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Abstract
Extramammary Paget's disease is an intraepithelial neoplasm, usually found in areas rich in apocrine gland concentration. The clinical features, histopathology, immunohistochemistry and management details of five patients (F = 3, M = 2) have been described here. While a well-defined persistent plaque with crusting and erosion was the most common presentation, hyperpigmentation, hypopigmentation and depigmentation were also observed in two patients. Characteristic Paget's cells with cytokeratin 7 and EMA positivity were seen on histopathology examination. Authors conclude that pigmentary alterations may be under-reported in extra mammary Paget's disease in the skin of colour.
Keywords: Cytokeratin 7, epithelial membrane antigen (EMA), extra mammary Paget's disease, paget cells, skin of colour
Introduction 
Extra mammary Paget's disease (EMPD) is a rare cutaneous malignancy, usually occurring in the areas of apocrine gland concentration, such as the axillae, anus or genitalia. It is an intraepithelial adenocarcinoma and can either be primary or be associated with cancers of nearby uro-gynaecologic structures like fallopian tubes, ovary, adnexae, testes, prostate, bladder, colon or rectum. It often mimics other genital dermatoses like recalcitrant psoriasis or eczema, leading to the diagnosis getting delayed by many years. In this retrospective series, we aimed to study the clinical, pathological and immunohistochemical characteristics of patients with confirmed extra mammary Paget's disease.
Materials and Methods The clinical, pathologic and immunohistochemical details of all the patients who had confirmed extra mammary Paget's disease between December 2017 and December 2021 were included in the study. All cases with a confirmed venereal or other aetiology were excluded. Relevant details of the patients were noted from clinical notes and pathological forms. This included patient demographics, medical history, presenting symptoms, physical examination, histological findings, treatment and follow-up outcomes.
Results A total of five patients (F = 3, M = 2) were examined. All patients were presented in the fourth or fifth decade of life, with one female being 39 years old. Clinically, three patients were presented with non-healing crusted erosions, while pigmentary alterations were present in the remaining two patients (one female with a hyperpigmented plaque with central hypo-depigmentation and one male with depigmented psoriasiform plaque). The pathological hallmark of Paget cells was seen in all the cases. IHC markers were performed in all cases which showed expression of cytokeratin 7 and EMA. While females underwent per speculum and per vaginum examination, the male patients underwent per rectal and prostate examination, to rule out contiguous spread from adjacent visceral malignancies. Relevant investigations like cystoscopy, colonoscopy, mammography and intravenous pyelogram were performed, which did not exhibit any abnormalities. All the patients were subjected to USG abdomen and pelvis. The clinical details, treatment and follow-up of individual patients are described below.
Case 1
A 48-year-old male patient was presented with a 9 × 8 cm erythematous, glazed, ulcerated, plaque with nodularity over the scrotum and extending onto the undersurface of the shaft of the penis, for the last 31 months [Figure 1]a. There was mild itching and oozing associated with a little bleeding. A differential diagnosis of Bowen's disease, squamous cell carcinoma and varicocele ulcer was kept in mind. A punch biopsy was submitted for histopathological examination. There was the intraepidermal presence of large, round, malignant cells with pale blue cytoplasm and pleomorphic nuclei within lacunar spaces which were typical of Paget's cells [Figure 2]a, [Figure 2]b, [Figure 2]c. The cells were present singly as well as in clusters. IHC revealed cytokeratin 7 and EMA positivity [Figure 3]a, [Figure 3]b, [Figure 3]c. Subsequently, USG abdomen and pelvis were advised along with cystoscopy and colonoscopy to look for a primary malignancy. Excision of the plaque was suggested, and the patient was referred to surgery; however, he was lost to follow-up.
