A Case of Concurrent Extramammary Paget Disease and Basal Cell Carcinoma of the Perianal Region.

An 83-year-old Japanese man who had been aware of a tumor near his anus for 2 years underwent tumor resection. Although he was diagnosed with basal cell carcinoma (BCC), extramammary Paget disease (EMPD) was also accidentally found in the same specimen. In the pathological histology of EMPD, there were large round cells with ample cytoplasm spread in the epidermis; these cells were positive for cytokeratin 7 and gross cystic disease fluid protein 15. No signs that are typically associated with EMPD, such as erythema or leukoderma, were observed near the anus. There have been only 4 reports in which BCC and EMPD developed in the same area, and the authors present the fifth case. In the reported case, no clear evidence was found for the corelative development of BCC and EMPD.

Basal cell carcinoma (BCC) is skin cancer with a relatively good prognosis and commonly presents in the exposed area of the head and neck; the incidence of BCC in the anal region is very low, accounting for less than 1% of all BCC cases.[1] Whereas the etiology of BCC in the unexposed area remains not fully understood, several factors can be deduced, such as chronic irritation, infection, trauma, burn scar, radiotherapy, advanced age, and human papillomavirus.[1] In histopathological findings of BCC, basaloid cells with nuclear mitotic activity form nodules and/or strands of atypical in the dermis, and fissure formation is often seen between the tumor lobules and the surrounding tissue.

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma derived from the apocrine sweat gland, commonly found in the vulva, anus, and axilla of elderly people. Several oncogenic mutations, associated with gene mutations of Ras/Raf and PI3K (Phosphoinositide 3-kinase)/Akt signal pathways, have been discovered by recent genetic analysis study; however, the etiology of cancer development has not been fully elucidated.[2,3] EMPD are classified into 2 types, primary(of cutaneous origin) and secondary(of extracutaneous origin), and several kinds of immunohistochemical staining are useful to distinguish one from the other. Primary EMPD is expected to be arisen from abnormally differentiated epidermal stem cells extending into the epidermis or appendages.[3] On the other hand, secondary EMPD results from intraepithelial spreads or intraepithelial metastasis of an underlying malignancy, mainly gastrointestinal or urothelial carcinoma.[3]

BCC and EMPD are quite different from each other, pathologically, embryologically, and biologically. There are only 2 foreign reports and another 2 cases in Japan that describe EMPD and BCC occurring simultaneously in the same region. We report a case in which EMPD was coincidentally discovered in the same specimen when anal BCC was excised.

CASE REPORT

An 83-year-old man was aware of an anal nodule and pain for several years. The patient had a history of hepatic cirrhosis due to chronic hepatitis C, hepatocellular carcinoma, hypertension, and myocardial infarction. Bleeding from the mass, he visited a hospital and underwent a biopsy. The tumor was diagnosed as BCC, and he underwent consultation to our department for surgical purposes. A black protuberant tumor with a diameter of 10 mm was on the right side of the anus, and no lesions of the erythema or white spots were found around the tumor (Fig. 1). We performed the first resection against the tumor at a 5-mm margin under local anesthesia. From pathological findings, BCC was observed in the center of the resected specimen, which was negative in the stump. Furthermore, Paget cells with pale cytoplasm that included round or oval nuclei were observed in the epidermis close by BCC. Figure 2 shows a sliced specimen that 2 tumors co-occur, BCC on the right side and EMPD on the other (Fig. 2A). In the interstice between them, there was a gap of approximately 2 mm in which Paget cells were not found. Immunohistochemical staining revealed the cells to be positive for cytokeratin 7 (CK7), gross cystic disease fluid protein 15 (GCDFP-15), and Mucin 5AC and negative for cytokeratin 20 (CK20), carcinoembryonic antigen, and mammaglobin. The staining pattern of CK7 and CK20 suggests that EMPD originated from the epidermis rather than the skin infiltration of gastrointestinal cancer. There were no other overlapping cancers in the scrotum, axilla, and intestinal tract. Because the stump of EMPD was positive, we made the additional surgery for the remaining EMPD after skin mapping by punch biopsies around the initial surgical wound and around the anus. As a result of the second surgery, no malignant cells, including Paget cell in the epidermis, were found in the surgical specimen. Follow-up observations of the patient have revealed no recurrence for 1 year.

Fig. 1.

Clinical findings: a nodule in the right side of the anus (arrow). No erythema and vitiligo around the tumor.

Fig. 2.

Pathological findings of EMPD and BCC: (A), EMPD (left) and BCC (right) are both involved in the same specimen, and there are no neoplasm cells between the 2 tumors. B, EMPD includes large round cells with abundant and clear cytoplasm in the epithelium. C, Basophilic cells in the dermis form the nest, nodular BCC (hematoxylin–eosin).

