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THE JOURNAL OP UROLOGY

Copyright © 1978 by The "\iVilliarns

VVilkins Co.

PENILE PAGETiS DISEASE AND PROSTATIC CARCINOIVIA MARIA J. MERINO, VIRGINIA A. LIVOLSI*

AND

BERNARD LYTTON

From the Departments of Pathology and Urology, Yale University School of Medicine, New Haven, Connecticut

ABSTRACT

A case ofprostatic adenocarcinoma and penile Paget's disease, a unique association, is reported. Possible histogenetic mechanisms are considered and the differential diagnosis of penile Paget's disease is discussed. Extramammary Paget's disease may occur in any site where apocrine glands are present, including the vulva, perianal

we report a case of penile Paget's disease and prostatic carcinoma, an association not recorded previously.

Fm. 1. A, photomicrograph of moderately differentiated adenocarcinoma in prostatic biopsy infiltrating stroma. B, crushed carcinoma cells (lower right) are seen within small nerve in prostatic biopsy. Reduced from x400.

skin, axilla and umbilicus. An underlying carcinoma, usually of the apocrine sweat gland type, is found in 50 to 80 per cent of the cases. 1 Paget's disease rarely involves the penis. Herein Accepted for publication September 30, 1977. * Requests for reprints: Department of Pathology, Yale University School of Medicine, 310 Cedar St., New Haven, Connecticut 06510.

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CASE REPORT

A 68-year-old white man was seen initially in 1967 because of recurrent episodes of urinary sepsis. N eurovesical dysfunction had developed after an injury in an automobile accident 4 years previously. An excretory urogram disclosed bilateral hydroureteronephrosis with some atrophy and scarring of the renal parenchyma bilaterally. A cystogram demonstrated a

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MERINO, LIVOLSI AND LYTTON

markedly trabeculated bladder with bilateral low pressure vesicoureteral reflux. There was only partial emptying on voiding. A left cutaneous ureterostomy and a right-to-left ureteroureterostomy were done. The degree of dilatation improved and the episodes of urinary sepsis ceased. The patient was rehospitalized in 1974 with a 1-year history of repeated excoriation of the penis. Pertinent physical findings were limited to urologic examination. A small, well circumscribed, hyperpigmented eczematous lesion was noted on the dorsum of the glans penis. There was no inguinal adenopathy. The prostate was hard and indurated, and it was difficult to determine whether there had been any change from prior examinations, since the patient had had previous transurethral resections of the prostate to reduce the outlet resistance. Laboratory examinations disclosed normal or negative results. Serum acid phosphatase was 4.3 units with a prostatic fraction of 1.1 units. Cystoscopy showed a stricture of the urethra and a small, contracted trabeculated bladder. Prostatic biopsy revealed a moderately well differentiated adenocarcinoma. Bilateral orchiectomy was done. Although 5-fluorouracil was applied topically to the penile lesion the excoriated area became larger and ulcerated, and inguinal adenopathy developed. After biopsy a partial penectomy was done. However, the disease progressed with perineal pain and enlargement of the inguinal nodes. Palliative radiation was administered to the prostate and the inguinal region but the condition of the patient deteriorated rapidly and he died 1 year later. Permission for post mortem examination was refused. PATHOLOGY

Prostatic biopsy. The core of prostatic tissue showed an infiltrating, moderately, well differentiated adenocarcinoma (fig. 1, A) with perineural invasion (fig. 1, B). Penile lesion. The penectomy specimen showed a slightly raised gray-red crusted lesion on the glans. Microscopically, the epidermis in the biopsy and resection specimens was infiltrated by large clear cells singly or in clusters (fig. 2). These cells, which had small nuclei, contained intracytoplasmic periodic acid, Schiff positive diastase resistant material. Zones of hyperkeratosis and ulceration with a focal dermal inflammatory response were seen. Special stains gave similar results in the prostatic and penile lesions (table 1). No invasive carcinoma was identified in the penile stroma and the penile urethra appeared to be uninvolved. DISCUSSION

