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Genital Paget’s disease in a man

European Journal of Dermatology. Volume 16, Number 1, 75-8, January-February 2006, Clinical report

Summary

Author(s) : Walter Krause, Andreas Krisp, Stefan Hörster, Rolf Hoffmann , Department of Andrology and Venerology, University Hospital, Philipp University, Deutschhausstr. 9, D-35033 Marburg, Germany, Department of Dermatology and Allergology, University Hospital, Philipp University, Marburg, Germany, Department of Dermatology, Albert-Ludwigs-Universität, Freiburg i. Br., Germany.

Summary : Pagetoid cells are large intraepidermal cells which spread intraepidermally. We report a 67-year old Caucasian male, who presented for the first time in 1993 with a long-standing pruritic lesion at the scrotum. He was treated for several years by antiinflammatory ointments. Only in July 2003 was a biopsy taken for the first time. The histopathological evaluation revealed the diagnosis of an extrammamary Paget’s disease (EMPD). Pagetoid cells are large intraepidermal cells with a large nucleaus and ample cytoplasm. EMPD consists of primary malignant cells of epidermal origin, but in rare cases, pagetoid cells may also originate from carcinomas with epidermotropic growth. EMPD is a slowly progressing disease, but invading and metastasing tumors may also develop. Considering the good prognosis with long-term survival, nonsurgical modalities should be considered as primary treatment for noninvasive EMPD.

Keywords : EMPD, Paget disease

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ARTICLE

Auteur(s) : Walter Krause¹, Andreas Krisp¹, Stefan Hörster², Rolf Hoffmann³

¹Department of Andrology and Venerology, University Hospital, Philipp University, Deutschhausstr. 9, D-35033 Marburg, Germany
²Department of Dermatology and Allergology, University Hospital, Philipp University, Marburg, Germany
³Department of Dermatology, Albert-Ludwigs-Universität, Freiburg i. Br., Germany

accepté le 19 Avril 2005

Extramammary Paget’s disease represents an unusual malignant neoplasia localized in sites with a high density of apocrine glands, such as the anogenital region, with a predilection for older individuals. Clinically, it presents as an erythematous, eczematoid, slowly spreading plaque. Interactable pruritus is a common presenting symptom. About 25% of all cases have an underlying cutaneus adnexal carcinoma, mostly of apocrine type. A further 10% of patients have an internal carcinoma.Pagetoid cells are large intraepidermal cells with a large nucleus and ample cytoplasm. The tumor cells in Pagets’s disease have abundant pale cytoplasm and large pleomorphic nuclei and contain mucopolysaccharides that are positive with PAS and alcian blue methods in about 60% of cases. The cells are arranged singly or in groups involving the entire thickness of the epidermis with the greatest concentration in the basal and parabasal regions. Occasional cells have an eccentric nucleus and the appearance of a signet ring. The tumor cells have relatively poor intercellular cohesion and often undergo detachment from one another, which results in the formation of “pseudobullae”. Mitoses are usually present.Most frequently, Paget’s disease occurs around the nipple as a consequence of the intraepidermal spread of an underlying mammary carcinoma. These pagetoid cells are cells of the carcinoma. Paget’s disease also occurs at extramammary sites, mostly in the genitoanal skin (extramammary Paget’s disease, EMPD) in women, while genitoanal EMPD in men is rare. Other sites of EMPD are the axilla, the eyelid, the oral cavity and the exernal ear canal. The origin of these cells is unclear, most authors assume a relationship to apocrine glands, since they occur in apocrine gland-bearing skin [1] and most but not all Paget cells stain positively for GCDFP-15, a marker of apocrine cells [2]. Woodruff and Seeds [3] stated that since the epidermis and their appendages, including apocrine glands, are derived from the same embryonic precursor cells, EMPD represents a malignant transformation of basal stem cells resting in the epidermis of the adult.

Case report

A Caucasian male, born in 1926, presented in our department for the first time in 1993. He presented a lesion on the scrotum, which he had observed since several years. He had been treated for tinea corporis, irritant and allergic contact dermatitis. However, no treatment modality solved the problem. In 1995, a patch test was performed to exclude contact dermatitis. It revealed positive reactions to paramix, nickel, and formaldehyde. The scrotal lesions were unchanged at that time. The patient continued to apply the ointments for the next few years.

In 2003, the patient returned to our clinic. We found an oval shaped, erythematous, non-scaling, tender lesion on the left part of the scrotum with a diameter of approx. 5 cm in length (( figure 1 )). The patient returned to our clinic in July 2003. At this time, a biopsy was taken for the first time. The histopathological evaluation revealed the diagnosis of an EMPD (( figure 2 )). These cells stained positive for CEA (( figure 3 )). Additionally, immunohistologic stainings (Prof. Moll, Institute of Pathology, University Hospital Marburg) revealed strongly positive reactions to cytokeratin 7 and to cytokeratin 18, but no reaction to cytokeratin 20, and a strongly positive reaction to the appocrine marker GCDFP 15. No inguinal lymphomas were present, no further staging was done.

After having established the diagnosis, treatment with Aldara^® (imiquimod) was initiated. The patient, however, stopped the treatment after only two weeks owing to the severe irritation caused by imiquimod. The patient also refused the treatment with ALA-PDT, which was offered subsequently. Instead of this, he returned to the treatment with an ointment containing corticosteroids and antimycotics.

In December 2004, he presented again in our clinic. There were two oval shaped, erythematous, non scaling lesions at the left part of the scrotum of a diameter of about 5 cm, with slight papillomatous surface. Inguinal lymph nodes were not palpable.

The patient was handicapped by a leg amputation 50 years ago. He was operated on the aortic valve in 1997, since that time he had been treated with ASS and cumarine. He suffered from benign prostatis hyperplasia, but until now, no prostatic cancer had been diagnosed.

