprisingly common. In particular, over-diagnosis of reactive epithelial changes as HPV-induced koilocytosis is a recurring issue. In response to injury, the superficial squamous cells of FEPs can develop voluminous clear cytoplasm, accompanied in some cases by centrally placed nuclei. This can be erroneously interpreted as koilocytosis, leading to the diagnosis of condyloma acuminatum. This is not a trivial mistake, as it may result in inappropriate follow-up and treatment and can also have significant social implications. In one series, 40% of polyps diagnosed as condyloma acuminata of the anus were actually FEPs.8 Attention to the architectural and cytological features helps avoid this misdiagnosis. FEPs do not have the verrucous pattern of a condyloma acuminatum and lack the genuine HPV-induced nuclear changes, such as binucleation, chromatin margination, nuclear indentation and central clearing. True HPV effect in FEPs is exceedingly rare and probably only occurs in the setting of HPV in the adjacent anal epithelium. In unresolved cases, immunohistochemistry can be applied. Ki67 staining will typically be negative in the upper two thirds of the epithelium in FEPs, whereas condyloma will usually show some positive staining in the upper layers. P16 is generally not helpful as it will usually be negative in both lesions.
þ Rarely; þþ sometimes; þþþ usually; þþþþ essentially always.
Table 1
True anal polyps Fibroepithelial polyp The fibroepithelial polyp (anal tag, hypertrophied anal papilla) is the most common anal polyp. They are non-neoplastic and typically
DIAGNOSTIC HISTOPATHOLOGY 20:1
39
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
glandular and squamous mucosa should be evident at least focally, but glandular mucosa predominates in most. At low power the polyps maintain a regular architecture, with even spacing of the crypts and without cribriform or complex growth patterns. Cystically dilated glands are frequent and diamondshaped crypts are a fairly characteristic feature. It is also common to see nests of displaced glands in the submucosa.9 Generally, these are easily recognized as benign by their rounded contour, accompanying lamina propria and the narrow gap in the muscularis mucosa. This contrasts with the irregular infiltration of malignant glands surrounded by desmoplastic stroma. The surface may show areas of erosion or ulceration. In some cases this can take on the ‘volcano-like’ pattern of injury more typically associated with Clostridium difficile toxin. This pattern of injury can of course be seen in any type of ischaemic mucosal injury and is not restricted to C. difficile. The lamina propria shows various degrees of fibromuscular consolidation and lymphoplasmacytic and histiocytic inflammation. In areas of erosion and ulceration an acute inflammatory component will also be present. The cytology of ICPs is typically bland. Goblet cells are preserved and there is obvious maturation from the crypt bases to the luminal surface. Mitoses are regular and mostly confined to the basal aspects of the crypts.
Figure 1 A fibroepithelial polyp with large numbers of granulomas in a patient with Crohn’s disease.
When stromal oedema is prominent, FEP may be confused with superficial angiomyxoma or aggressive angiomyxoma. Common expression of CD34 (and desmin in the case of aggressive angiomyxoma) can further confuse the issue. Careful attention to the clinical setting, lack of an infiltrative border and presence of multinucleate cells aids separation of FEP from aggressive angiomyxoma, while absence of a lobulated architecture, epithelial inclusions and neutrophil infiltration is against superficial angiomyxoma.
Diagnostic pitfalls: over-interpretation of reactive epithelial changes as neoplastic is the most common pitfall. This invariably occurs adjacent to areas of erosion and ulceration, thus caution is warranted when assessing the cytology in these areas. Paying attention to the preserved architecture at low power is helpful. Also, the reactive epithelium will merge gradually with the surrounding, obviously benign epithelium, rather than having an abrupt transition as in true dysplasia. The presence of maturation and a high nuclear to cytoplasmic ratio are also useful clues to the reactive nature. In difficult cases immunohistochemistry can be helpful. Reactive lesions are typically negative for p53 and Bcatenin.10 Dysplasia will often show the opposite pattern. When the staining is equivocal, reliance on the histological appearance is appropriate. Similar to the above, over-interpretation of displaced glands in the submucosa can be misinterpreted as invasive malignancy. This usually occurs in small biopsies where the overall benign architecture of the displaced glands cannot be appreciated. Recognition of the benign cytology along with accompanying lamina propria is helpful, remembering that the lamina propria often shows fibromuscular consolidation. Immunohistochemistry as above can also be applied. In contrast to the above, ICPs can rarely harbour genuine neoplastic elements. These can be glandular or squamous in origin.10,11 Adenomatous elements can be recognized by loss of the normal architectural pattern, with crowding and effacement of crypts. The dysplastic glands have a top-down arrangement, with the most atypical and mitotically active cells at the luminal surface. Immunohistochemistry will be opposite to the benign mucosa described above. Squamous dysplasia shares the same aetiology and nomenclature as for anal intraepithelial neoplasia (AIN), discussed further below. Reactive squamous metaplasia can closely mimic high-grade squamous dysplasia. In these instances immunohistochemistry for p16 can be very useful, with block positive staining strongly favouring high-grade dysplasia.
