Case 5 -
Secondary Perianal Paget Disease
Scott Owens, University of Michigan, Ann Arbor, MI
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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).
Primary perianal Paget disease Secondary perianal Paget disease Anal melanoma with pagetoid spread
Anal squamous cell carcinoma with pagetoid spread Anal gland/duct adenocarcinoma
Secondary perianal Paget disease
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.
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.
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