Case 5 -

Secondary Perianal Paget Disease Scott Owens, University of Michigan, Ann Arbor, MI

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Clinical History A 62-year-old man presented with perianal pruritis. On physical examination, he was found to have a perianal rash with areas of excoriation and ulcers. There was no other significant medical history and the patient was otherwise healthy. Case 5 - Figure 1 Gross image of resected perianal skin, with nodular, raised, ulcerated and excoriated rash. Case 5 - Figure 2 Low-power photomicrograph of perianal skin, in which innumerable infiltrating epithelioid cells with pale cytoplasm are scattered among the squamous cells in a pagetoid fashion. Case 5 - Figure 3 Slightly higher magnification, showing similar cells in the anal squamous epithelium immediately adjacent to the distal rectal mucosa. Case 5 - Figure 4 Medium-power view showing cytology of the malignant cells, including several signet ring-type cells and abundant apoptotic debris. Note predilection of the cells to involve the deeper epithelium. Case 5 - Figure 5 High-power view of malignant cells, showing vacuolated cytoplasm, pleomorphic nuclei with prominent nucleoli, and a mitotic figure at the bottom of the field. Case 5 - Figure 6 CEA immunohistochemical stain, highlighting the pagetoid cells. Case 5 - Figure 7 CK20 immunohistochemical stain. Case 5 - Figure 8 CDX-2 immunohistochemical stain. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The patient underwent a wide local excision of the perianal region (Figure 5a). Grossly, the perianal skin contains a pruritic rash with numerous raised nodules and ulcers. There is evidence of excoriation. Low-power photomicrographs reveal acanthosis with hyperkeratosis and parakeratosis, as well as innumerable large cells with ample pale cytoplasm spreading throughout the epidermis and the squamous epithelium of the anal canal (Figures 5b and 5c). At higher magnification, the cells concentrate in the deeper epidermis and have pleomorphic nuclei with prominent nucleoli. Mitotic figures and apoptotic debris are abundant, and some of the cells have signet-ring morphology with intracytoplasmic mucin vacuoles (Figures 5d and 5e). The cells are immunohistochemically positive for CEA, cytokeratin 20, and CDX-2 (Figures 5f-h). Cytokeratin 7, GCDFP-15, S-100 and p63 immunostains are negative (not shown). Differential Diagnoses: Primary perianal Paget disease Secondary perianal Paget disease Anal melanoma with pagetoid spread Anal squamous cell carcinoma with pagetoid spread Anal gland/duct adenocarcinoma Final Diagnosis: Secondary perianal Paget disease Case Discussion: Several neoplastic processes can present with pagetoid spread of malignant cells in the perianal skin, and all can have a similar appearance on H&E-stained sections. Fortunately, immunohistochemistry is very helpful in sorting out the differential diagnosis. Primary (extramammary) perianal Paget disease is a rare but fascinating entity with a controversial origin that is currently thought to arise from (or differentiate toward) apocrine gland epithelium in the perineal and perianal skin. The cells in this disease have an immunophenotype unlike colorectal or anal gland epithelium: CK7+; GCDFP- 15+; MUC1+; CK20−; CDX-2−; MUC2−. In contrast, secondary perianal Paget disease, which is usually the pagetoid extension of cells from a colorectal adenocarcinoma into the perianal epidermis, has an immunophenotype typical of colonic epithelium: CK20+; CDX-2+; MUC2+; CK7-/+; GCDFP- 15−; MUC1−. The secondary form may also have more prominent signet-ring morphology. Both primary and secondary perianal Paget disease can be immuno-positive for CEA, and produce cytoplasmic mucin (which can be highlighted by mucicarmine or PAS-Alcian Blue). The distinction between these two entities is clinically important, because the primary form of the disease—while prone to local recurrence—is not associated with a separate carcinoma, while the secondary form by definition is associated with a colorectal (or very rarely anal) adenocarcinoma that may require additional therapy. Anal melanoma and squamous cell carcinoma with pagetoid spread into the surrounding skin are immunohistochemically positive for S-100 and p63, respectively, and do not produce mucin. Melanoma is also typically positive for other melanocytic markers, like HMB-45 and melan-A/MART-1, while squamous cell carcinoma is often associated with human papillomavirus infection. Finally, anal gland/duct adenocarcinoma is an extremely rare malignancy arising in the anal region that can also spread in a pagetoid fashion. It is typically CK7+, MUC5AC+, CK20−, and CDX-2−. Table 1. Differential immunohistochemical profiles of various neoplasms that can present with pagetoid spread in the perianal region. PPPD=primary perianal Paget disease; CRC/SPPD=secondary