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2010—March Case of the Month

Posted March 26, 2010

CLINICAL SUMMARY: ANUS  

CAP Foundation March 2010 Online Case of the Month

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After reading the summary, try answering the three related multiple-choice questions below.

A 56-year-old woman presented with perianal fullness and pain. Direct examination revealed a superficially ulcerated mass extending from the anal canal to beyond the anal verge. An abdominal-perineal resection yielded 47 cm of sigmoid colon and rectum with attached anal canal and perianal skin. A 7.2 x 4.2 x 1.8 cm tan-brown, ulcerated, sessile, polypoid mass extended from the distal rectum to the perianal skin. A 2.0 cm firm tan nodule was noted in the perirectal adipose tissue.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2007, Case 5 and is a melanoma.

Criteria for Diagnosis and Comments: This large cell malignancy, forming an ulcerated mass in the anal canal, represents an invasive melanoma. The slides show a varying admixture of spindled and epithelioid large cells with the former predominating. There is marked cytologic atypia including prominent nuclear pleomorphism, clearly indicating the malignant nature of the process. The high mitotic rate with atypical mitotic figures also supports a malignant diagnosis. For triage purposes, based on the H&E alone, it is best to think of this as an undifferentiated large cell malignancy. Differential diagnosis includes carcinoma, melanoma and sarcoma. The cell cohesion, extracellular matrix and spindling essentially exclude a hematolymphoid neoplasm. Most, although not all of the slides, contain scattered melanin pigment and/or interface and Pagetoid involvement of the overlying squamous epithelium. These features strongly support a diagnosis of melanoma. Immunohistochemical studies, including melan A, cytokeratin and CD117 (c-kit), represent a useful triage panel to use in conjunction with the specific morphologic features. This panel should be altered based on specific histologic findings; for instance, if there was a question of Kaposi sarcoma or angiosarcoma, HHV-8, CD31, CD34 and factor VIII immunostains could also be employed.

Anal melanoma is an uncommon malignancy affecting adults. It tends to be aggressive. The stage is reported using the TNM classification of tumors of the anal canal and these tumors tend to present at high stage with risk of both lymphatic and hematogenous dissemination. Five-year survival is reported to be less than 10% although there is some variation in the literature. Surgery, including abdominal-perineal resection for advanced tumors, is the treatment of choice. Like diffuse large B-cell lymphoma and Kaposi sarcoma involving the anus, anal melanomas have an increased incidence in immunosuppressed states such as AIDS, although the majority of cases present in immunocompetent adults.

The clinical and pathological diagnosis of melanoma is relatively straightforward at this location if significant melanotic pigmentation is present. However, many cases are hypo- or amelanotic. There is typically nothing distinctive about the gross morphology, which can be either sessile or polypoid. The histology is that of an undifferentiated large cell malignancy with variable epithelioid and spindled cytology. In addition to pigmentation, a major clue to the diagnosis of melanoma is interface or Pagetoid involvement of the overlying squamous epithelium. In all but the most obvious cases, a diagnosis of melanoma should be confirmed by immunohistochemical studies with the most specific marker being melan A and the most sensitive being S-100. HMB45 should also be positive in melanoma while differential diagnostic markers such as cytokeratin and leukocyte common antigen (CD45) should be negative. Vimentin is strongly positive in most melanomas, but is not a discriminating marker from many other high-grade malignancies.

In situ melanoma of the anus has extramammary Paget disease as a major differential diagnostic consideration. Paget disease may be an isolated finding, or be accompanied by an underlying rectal adenoma or adenocarcinoma. As long as this differential diagnosis is identified, the entities can be easily differentiated using immunohistochemistry for cytokeratin (positive in Paget disease) and melan A.

Melanomas with extensive spindling, as in this case, have sarcoma as a major differential diagnostic consideration. Gastrointestinal stromal tumor is the most significant differential consideration given the location and the fact that a minority of melanomas stain positively with CD117. Pairing CD117 with melanoma markers, including S-100 and melan A, will simplify this differentiation. Squamous cell carcinoma, including those with basaloid (cloacogenic) differentiation and small cell carcinoma should stain positively for cytokeratins and negatively for melan A. These immunophenotypic studies are very important in confirming the lineage of high-grade large cell malignancies.

Diffuse large B cell lymphoma can present as an aggressive perirectal mass, especially in immunosuppressed individuals. It is critical to consider lymphoma in the differential diagnosis of undifferentiated large cell malignancies given the availability of effective treatments. CD45 (LCA) and CD20 provide excellent confirmatory markers for lymphoma. Occasionally, plasmablastic lymphomas in this location can have weak or negative CD20 staining and should be considered in unusual circumstances where no positive immunophenotypic marker is identified.

Best practices for the diagnosis of melanoma at this time include confirming with melan A, with consideration of S100 and HMB45 staining in problematic cases. The immunophenotypic battery should also include markers specific to the predominant differential diagnostic consideration in that particular case. Typically, a large battery of antibodies is not required. It may be reasonable to do CD117 staining at the request of the treating oncologist, although Imatinib has not been shown to be efficacious in very limited studies to this point.

Supplementary Questions For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
Which immunostains are most useful in differentiating melanoma from gastrointestinal stromal tumor? A.  CD117 (c-kit) and CD45 (LCA)
B.  CD117 (c-kit) and cytokeratin
C.  CD117 (c-kit) and melan A
D.  Cytokeratin and CD45 (LCA)
E.  Melan A and cytokeratin
Which immunostains are most useful in differentiating melanoma from extramammary Paget disease? A.  CD117 (c-kit) and CD45 (LCA)
B.  CD117 (c-kit) and cytokeratin
C.  CD117 (c-kit) and melan A
D.  Cytokeratin and CD45 (LCA)
E.  Melan A and cytokeratin
3. Which of the following anal tumors does NOT show increased incidence with immunosuppression? A.  Diffuse large B-cell lymphoma
B.  Extramammary Paget disease
C.  Kaposi sarcomanoma
D.  Melanoma

References

  1. Cooper P, Mills SE, Allen M. Malignant melanoma of the anus: report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum. 1982;25:693-703.
  2. Rossetti C, Koukouras D, Eboli M, et al. Primary anorectal melanomas: an institutional experience. J Exp Clin Cancer Res. 1997;16:81-85.
  3. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92:1398-1405.
  4. Willmore-Payne C, Holden JA, Tripp S, et al. Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution aplicon melting analysis. Hum Pathol. 2005;36:486-493.
  5. Hamilton SR, Aaltonen LA. World Health Organization Classification of Tumours. Pathology & Genetics: Tumours of the Digestive System. Lyon, France: IARC Press; 2000:154.

Author:
2007
Lawrence J. Burgart, MD
Surgical Pathology Committee
Hospital Pathology Associates /Abbott Northwestern Hospital
Minneapolis, MN