Genital Paget's disease and urinary tract malignancy

Journal of the American Academy of Dermatology

J orizzo et al

9. 10.

11. 12. 13. 14.

15.

syndrome: Immune regulation, circulating immune complexes, neutrophil migration, and colchicine therapy. J AM ACAD DERMATOL 10:205-214, 1984. Levinsky RJ, Lehner T: Circulating soluble immune complexes in recurrent oral ulceration and Behget's syndrome. Clin Exp Immunol 32:193-198, 1978. Nazzarro P: Cutaneous manifestations of Behc;et's disease, in Monacelli M, Nazzarro P, editors: International Symposium on Behc;et's Disease, Rome, 1964. Basel, 1966, S. Karger AG, pp. 15-41. Muller W, Lehner T: Quantitative electron microscopical analysis of leukocyte infiltration in oral ulcers ofBehc;et's syndrome. Br J Dermatol106:535-544, 1982. Djawari D, Hornstein OP, Schotz J: Enhancement of granulocyte chemotaxis in Behget's disease. Arch Dermatol Res 270:81-88, 1981. Jorizzo IL: Pustular vasculitis: An emerging disease concept. I AM ACAD DERMATOL 9:160-162, 1983. Braverman 1M, Yen A: Demonstration of immune complexes in spontaneous and histamine-induced lesions and in normal skin of patients with leukocytoclastic angiitis. I Invest DermatoI64:105-112, 1975. Iorizzo IL, Daniels JC, Apisarnthanarax P, et al: Histamine triggered localized vasculitis in patients with sero-

16.

17.

18. 19. 20.

21.

positive rheumatoid arthritis. J AM ACAD DERMATOL' 9:845-851, 1983. Davis BK, Cavallo T: Membranoproliferative glomerulonephritis: Localization of early components of complement in glomerular deposits. Am J Pathol 84:283398, 1976. Nelson RD, Quie PG, Simmons RL: Chemotaxis under agarose: A new and simple method of measuring chemotaxis and spontaneous migration of human polymorphonuclear leukocytes and monocytes. J Immunol115: 1650-1656, 1975. Boyum A: Isolation of mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest (suppl 97) 21:77-89, 1967. Agnello V: Immune complex assays in rheumatic diseases. Hum PathoI14:343-349, 1983. Ritzmann SE, Daniels JC: Immune complexes;' Characteristics, clinical correlations, and interpretive approaches in the clinical laboratory. Clin Chern 28: 12591271, 1982. Iorizzo JL, Schmalstieg FC, Dinehart SM, et al: Bowelassociated dermatosis-arthritis syndrome: Immune complex-mediated vessel damage and enhanced neutrophil migration. Arch Intern Med 144:738-740, 1984.

Genital Paget's disease and urinary tract malignancy Frank C. Powell, M.B., M.R.C.P.I., Johannes Bjornsson, M.D., John A. Doyle, M.B., and Alan J. Cooper, M.B., B.Sc. Rochester, MN Eight cases of Paget's disease of genital mucosa with malignancy of the lower urinary tract are described. In five it was apparent that there was concurrence of two separate malignancies. In one patient with long-standing Paget's disease of the genital mucosa, carcinoma of the urethra and bladder developed subsequently in continuity with the genital lesion; the two lesions were indistinguishable histologically, suggesting extension of the Paget's disease into urothelium. In two patients with bladder malignancy, there was histologic evidence of outward pagetoid extension of this process along urothelium and onto the genital mucosa. The significance of genital Paget's disease is discussed in the light of these findings, and the possible origins of Paget cells within the epidermis are reviewed. (J AM ACAD DERMATOL 13:84-90,

1985.)

From the Departments of Dermatology and Pathology, Mayo Clinic and Mayo Foundation. Accepted for publication Feb. 27, 1985. Reprint requests to: Dr. John A. Doyle, Mayo Clinic, 200 First St. SW, Rochester, MN 55905.