Treatment: management depends on the clinical scenario but treatment of any underlying inflammatory condition is warranted. If they become overly irritating, simple excision at the base is curative, although there is a risk of post-operative complications, such as infection and incontinence. Inflammatory cloacogenic polyp Lobert and Appleman first described the inflammatory cloacogenic polyp (ICP) in 1981.9 They arise in the setting of chronic injury, probably secondary to mucosal prolapse. They are more frequent in the developed world, possibly due to low-fibre diets. They have a close aetiological and histological relationship to the mucosal prolapse syndrome and the two entities may represent spectrums of the same disease. In contrast to the mucosal prolapse syndrome, ICPs present as a distinct polypoid mass, rather than a flat erythematous or ulcerated area. ICPs are relatively uncommon lesions, representing less than one percent of lower gastrointestinal tract polyps. Clinical and endoscopic findings: ICPs occur in middle aged to elderly patients of both sexes. They can present with episodic per rectal bleeding or mucoid discharge but are frequently asymptomatic. The polyps are usually palpable at the extent of digital examination. Early lesions are more often anterior, but advanced lesions can be circumferential. At endoscopy they appear as broad based masses of the ATZ. Erythema and foci of ulceration can easily give an endoscopic impression of malignancy. Pathological features: specimens received by pathology are typically either biopsy fragments or polypectomy specimens. Grossly they appear as erythematous and often oedematous masses. Histopathological assessment demonstrates the nonneoplastic nature of these polyps. Components of both
DIAGNOSTIC HISTOPATHOLOGY 20:1
40
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Diagnostic pitfalls: diagnostic issues are rare. While misdiagnosis of FEPs as condyloma acuminata is relatively common, the converse is unusual. Ensuring that foci of high-grade dysplasia are identified is important, as this will impact patient management. Finally exclusion of a verrucous carcinoma is required. In the anus they are also known as the BuschkeeLowenstein tumour or as giant condylomata (Figure 2A). Although these lesions are also associated with the low risk HPV genotypes 6 and 11, they are locally destructive tumours. The invasive front is broad based and the cytology is indistinguishable from a typical condyloma, making diagnosis on biopsy specimens difficult or impossible (Figure 2B). In excision specimens, clinical and macroscopic evidence of local invasion are helpful in making the correct diagnosis. Thorough sampling is essential as foci of overt squamous cell carcinoma may arise in these tumours. Identifying such foci is important, as pure verrucous carcinomas have very limited or no metastatic potential.
Careful assessment for invasive malignancy is of course warranted when true neoplastic elements are seen. Overall, it is worth remembering that true neoplasia in ICPs is very unusual and as such careful exclusion of a non-neoplastic mimic should be conducted prior to making such a diagnosis. Treatment: management depends on the clinical setting and the nature of the polyp. Asymptomatic cases can be observed with dietary and lifestyle advice to minimize further mucosal prolapse. If symptomatic and not responding to other measures, local resection is typically performed. This can be either endoscopic or transanal depending on size and local preference. In rare cases of severe, treatment refractory disease, proctectomy may be offered. Condyloma acuminatum Condyloma acuminata (anal warts) are common anal polyps that arise in the setting of HPV infection. Infection is typically, but not invariably, with a low risk genotype. Receptive anal intercourse, immunosuppression and other lower anogenital tract HPV infection are key risk factors for HPV-related anal pathology.12
Treatment: treatment options depend on size, location and local preference. A range of topical treatments are available, or else simple excision can be performed.12 Importantly, none of the treatments will eradicate the HPV infection and as such, ongoing surveillance is warranted. Peri-anal condylomata are the most