The pathogenesis of Paget's disease remains unknown. In the breast, which is the most common location for this lesion, Paget's disease of the nipple always implies that an underlying ductal carcinoma will be found in that breast. 2 In extramammary Paget's disease an associated carcinoma, usually of the apocrine type, is recognized in 50 to 80 per cent of the cases. 1 When no underlying cancer is found, even on careful microscopic evaluation, the lesion is believed to arise via neoplastic transformation of intraepidermal extensions of sweat gland ducts. 3 Some cases of extramammary Paget's disease have occurred in patients with adenocarcinomas of the non-apocrine type. Thus, the perianal Paget's lesion has been associated with rectal carcinoma. 4· 5 Despite the important neoplastic significance of Paget's disease the bistogenesis of the epidermal lesion remains controversial. Several theories have been proposed but objections may be raised to each of them. 6 Cheatle suggested the spontaneous development of carcinoma in the squamous epithelium of the epidermis and underlying apocrine ducts simultaneously. 7 The absence of dyskeratosis near the epidermal lesion or of squamous differentiation in the underlying tumors contraindicates this concept. 6 Pinkus and Gould proposed that

FIG. 2. Paget's disease of penis. Note clear cells in surface epithelium. Reduced from x240. TABLE

1. Staining reactions ofprostatic and penile lesions

Periodic acid, Schiff Periodic acid, Schiff-diastase Alcian blue (pH 2.5) Fontana-Masson

Penile Paget's Disease

Prostatic Ca

Pos. Pos. Pos. Neg.

Pos. Pos. Pos. Neg.

Paget's cells represent metastasis of carcinoma cells to the epidermis. 8 The finding of a non-invasive or minimally invasive underlying cancer and the late development of metastases to other tissues do not support this hypothesis. 6 Paget's cells may represent parasitic malignant elements of extraepidermal origin that are guided via an epidermotrophic mechanism to the overlying epithelium. 2 • 9 Electron microscopic studies of mammary and extramammary Paget's disease have shown ultrastructural similarities between Paget's and apocrine gland cells. 9• 10 Ferenczy and Richart concluded that migration of underlying cancer cells to the epidermis was the favored theory of histogenesis of Paget's disease in any location. 9 The migration theory could explain the development of the perianal Paget's disease in patients with rectal carcinoma.4· 5 Murrell and McMullan objected to this hypothesis and indicated that the defluvial current of epithelium is directed toward the alveolar spaces of apocrine glands and not toward the epidermis. 6 It has been suggested that Paget's disease reflects a multicentric malignant transformation of histogenetically similar cells that migrate together during embryonic life. 6 These cells would then respond independently to a neoplastic stimulus. This hypothesis explains skip areas between the underlying

123 lesion. Also, it would account for a.11.1c1.au.11su Paget's disease without associated cases of carcinoma.° Although some authors question the embryologic , evidence others accept this theory. 11 In our patient the absence of tumor within the urethra or penile stroma suggests that the last theory may be most applicable. The case of prostatic carcinoma associated with urethral Paget's disease reported by Salazar and Frable also fits the multicentric origin theory." Paget's disease of the penis must be differentiated from other dermatologic conditions occurring in this region, including erythroplasia of Queyrat, Bowen's disease, epidermoid carcinoma and melanoma. 12 Erythroplasia of Queyrat, a precancerous lesion that can simulate Paget's disease clinically, is characterized microscopically by acantolytic plaques with parakeratosis, thickening of the epidermis and a marked inflammatory reaction. 13 The absence of large clear cells in the epidermis differentiates it from Paget's disease. Bowen's disease is considered squamous carcinoma in situ. 12 The presence of abnormal atypical cells, bizarre mitotic figures and full thickness involvement of the epidermis distinquishes this entity from Paget's disease. Erythroplasia and Bowen's disease may progress to invasive squamous carcinoma. 12 • ,:, Carcinoma of the penis is nearly always epidermoid and resembles squamous cell carcinoma occurring elsewhere. It is characterized by the presence of intracellular bridges and keratin formation. Paget's cells are not seen in these tumors. Malignant melanoma may produce difficulties in differential diagnosis, especially if the lesion is amelanotic (table 2).1. 12 • 14 Taki and Janovski, in a survey for patients with malignant melanoma of the vulva, reported 3 cases that were misdiagnosed and reclassified as extramammary Paget's disease. 14 Although useful for demonstrating melanin pigment in melanoma cells the Fontana stain may disclose the presence of melanin granules within the cytoplasm of the Paget's cell. It has been postulated that the melanin granules are transferred from the melanocytes to squamous or Paget's cells in the epidermis and, hence, the Fontana stain may be misleading. 1• However, other histochemical stains may prove useful in differentiating melanoma from Paget's disease. The presence of mucin, demonstrable alcian green, alcian blue or mucicarmine stains, affords a reliable diagnostic criterion. Periodic acid, Schiff reagent gives a positive stain with Paget's cells before and after diastase treatment, whereas malignant melanoma is negative. Hence, melanoma cells contain no mu.copolysaccharides. 14 If an adenocarcinoma is present the diagnosis of assured. However, abnormal