Discussion

Pagetoid cells are also found in clinically normal skin. They were first described in the normal nipple by Toker [5] in 11% of cases. He also described an increase in the number of these cells along the milk ridge as “clear cell papulosis”. Thus pagetoid cells may not be primarily malignant. Up to now, an association of this clear cell papulosis and EMPD has not been demonstrated, although it was speculated that Toker cells also occur outside the nipple [6]. Val-Bernal and Garijo [4] described pagetoid dyskeratosis as a special kind of epidermolytic hyperkeratosis in intertriginous areas.

When using CK7 as a marker, Lundquist et al. [7] were able to identify Toker cells in the nipple in 15/18 autopsy cases. Positive staining for CK7 is also common in EMPD. Lau and Kohler [8] published a literature survey and found descriptions of positive CK7 staining in EMPD in 99 of 105 cases. EMPD did not express CK 5 or 6. The important differential diagnosis of EMPD, pagetoid squamous cell carcinoma in situ, showed CK7 staining in none of the cases. However, squamous cell carcnoma and EMPD shared the staining with CEA antibodies.

In EMPD, malignant pagetoid cells appear, which behave like an intraepidermal in-situ carcinoma. In comparison to other in-situ carcinomas, their malignant potential may be limited. Zollo and Zeitouni [9] quoted 21 patients with EMPD, in which the follow-up was up to 233 months in scrotal EMPD. Also the other scrotal diseases of that study (6 cases) were pre-invasive, but 6/21 vulvar EMPD showed invasive disease. Tulchinsky et al. [10] confirmed the benign course in their observation of 5 patients. In our patient, the lesions were observed for at least 11 years (132 months).

Only in some cases do the primarily intraepidermal pagetoid cells form an invasive neoplasm and only at this stage do lymphogenic metastases become possible. In a series of Hatta et al. [11], 4 of 13 patients with genital EMPD had positive sentinel lymph nodes, three of them also developed distant metastases. In the series of Lai et al. [1], 33 patients with peno-scrotal EMPD were treated and followed up from 1982 to 2001. An underlying adnexal carcinoma was observed in 7/33 patients. 3/33 had distant metastases and ultimately died of metastatic carcinoma. As expected, the risk of lymphogenic metastases corresponds to the level of invasion of the pagetoid cells. In 14/33 patients the EMPD was limited to the epidermis, in 10/33 the pilosebaceous unit was involved, and in 7/33 an infiltrating adnexal carcinoma was diagnosed. Patients with invasion of the dermis had a worse prognosis than patients without.

Tsutsumida et al. [12], who reported on 34 patients, confirmed the prognostic significance of the level of invasion. In patients showing carcinoma in-situ or micro-invasion to the papillary dermis, no patients appeared to have any lymph node involvement. When invasion to the reticular dermis or to subcutaneous tissues was evident, 8 of 12 patients showed lymph node metastasis, and all of them died due to metastasis of the tumor. Obviously, the invasion occurs at a late stage of the disease, but indicates a fatal course. Kim et al. [13] observed in 2/7 cases with EMPD, who had been followed for many years, a fulminant progression with liver metastasis after the first detection of inguinal lymph nodes.

Enjoji et al. [14] described a novel tumor-related antigen RCAS1 (receptor binding cancer antigen expressed on SiSo cells, a cell line of cervical cancer) and found it to be expressed in a high percentage of EMPD. The serum levels of the protein were increased in a case with metastases in the retroperitonem and the liver. RCAS1 is expressed by many carcinomas, its specifity is low, but it may also be of use as a marker of disease activity in EMPD.

Malignant pagetoid cells in the epidermis may also originate from carcinomas with epidermotropic growth. The term Paget’s disease originally refers to cells of a breast cancer, which spread intraepidermally. Other examples for intraepidermal spread of pagetoid cells of carcinomas were reported by Salamanca et al. [15], who observed two patients with bladder carcinoma, where EMPD-like lesions occurred at the glans and Allan et al. [16], who described a patient with carcinoma of the prostate presenting with a EMPD-like lesion. The intraepidermal tumour cells expressed prostate-specific antigen. The cases of metastatic carcinoma resembled primary EMPD, but their immunostaining pattern was identical to that of the primary tumor [4].

Additionally, approximately 5% of cutaneous squamous cell carcinomas in situ (SCCIS) also have a pagetoid pattern, referred to as pagetoid Bowen’s disease. It cannot be differentiated from EMPD by CK7 staining. In the studies of Raju et al. [17] and Williamson et al. [18], unlike the pagetoid cells of EMPD, SCCIS were devoid of mucin and were not immunoreactive with GCDFP-15, CEA, CAM5.2, and c-erbB2, CK20, S-100, and Melan A.

Treatment of EMPD is usually performed by surgical procedures. Unfortunately, there is a high rate of recurrence, up to 50% depending on the method of surgery, due to the fact that the disease extends beyond the clinically visible margins [9]. Considering the good prognosis with long-term survival, nonsurgical modalities should be considered as alternative treatment for noninvasive EMPD [10]. In cases like in our patient, where EMPD was stable over years, the treatment may be symptomatic. A trial with imiquimod 5% cream [19, 20] or photodynamic therapy, using topical aminolaevulinic acid (ALA-PDT; [21]) can also be recommended. Ablative treatment with CO2 laser appears to be possible. A final estimation of the recurrence rate of these treatments is not possible at this time, but in the study of Shieh et al. [21], 3/8 EMPD recurred at 9 to 10 months. Patients with aggressive, invasive EMPD, however, should definitely be treated with radical surgery and adjuvant radiation or chemotherapy.

References

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