Clinical features: condylomata are frequently multiple and can occur in all compartments of the anus but most often present around the anal verge. They are variable in size, ranging from a few millimetres to several centimetres. Patients typically present due to local irritation or with concern relating to the growth. Examination of the entire lower anogenital tract is warranted in these patients to exclude synchronous disease at other sites. Pathological features: grossly, they are pale, fleshy, exophytic lesions. They often occur in clusters and are quite friable. Histologically they have a verrucous growth pattern and because they are prone to trauma, the surface frequently shows parakeratosis and a granular layer. At high power the epithelium is normally bland but koilocytes are usually readily identified. Mitoses rarely extend above the basal third of the epithelium. However, in around 15% of cases, condylomata harbour highgrade dysplasia and this usually indicates co-infection with a high risk HPV genotype(s).13 In our experience, condylomata with high-grade dysplasia tend to occur at the ATZ. Invasive squamous cell carcinoma is rare but must be excluded. Terminology surrounding condylomata continues to be controversial. It is now accepted that all HPV driven lesions require a designation regarding degree of dysplasia. Similar to the cervix, the competing terminologies are low-grade and high-grade squamous intraepithelial lesion (LSIL and HSIL) versus anal intraepithelial neoplasia (AIN) grades 1e3. LSIL corresponds to either koilocytosis or AIN 1 and HSIL corresponds to AIN 2&3. Many authorities now consider AIN 2 to be an indeterminate diagnosis requiring further workup with p16 immunohisto chemistry.14 P16 positive AIN 2 is diagnosed as HSIL, whereas p16 negative AIN 2 is downgraded to LSIL. In concordance with the recommendations of the recent lower anogenital squamous terminology (LAST) project paper15 we prefer the SIL terminology, as it is biologically more meaningful. LSIL correlates with low-risk HPV genotypes and carries a negligible risk of malignant progression; in contrast HSIL correlates with high-risk genotypes and has a significant risk of malignant progression. In practice, we report both terminologies. The majority of condylomata, particularly of the anal verge or peri-anal region are low-grade.
DIAGNOSTIC HISTOPATHOLOGY 20:1
Figure 2 (a) Cut section of a verrucous carcinoma showing the broad based nature of the invasive front and (b) the corresponding histological section.
41
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
easily managed, as the risk of complications is minimal. Intra-anal lesions are more problematic, particularly for surgeons, as postoperative scarring can result in anal stenosis. High-resolution anoscopy may be performed to detect synchronous flat AIN, particularly if high-grade dysplasia has been diagnosed elsewhere. Colorectal adenoma Conventional adenomas sometimes occur in the rectal type mucosa of the proximal anus. In particular we find that traditional serrated adenomas have a propensity to arise at this site. The diagnosis of these polyps is no different to elsewhere in the colorectum. Some patients with previous proctocolectomy will develop conventional adenomas in the strip of rectal mucosa left after surgery. This is of particular relevance to surveillance of patients after prophylactic proctocolectomy for a polyposis syndrome. We have also encountered conventional adenomas in the remnant rectal cuff of mucosa following proctocolectomy for ulcerative colitis. Condyloma lata The condyloma lata is now a very rare anal polyp and represents a cutaneous manifestation of secondary syphilis. Patients typically present with a painless, flat-topped polypoid lesion (Figure 3A). In many instances the diagnosis is not suspected clinically, making pathological diagnosis extremely challenging. The lesions show psoriasiform epidermal hyperplasia overlying a heavy mixed inflammatory infiltrate rich in plasma cell, lymphocytes and histiocytes (Figure 3B). A peri-vascular distribution may be evident and in occasional cases obliterative endarteritis and granulomas may be seen. The diagnosis is confirmed by the demonstration of spirochaetes in the lesion. The spirochaetes are typically present in large numbers and are located in the squamous epithelium. A silver stain, such as a Warthin-Starry is usually adequate to identify the spirochaetes (Figure 3C), but more recently an immunohistochemical stain for Treponema pallidum has become available and has a better specificity.
Polyp-like lesions of the anal tract Figure 3 (a) Low power view of a condyloma lata showing the flat-topped nature of these polyps with psoriasiform hyperplasia of the epidermis and heavy dermal inflammatory infiltrate. (b) High power of the heavy lymphoplasmacytic and histiocytic inflammation. (c) High power of the WarthineStarry stain showing large numbers of spirochaetes in the epidermis.