perianal Paget disease associated with colorectal adenocarcinoma; AGC=anal gland carcinoma; AM=anal melanoma; SCC=squamous cell carcinoma Disease CK7 CK20 GCDFP-15 CDX-2 S-100 Melan-A p63 PPPD + - + - - - - CRC/SPPD -/+ + - + - - - AGC + - - - - - - AM - - - - + + - SCC - - - - - - + Review of the Literature/Treatment Options: Primary perianal Paget disease is rare and affects both sexes equally. The diagnosis is usually made in the 5th or 6th decade of life, when the disease presents with a variable "rash" of the distal anus and/or perianal skin, which can be nodular, plaque-like, scaly, eroded, ulcerated, or excoriated, the last of these due to the common clinical symptom of pruritus. The perianal form of the disease may accompany vulvar/perineal Paget disease in affected women as well. The large, atypical cells infiltrate among the squamous cells and may preferentially affect the deeper squamous epithelium/epidermis, a feature that is said to be most prominent in the primary form of the disease. The "cell of origin" of the primary form is controversial, with some suggesting that it arises from an apocrine gland or duct, and others invoking a multipotent stem cell of the epidermis. Secondary perianal Paget disease can accompany rectal or anal adenocarcinomas, and is essentially the distal extension of cancer in a pagetoid fashion. Both primary and secondary diseases may be more extensive than the macroscopic rash suggests on physical examination, with malignant cells spreading in the epidermis well beyond the grossly-visible boundary of the rash. Paget disease is amenable to surgical resection, still the treatment of choice, although there are reports of other therapies, including topical imiquimod and radiotherapy. The underlying rectal or anal carcinoma in secondary perianal Paget disease may be diagnosed before, concurrently, or after the perianal disease, but such underlying cancer should be considered when the immunohistochemical findings suggest the secondary form (see Table) to avoid missing the diagnosis. Generally, the clinical course of primary disease is prolonged, with a reported 60% recurrence rate within 5 years. While the concept of "invasive" primary perianal Paget disease is touched on in the literature, this notion is complicated by the fact that some reports do not discriminate between the primary and secondary forms. Recently, reports of HER- 2/neu overexpression in perianal Paget disease have surfaced, which may provide an opportunity for targeted therapy. Conclusion(s): Perianal Paget disease is a rare entity that may be primary (thought to arise from an apocrine gland/duct origin or a multipotent epidermal cell) or secondary (spreading from a colorectal or anal adenocarcinoma). Immunohistochemical stains are very helpful in making the diagnosis and discerning between the primary and secondary forms, an important clinical distinction due to the potential of an adjacent or separate tumor in the secondary form. Immunohistochemistry is also very useful in excluding other malignancies that may have pagetoid spread of cells into the perianal skin, such as melanoma and squamous cell carcinoma. References: Goldblum JR, Hart, WR. Perianal Paget's disease: a histological and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol. 1998;22:170-179. Grelck KW, Nowak MA, Doval M. Signet ring cell perianal Paget disease: loss of MUC2 expression and loss of signet ring cell morphology associated with invasive disease. Am J Dermatopathol. 2011;33:616-620. Iacobuzio-Donahue CA. Inflammatory and Neoplastic Disorders of the Anal Canal. In: Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, pp. 733-761. Odze RD and Goldblum JR, Eds. Philadelphia: Saunders Elsevier, 2009. Kuan SF, Montag AG, Hart J, Krausz T, Recant W. Differential expression of mucin genes in mammary and extramammary Paget's disease. Am J Surg Pathol. 2001;25:1469-1477. Lian P, Gu WL, Zhang Z, et al. Retrospective analysis of perianal Paget's disease with underlying anorectal carcinoma. World J Gastroenterol. 2010;16:2943- 2948. Masuguchi S, Jinnin M, Fukushima S, et al. The expression of HER-2 in extramammary Paget's disease. Biosci Trends. 2011;5:151-155. McCarter MD, Quan SH, Busam K, Paty PP, Wong D, Guillem JG. Long-term outcome of perianal Paget's disease. Dis Colon Rectum. 2003;46:612-616. Mitchell KA, Owens SR. Anal carcinoma and its differential diagnosis. Diagn Histopathol. 2008;14:61-67. Nowak MA, Guerriere-Kovach P, Pathan A, Campbell TE, Deppisch LM. Perianal Paget's disease: distinguishing primary and secondary lesions using immunohistochemical studies including gross cystic disease fluid protein-15 and cytokeratin 20 expression. Arch Pathol Lab Med. 1998;122:1077-1081. Owens SR. Paget Disease. In: Greenson JK, et al. Diagnostic Pathology: Gastrointestinal, pp 6-16—6-21. Salt Lake City: Amirsys, 2010.