TABLE

2. lv!elanoma versus Pagefs disease

Histological differences: Basal layer of epidermis intact in Paget's disease Junctional neurocytic component found in melanoma Underlying adenocarcinoma frequently found in Paget's disease Histochemical differences: Paget's and melanoma cells may contain melanin Paget's cells but not melanoma cells can contain mucin Electron microscopic differences: Melanoma cells- contain pre-melanosomes and melanosomes, not found in Paget's cells Paget's cells resemble apocrine cells o:r apocrine duct cells, 10 or eccrine duct cells'

melanocytes or the presence of a nevus favors the diagnosis of melanoma. 12 REFERENCES

1. Mitchell, R. E.: Mammary and extramammary Paget's disease.

Aust. J. Derm., 15: 51, 1974. 2. Haagensen, C. D.: Diseases of the Breast. Philadelphia: W. B. Saunders Co., 1971. 3. Creasman, W. T., Gallager, H. S. and Rutledge, F.: Paget's disease of the vulva. Gynecol. Oncol., 3: 133, 1975. 4. Williams, S. L., Rogers, L. W. and Quan, S. H.: Perianal Paget's disease: report of seven cases. Dis. Colon Rectum, 19: 30, 1976. 5. Jackson, B. R.: Extramammary Paget's disease and anaplastic basaloid small cell carcinoma of the anus: report of a case. Dis. Colon Rectum, 18: 339, 1975. 6. Murrell, T. W., Jr. and McMullan, F. H.: Extramammary Paget's disease. A report of two cases. Arch. Derm., 85: 600, 1962. 7. Cheatle, G. L.: Paget's disease of the nipple. Brit. J. Surg., 11: 295, 1923. 8. Pinkus, H. and Gould, S. E.: Extramammary Paget's disease and intraepidermal carcinoma. Arch. Derm. Syph., 39: 479, 1939. 9. Ferenczy, A. and Richart, R. M.: Ultrastructure of perianal Paget's disease. Cancer, 29: 1141, 1972. 10. Neilson, D. and Woodruff, J. D.: Electron microscopy in in-situ and invasive vulvar Paget's disease. Amer. J. Obst. Gynec., 113: 719, 1972. 11. Salazar, G. and Frable, W. J.: Extramammary Paget's disease: a case involving the prostatic urethra. Amer. J. Clin. Path. 52: 607, 1969. 12. Eisenberg, R. B. and Theuerkauf, F. J.: Extramammary Paget's disease: report of a case. Amer. J. Clin. Path., 25: 642, 1955. 13. Graham, J. H. and Helwig, E. B.: Erythroplasia of Queyrat. A clinicopathological and histochemical study. Cancer, 32: 1396, 1973. 14. Taki, I. and Janovski, N. A .. Paget's disease of the vulva: presentation and histochemical study of four cases. Obst. Gynec., 18: 385, 1961.

Penile Paget's disease and prostatic carcinoma.

0022-5347 /78/1201-0121$02. 00/0 Vo:, Printed THE JOURNAL OP UROLOGY Copyright © 1978 by The "\iVilliarns VVilkins Co. PENILE PAGETiS DISEASE AND...
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