Melanoma The anus is a leading site for mucosal malignant melanoma. They arise from the native anal melanocytes and pass through an in situ phase the same as for cutaneous melanoma. Also in parallel with the their cutaneous counterparts, most anal melanomas go through a nodular phase of invasive growth and this is the point when they may present as an anal polyp or be confused with a haemorrhoid. The prognosis for anal melanoma is poor, with a five-year survival of around 20%.16
mixed pattern and tumour giant cells are fairly common. They are usually thick (mean 8.9 mm)16 and mitotically active at diagnosis and pigment is generally obvious. By immunohistochemistry the tumours stain for the usual melanoma markers, of S100, Melan-A and HMB45. Mucosal melanoma has a higher rate of CD117 immunohistochemical expression (27e40%)17,18 than cutaneous melanoma and this can create confusion with a gastrointestinal stromal tumour (GIST) if unwary. Conversely, only about 5% of mucosal melanomas harbour BRAF mutations.17,18
Clinical presentation: because they are not usually visible, anal melanomas present late compared to cutaneous melanoma. They come to attention once local symptoms such as PR bleeding, pain or obstruction develop. Pathological features: the gross appearance depends on the size at diagnosis, but they can present as a black polypoid nodule, although up to 20% are amelanotic. The histological appearances are similar to cutaneous melanomas. The tumours can display an epithelioid, spindled or
DIAGNOSTIC HISTOPATHOLOGY 20:1
Diagnostic pitfalls: the diagnosis of anal melanoma is not difficult provided adequate tissue is received. In poorly differentiated
42
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Unlike other sites, leiomyosarcoma is probably more common in the anus than leiomyoma. Both tend to present as a polyp, with leiomyosarcoma having a particular tendency to bulge into the lumen.20 The histology is the same as for smooth muscle neoplasms elsewhere. Immunohistochemical expression of smooth muscle markers and absence of staining for CD117 separate of these very rare neoplasms from the more common GIST, as discussed above.
cases without an in situ component, immunohistochemistry will usually be required, but will easily differentiate melanoma from the usual differential diagnoses of poorly differentiated adenocarcinoma, poorly differentiated squamous cell carcinoma, neuroendocrine carcinomas and high-grade lymphomas. GIST can occasionally be confused with spindle cell predominant malignant melanoma, particularly if the melanoma is CD117 positive. Recognition of pigment or an in situ component, are morphological clues to the correct diagnosis and application of appropriate immunohistochemistry will ensure the correct diagnosis.
Basal cell carcinoma Basal cell carcinoma (BCC) of the anus is very rare, accounting for less than 0.2% of anal tumours.21 It presents similarly to lesions on the sun-exposed skin as a raised nodule often with central ulceration. Anal BCCs are restricted to the perianal region, although if neglected can involve the anal canal. The major clinical and pathological dilemma is distinction of the very favourable BCC from the much more aggressive basaloid SCC. Anal BCCs are histologically analogous to BCCs at sun-exposed locations and will not be further elaborated here. Most important is the distinction from basaloid SCC. In the recent study of Patil et al, retraction artifact and lack of atypical mitoses are histological features that favour a BCC.21 In contrast, an in situ component confirms a basaloid SCC. By immunohistochemistry a BerEP4 and Bcl2 positive and p16 negative immunoprofile is very likely to represent BCC.21 p16 is the most helpful of these markers.
Treatment: there is a tendency towards wide local excision rather than abdominoperineal resection, as survival rates for both groups are similar,19 but in some advanced cases, local control cannot be achieved without radical surgery. Postoperative treatment options are limited and typically reserved for patients with either lymph node involvement or widespread metastasis. As mentioned, mucosal melanomas are more frequently CD117 positive and this predicts response to treatment with tyrosine kinase inhibitors such as imatinib. BRAF mutation is rare in mucosal melanoma and as such vemurafinib is rarely indicated. Gastrointestinal stromal tumour GISTs are the most common mesenchymal tumour of the gastrointestinal tract. They most often develop in the wall of the stomach or small bowel, with oesophagus and anus being the least common sites. That said, anal GISTs are well recognized and can be diagnostically troublesome when they occur in this unusual location.
Hidradenoma papilliferum Hidradenoma papilliferum (papillary hidradenoma) are derived from either ectopic breast tissue or apocrine adnexal glands. They are more frequently associated with the lower female genital tract but can occur in many locations, including the perianal region. They present as either a cutaneous nodule or as an ulcerating lesion. Hidradenoma papilliferum are well circumscribed and rarely larger than 20 mm. They are benign and local excision is curative. Histologically, hidradenoma papilliferum is characterized by a papillary growth pattern. The papillary fronds are lined by a double-layered epithelium analogous to the normal breast.