DISCUSSION

EMPD is a rare cutaneous carcinoma and diagnosis is frequently delayed because of its unremarkable cutaneous signs. In early EMPD, minor depigmentation spots are observed, followed by irregularly pale red spots like eczema, accompanied by an incongruity and itching. Eventually, irregular induration and nodules appear, often with vice lesions away from the main lesion. The so-called double or triple Paget disease, which occurs frequently in the vulva and axilla where the apocrine gland is distributed, is widely known. The incidence of underlying adnexal carcinoma has been reported to vary, for example, Chanda[4] found that 24% of 196 cases from English literature from 1962 to 1982 had an underlying adnexal carcinoma. In a Japanese study, Kamiya[5] reported that in 2008 about 11.3% of patients with EMPD have malignant tumors, including gastric cancer, colon cancer, prostate cancer, lung cancer, breast cancer, liver cancer, and so on.

Histopathological findings of EMPD show that nucleoli are clearly distinct, and characteristic Paget cells, with circular or oval nucleus and bright cytoplasm, grow in the epidermis and sometimes in the epithelium of the appendages. Paget cells are positive in periodic acid schiff (PAS) staining and alcian blue pH2.5 staining, and the most common immunohistochemical markers positive for Paget cells are CK7, carcinoembryonic antigen, anticytokeratin, and GCDFP-15.[3] Differential diagnosis of intraepidermal Pagetoid neoplasms includes Bowen disease (squamous cell carcinoma in situ) and superficial spreading of malignant melanoma in situ, which can be distinguished by histologic presence using several immunochemical markers. Melanoma in situ is positive for S-100 protein and human melanin black-45 (HMB45), and Bowen disease is positive for AE1AE3 (pancytokeratin), protein 63 (p63), and eventually CK7.[6] Regarding perianal lesion of Paget disease, immunohistochemical staining should be enforced to distinguish whether its origin is the epidermis itself (primary EMPD) gastrointestinal cancer (secondary EMPD, so-called Pagetoid phenomenon). Although the tumor derived from the epidermis is positive for CK7 and negative for CK20, it expresses the opposite pattern and is negative for GCDFP-15 when the tumor is secondarily derived from the intestine.[3,6]

The literature review by the authors includes 4 case reports where BCC and EMPD occurred simultaneously in the same region. The first report in which BCC occurred within EMPD of the vulva was made by Ishizawa et al[7] in 1998. Table 1 summarizes the demographic and clinical variables in 5 patients, including our case.[7-10] There are 2 major opinions on a mechanism by which BCC and EMPD co-occur: a theory that one tumor plays a contributing role in the occurrence of the other tumor,[7,9] and a theory that 2 tumors arise individually with no causal relevance between them.[8,10] We believe the latter theory is more likely in our case for the following 2 reasons. First, on histopathological examination, BCC and EMPD are definitely parted from each other by the epithelium with no malignant cells. Second, it was impossible to prove a temporal relationship between the 2 tumors in our case; for example, if the onset of BCC evidently preceded that of EMPD, it can be hypothesized that the occurrence of BCC reduced local immunity in some way and contributed to the occurrence of EMPD; however, in the present case, we could not know which of them first occurred because of the defect of cutaneous signs of EMPD and whether one interferes with the other. In conclusion, we inferred 3 potentialities in the occurrence of EMPD in our case, immunodeficiency due to cirrhosis, complication with underlying internal malignancy (hepatocellular carcinoma), and completely independent occurrence. However, which of them is true could not be proven in just 1 case.

Table 1.

Summary of Clinical Features of 5 Patients with Concurrent BCC and EMPD

Reference (Year)	Age/Sex	Location	Clinical Presentation of BCC	Clinical Presentation of EMPD	Immunohistology	Treatment
Ishizawa et al[7] (1998)	85/Woman	Vulvar	Ulceration	Erythema	CEA(+)	—
Kobayashi et al[8] (2003)	52/Man	Scrotum	14 × 12 mm nodule	Vitiligo	—	Wide resection with 3 cm margin from vitiligo lesion
Abdelbaqi et al[9] (2012)	82/Woman	Vulvar	A heaped-up erythema lesion	Erythema (recurrence of EMPD)	—	Radial vulvectomy
Kang et al[10] (2016)	73/Woman	Scalp	20 mm nodule	Alopecia	CAM5.2(+), CK7(+)	Wide local resection
This case (2017)	83/Man	Perianal	10 mm nodule	None	CK7(+), GCDFP-15(+), MUC5AC(+)	Wide local resection around the last scar

CAM5.2, anticytokeratin; CEA, carcinoembryonic antigen; MUC5AC, Mucin 5AC.

SUMMARY

We experienced a case of concurrence of BCC and EMPD around the anus; however, the mechanism by which 2 different skin cancers coexisted remains unknown in our case. With the aging of the population in the future, an increase in the number of patients with multiple skin cancers is expected. Attentive immunochemical staining may be useful to distinguish a perianal tumor from other conceivable differential diagnoses.

ACKNOWLEDGMENT

The authors would like to thank Dr. Kazuo Ono for his assistance in the pathological diagnosis of this case.