Figure 1: (a) Glazed, ulcerated, nodular plaque over the scrotum of 48-year-old male (b) Erythematous to hypopigmented psoriasiform plaque over the scrotum of 50-year-old male (c) Well-defined erosion over labia, inguinocrural fold and inner thigh of 39-year-old female (d) Well-defined hyperpigmented, slightly hypertrophic plaque, with central hypo-depigmentation over labia majora of 53 year-old-female (e) Well-defined depigmented plaque with peripheral hyperpigmentation, 10 x 7 cm, over labia majora and minora
Figure 2: (a) Large, round, malignant cells with pale blue cytoplasm and pleomorphic nuclei typical of Paget's cells present in epidermis, haematoxylin and eosin, 40X (b) Epidermis shows presence of clusters of cells with abundant pale blue cytoplasm and large vesicular nuclei, haematoxylin and eosin, 100X (c) Presence of mitotic figures, haematoxylin and eosin, 400X
Figure 3: (a and b) Immunohistochemistry showing cytokeratin 7 positivity (100×) c) EMA positivity in the lesional cells within the epidermis (400×)Case 2
A 50-year-old male patient was presented with a well to ill-defined erythematous to hypopigmented psoriasiform plaque measuring 11 × 6 cm over the scrotum, extending onto its under surface, for a duration of 22 months [Figure 1]b. He had been treated previously as eczema with topical steroids with no improvement. Skin biopsy revealed full-thickness epidermal dysplasia with pale-staining vacuolated Paget cells. IHC showed cytokeratin 7 and EMA positivity. Imaging studies did not reveal any abnormalities. The patient was referred to an onco-surgeon for further management.
Case 3
A 39-year-old female was presented with itching and oozing over the vulva for the last 9 months. On examination, there was a well-defined erosion measuring 6 × 7 cm over labia majora, extending onto the inguinocrural fold and inner thigh on the right side [Figure 1]c. The lesion was associated with a moderate amount of sero-sanguineous discharge along with burning and pain. She had not taken any treatment previously, and this was her first visit to a doctor. There was no regional lymphadenopathy. An incisional biopsy from the specimen revealed intraepidermal dysplasia with pale round cells typical of Paget cells. Cytokeratin 7 and EMA stained positive on IHC. The pap smear was negative. Mammography, CXR, USG pelvis and other directed scopies did not reveal any abnormality. Wide local excision was performed under regional anaesthesia, and the patient continues to be disease free at 14 month's follow-up.
Case 4
A 53-year-old postmenopausal woman was presented to our OPD with a hyperpigmented, thick plaque with sharp borders, with burning and itching over the pubis for the past 24 months. She had visited multiple doctors in the past and had variably been treated with topical steroids and antifungals with no improvement. On examination, there was a 5 × 6 cm well-defined hyperpigmented, mildly hypertrophic plaque, with central hypo-depigmentation over the right labia majora [Figure 1]d. There was mild peri-lesional erythema with lichenification. A 4 × 4 mm punch biopsy revealed the presence of Paget cells within the epidermis with CK7 and EMA positivity noted on IHC. The dermo-epidermal junction was not breached. Following this, imaging diagnostics were run but were normal. A hemi-vulvectomy was performed, and the patient remained lesion free at the last follow-up at 8 months.
Case 5
A 47-year-old peri-menopausal female was presented with 13 months' history of slowly enlarging itchy lesions of the groin. On examination, there was a well-defined erythematous moist plaque of size 10 × 7 cm with scaling, crusting and mild oozing, involving the entire labia majora [Figure 1]e. There was no history of bladder or bowel disturbances. Skin biopsy showed large round cells with ample pale-staining cytoplasm, suggestive of Paget cells, scattered throughout the epidermis. A few similar cells were noticed in the hair follicles also. Cytokeratin 7 and EMA positivity was noted on IHC. Patient was advised USG abdomen and pelvis, pap smear, mammography and colonoscopy and was counselled regarding surgery. However, she was lost to follow-up.
Discussion Extra mammary Paget's disease is a rare entity, and its exact incidence is unknown. Although widely reported in Caucasian women, its prevalence in the skin of colour is likely under-reported. It is seen in areas of high apocrine gland concentration like the genitalia, underarms and anus.
Two forms are described: primary and secondary, each believed to have its own distinct pathogenesis. The primary form is intraepithelial in origin and likely arises from pluripotent cells. This type of EMPD is not associated with internal malignancy, although long-standing cases can become locally invasive over a period of time. Secondary EMPD, however, is believed to be secondary to contiguous spread from a nearby internal malignancy.