Clinical presentation: anal GISTs usually present as a mural nodule. In some instances there will be ulceration of the overlying mucosa. They may also present as a pelvic mass or as a lesion of the posterior vaginal wall, which can be particularly problematic for diagnosis. Pathological features: macroscopically they appear as circumscribed mural based lesions. The cut surface can be either soft or firm and is usually off-white. Areas of haemorrhage are common, particularly in larger lesions. The microscopic appearance is the same as for GISTs occurring elsewhere in the GI tract. Spindled cell morphology dominates (65%) and most of the remainder are mixed spindled and epithelioid.20
Granular cell tumour Granular cell tumours are derived from a neuroectodermal precursor and rarely involve the anus, but when they do they present as an anal polyp (Figure 3A and B). The histological appearance of the tumours is the same as elsewhere, being composed of large cells with abundant eosinophilic, granular cytoplasm. The overlying epithelium often shows pseudoepitheliomatous hyperplasia and should not be confused with SCC. The tumour cells are positive with the periodic acid Schiff stain and with the S100 immunohistochemical stain.
Diagnostic pitfalls: anal GISTs are usually only misdiagnosed if they do not enter the differential diagnosis of the reporting pathologist. Spindle cell GIST may be misdiagnosed as a sarcoma; in particular leiomyosarcoma as around 30% will express SMA. Bland lesions may be misdiagnosed as a leiomyoma. Awareness is the key to diagnosis. GIST must enter the differential diagnosis of any spindle cell lesion of the anus. Immunohistochemistry makes diagnosis straightforward. In the rare CD117 negative cases, DOG1 will usually be definitive.
Lymphangioma Lymphangiomas of the anal canal are rare and usually inconsequential lesions. They may represent developmental or acquired lesions and can present incidentally, with PR bleeding or as a mass.22 Macroscopically they are soft and fleshy. Microscopically they are composed of dilated, thin-walled vascular spaces, immediately underlying the squamous epithelium. The epithelium frequently shows acanthosis and hyperkeratosis, presumably secondary to irritation.22 The diagnosis is typically straightforward. Dilated lymphatic vessels are common in FEP
Other mesenchymal lesions Essentially any mesenchymal lesion can present in the anus. Smooth muscle tumours are the most likely to present as a polyp.
DIAGNOSTIC HISTOPATHOLOGY 20:1
43
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
Figure 4 (a) Low power view of a tailgut cyst giving rise to an adenocarcinoma. (b) A higher power view showing adenocarcinoma adjacent to residual tailgut cyst epithelium. 2 Pandey P. Anal anatomy and normal histology. Sex Health 2012 Dec; 9: 513e6. 3 Balachandra B, Marcus V, Jass JR. Poorly differentiated tumours of the anal canal: a diagnostic strategy for the surgical pathologist. Histopathology 2007 Jan; 50: 163e74. 4 Welton ML, Sharkey FE, Kahlenberg MS. The etiology and epidemiology of anal cancer. Surg Oncol Clin N Am 2004 Apr; 13: 263e75. 5 Clemmensen OJ, Fenger C. Melanocytes in the anal canal epithelium. Histopathology 1991 Mar; 18: 237e41. 6 Groisman GM, Polak-Charcon S. Fibroepithelial polyps of the anus: a histologic, immunohistochemical, and ultrastructural study, including comparison with the normal anal subepithelial layer. Am J Surg Pathol 1998 Jan; 22: 70e6. 7 Bonheur JL, Braunstein J, Korelitz BI, et al. Anal skin tags in inflammatory bowel disease: new observations and a clinical review. Inflamm Bowel Dis 2008 Sep; 14: 1236e9. 8 Pirog EC, Quint KD, Yantiss RK. P16/CDKN2A and Ki-67 enhance the detection of anal intraepithelial neoplasia and condyloma and correlate with human papillomavirus detection by polymerase chain reaction. Am J Surg Pathol 2010 Oct; 34: 1449e55. 9 Lobert PF, Appelman HD. Inflammatory cloacogenic polyp. A unique inflammatory lesion of the anal transitional zone. Am J Surg Pathol 1981 Dec; 5: 761e6. 10 Parfitt JR, Shepherd NA. Polypoid mucosal prolapse complicating low rectal adenomas: beware the inflammatory cloacogenic polyp!. Histopathology 2008 Jul; 53: 91e6. 11 Jaworski RC, Biankin SA, Baird PJ. Squamous cell carcinoma in situ arising in inflammatory cloacogenic polyps: report of two cases with PCR analysis for HPV DNA. Pathology 2001 Aug; 33: 312e4. 12 Lee PK, Wilkins KB. Condyloma and other infections including human immunodeficiency virus. Surg Clin North Am 2010 Feb; 90: 99e112. Table of Contents. 13 Longacre TA, Kong CS, Welton ML. Diagnostic problems in anal pathology. Adv Anat Pathol 2008 Sep; 15: 263e78. 14 Palefsky JM, Darragh TM. Classification of anal squamous intraepithelial lesions: 2-Tiered terminology and the quest to reduce the incidence of anal cancer among at-risk individuals. Pathol Case Rev 2013 July/August; 18: 200e8.
but the presence of other stromal and vascular elements points to the correct diagnosis. Heterotopias A range of heterotopias can occur in the anus. Probably the most common is gastric heterotopia, followed by prostate and breast. Some cases will be incidental findings, others will present with anal discharge, PR bleeding or pruritus ani. Gastric heterotopia of oxyntic type can result in peptic ulceration.23 Endoscopically they appear as a sessile polyp. Associated anorectal developmental anomalies, in particular duplications, are not uncommon.23 The diagnosis tends to be straightforward, with the heterotopic islands nicely recapitulating the organ of origin. Cysts A range of developmental and acquired cysts can occur in the anal region. They include anal duplications, tailgut, epidermoid, dermoid, median raphe and anal duct cysts.24 All are benign but have at least a theoretical risk of malignant transformation (Figure 4A & B). They may present as an incidental polyp or nodule or can become infected and painful in which case they are often mistaken for an abscess. In some instances developmental cysts are associated with other anorectal abnormalities. When solitary, surgical excision is curative.
Conclusions Anal polyps continue to be a neglected part of pathology practice and knowledge of the basic embryology, anatomy and histology of the anus tends to be fairly poor amongst pathology trainees and specialists alike. Although anal polyps are relatively uncommon, issues with misdiagnosis are frequent and can have significant management implications. Knowledge of the common diagnostic pitfalls will assist in avoiding such errors. A
REFERENCES 1 Dujovny N, Quiros RM, Saclarides TJ. Anorectal anatomy and embryology. Surg Oncol Clin N Am 2004 Apr; 13: 277e93.
DIAGNOSTIC HISTOPATHOLOGY 20:1
44
Ó 2013 Elsevier Ltd. All rights reserved.
MINI-SYMPOSIUM: PATHOLOGY OF GASTROINTESTINAL POLYPS AND POLYPOSES
15 Darragh TM, Colgan TJ, Cox JT, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012 Oct; 136: 1266e97. 16 Bello DM, Smyth E, Perez D, et al. Anal versus rectal melanoma: does site of origin predict outcome? Dis Colon Rectum 2013 Feb; 56: 150e7. 17 Omholt K, Grafstrom E, Kanter-Lewensohn L, et al. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res 2011 Jun 15; 17: 3933e42. 18 Ni S, Huang D, Chen X, et al. c-kit gene mutation and CD117 expression in human anorectal melanomas. Hum Pathol 2012 Jun; 43: 801e7. 19 Kiran RP, Rottoli M, Pokala N, et al. Long-term outcomes after local excision and radical surgery for anal melanoma: data from a population database. Dis Colon Rectum 2010 Apr; 53: 402e8. 20 Miettinen M, Furlong M, Sarlomo-Rikala M, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: a clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 2001 Sep; 25: 1121e33.
DIAGNOSTIC HISTOPATHOLOGY 20:1
21 Patil DT, Goldblum JR, Billings SD. Clinicopathological analysis of basal cell carcinoma of the anal region and its distinction from basaloid squamous cell carcinoma. Mod Pathol 2013 Oct; 26: 1382e9. 22 Val-Bernal JF, Mayorga M, Diego C, et al. Pedunculated polypoid lymphangioma of the anal canal. Pathol Int 2008 Jul; 58: 442e4. 23 Steele SR, Mullenix PS, Martin MJ, et al. Heterotopic gastric mucosa of the anus: a case report and review of the literature. Am Surg 2004 Aug; 70: 715e9. 24 Johnson KN, Young-Fadok TM, Carpentieri D, et al. Case report: misdiagnosis of tailgut cyst presenting as recurrent perianal fistula with pelvic abscess. J Pediatr Surg 2013 Feb; 48: e33e6.
Practice points C
C
C
45
Basic knowledge of the normal anal anatomy and histology is critical to reporting anal lesions Over diagnosis of fibroepithelial polyps as condyloma acuminata is common Implementation of the lower anogenital squamous terminology should be encouraged
Ó 2013 Elsevier Ltd. All rights reserved.