On examination, they present as a well-defined erythematous plaque with scaling, ulceration and bleeding, associated with burning, pain or itching. Depigmented to hypopigmented macules to patches have been described in East Asian patients.[1] Hypertrophic and verrucous lesions may occur.[2] The authors reviewed the published Indian literature on EMPD and found that while many images showed the presence of pigmentary alterations (hypo-, de-, and hyperpigmentation), the same was not reflected in the case description in those reports.[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] Hence, we believe that pigmentary changes in EMPD may be under-reported in brown-skinned individuals, reflecting a lack of awareness about the same.
The most common site of involvement is the vulva, comprising nearly 65% of all cases of EMPD, followed by the perianal region, accounting for about 20% of all cases of EMPD and then male genitalia, which accounts for 11% of all cases. Rare presentations include familial EMPD and involvement of 'ectopic' sites like eyelids, abdomen and cheek, which are devoid of any apocrine glands. Synchronous EMPD, with simultaneous lesions over multiple sites like anogenital and axillary regions, can also occur. Differential diagnoses include other conditions like eczema, intertrigo, psoriasis or fungal infections, Langerhans cell histiocytosis, squamous cell carcinoma in situ or mycosis fungoides. Depigmented lesions with erosions are often confused with lichen sclerosus et atrophicus (LSA). Sexually transmitted infections and HIV/AIDS must always be excluded.[15]
Skin biopsy with special immunohistochemistry (IHC) stains is diagnostic. Paget cells are seen, which are large, round, atypical intraepithelial, cells containing pale-staining vacuolated cytoplasm and pleomorphic nuclei with occasional prominent nucleoli. The large cytoplasmic vacuoles are due to abundant mucin secretion by these cells, which is easily recognised by histochemical stains such as PAS, alcian blue, colloidal iron and mucicarmine E (copy paste). Immunohistochemical markers like carcinoembryonic antigen (CEA), EMA, GCDFP-15 and cytokeratin 7 are positive and help in the diagnosis of EMPD. Histopathological differential diagnoses include pagetoid Bowen's disease and pagetoid malignant melanoma. The distinction of EMPD from the latter diseases by a panel of IHC markers is important as EMPD is often associated with visceral malignancies.[16]
Once the diagnosis is confirmed on histopathology, an aggressive search must be mounted to look for any other associated malignancy, as over one-third of the cases are associated with internal malignancy. The type of malignancy depends upon the location of the lesion as well as gender. For example, perianal lesions usually co-occur with rectal or anal adenocarcinoma; scrotal lesions in males are seen with prostate, testes or bladder cancer and lesions in females are seen in association with tubo-ovarian or cervical cancers. Hence, organ-specific investigations are indicated, for example, per vaginal examination with pap smear, per rectal and prostate examination, mammography, proctoscopy, colonoscopy and cystoscopy. The physician may request for an ultrasound abdomen and pelvis with a CT or MRI scan if there is a suspicion of visceral malignancy. Locally invasive disease along with positive sentinel lymph node biopsy indicates a poor prognosis. Although PET CT has been used, it may not be able to pick up microscopic metastases.
Multi-disciplinary approach through a team of dermatologists and onco-surgeons is ideal. Wide local excision can have recurrence rates as high as 30–60%, and hence, Mohs micrographic surgery is considered as the treatment of choice. It must be remembered that the disease often extends sub-clinically under normal appearing skin, and this may lead to positive margins at the time of resection. Other treatments that have been tried include photodynamic therapy, radiotherapy, CO2 ablation and medical therapy with 5-fluorouracil, imiquimod and bleomycin. With regard to chemotherapy, there is no fixed regimen and multiple regimens have been tried. While primary EMPD has a good prognosis, in secondary EMPD, the prognosis depends on the underlying malignancy.[1]
Conclusion Extra mammary Paget's disease is usually described in Caucasian women or Asian men in the age group of 60–80 years. Our case series is unique for the relatively lower age at presentation. It is also one of the fewer series described in the South Asian population. Our data suggest that pigmentary alterations (both depigmentation and hyperpigmentation) in EMPD may be more common in brown-skinned individuals. A high degree of suspicion is required in all patients not responding to topical corticosteroids or antifungals for groin lesions. A panel of IHC markers should be carried out while encountering intraepidermal atypia in a site known to be rich in apocrine glands. A correct diagnosis is important because EMPD can be associated with visceral malignancy and warrants age-appropriate cancer screening panels. Our series adds to the current literature on EMPD in the skin of colour.
Limitation
Small sample size was a limitation of the study.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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