84

Cutaneous disease of the mammary areola as a manifestation of cancer of the mammary gland was described by Sir James Paget l in 1874 and became known as Paget's disease of the breast. Paget's disease occurs less frequently in extra-

Volume 13 Number I July, 1985

mammary sites, and its significance is not as well understood as Paget's disease of the breast. The anogenital region is typically involved, although cases of epidermal Paget's disease have been reported in the axilla,2,3 eyelid,2.4 and external auditory canal. 5 Clinically, Paget's disease appears as an erythematous exudative dermatitis, usually with a well-defined margin. Histologically, the characteristic findings are large, pale cells within the epidermis; in these cells the cytoplasm is pale, the nucleus is large, and a prominent nucleolus frequently is observed. These cells usually occur in the suprabasilar region of the epidermis and also may be found in the cutaneous appendages. Granules that are positive and diastase-resistant on the periodic acid-Schiff test are found within the cytoplasm, 6 which helps to distinguish these cells from those of melanoma or Bowen's disease. The origin of these cells is uncertain, however. The association of Paget's disease of the breast and underlying ductal adenocarcinoma has been clearly established. The relationship ofPaget's disease of extramammary sites to internal malignancy is less clear. In a study by Helwig and Graham7 of forty patients with anogenital extramammary Paget's disease, 33% had an underlying adnexal carcinoma and an additional 25% had internal or cutaneous malignancy. In patients with perianal Paget's disease, carcinoma of the rectum is the most common internal malignancy found. 8 We wish to draw attention to the less-frequent but equally important association of Paget's disease of the genital mucosa with carcinoma of the lower urinary tract. We report eight cases in which this association was seen. CLINICAL OBSERVATIONS Seven women and one man who had Paget's disease of the genital region and of the lower urinary tract were seen at the Mayo Clinic between 1960 and 1982. The cases are summarized in Table 1.

Cases 1 to 5 In Case 1, genital Paget's disease was followed by the discovery of transitional cell carcinoma (TCC) of the bladder, whereas Case 2 demonstrates the onset of TCC in the bladder with subsequent metastasis to the vagina and then apparently coincidental appearance of Paget's disease of the vulva. In Case 3, Paget's disease

Paget's disease and urinary tract malignancy 85

of the vagina became apparent 18 months after operation for TCC of the bladder. The onset of genital Paget's disease predated the development of urinary tract carcinoma by 3 years in Case 4. Despite the extension of TCC from the bladder along the urethra and the coexistence of Paget's disease of the genital mucosa, these cancers were probably unrelated in this patient. A 13-year history of genital Paget's disease in Case 5 was followed by the discovery of Tce of the bladder. This patient remains well with a follow-up of 2 years to date.

Case 6 In this patient, Paget's disease of the vulva was discovered at age 54 years. Partial vulvectomy was carried out, but recurrence of the Paget's disease necessitated radical vulvectomy 18 years later. In 1970, at 76 years of age, she underwent removal of the uterus, vagina, and a portion of the urethra and perineum for recurrence of extensive exudative Paget's disease (Fig. 1, A). Histologic examination revealed intraepithelial pagetoid adenocarcinoma of the vulva (Fig. 1, B), vagina, distal urethra (Fig. 1, C), and cervical epithelium (Fig. 1, D), including endocervical mucus glands. Mucin stains were strongly positive in sections from all sites. The patient made a good recovery from her operation but died 3 years later of unrelated causes. This case represents invasion of long-standing genital Paget's disease into internal genitalia and the urethra.

Case 7 This patient presented in 1962 with itching and burning of the vulvar region. Radical vulvectomy with vaginectomy and removal of a portion of the uterine cervix was carried out, and histologic examination showed invasive grade 4 TCC of the urethra. Extending contiguously on the vulva was typical intraepidermal adenocarcinoma of Paget's disease, suggesting intraepidermal spread of an initial TCC of the urethra to the vulvar mucosa.

Case 8 At 56 years age, in 1971, this man presented with dysuria and hematuria. Cystoscopy and biopsy showed an invasive grade 3 Tce of the bladder (Fig. 2, A), which was treated with fulguration. He remained well for the next 9 years, but in August, 1980, he presented with induration of the penis. Urethrectomy was performed and revealed grade 3 TCe of the urethra, spreading within the urothelium in a pagetoid fashion (Fig.

Joumal of the American Academy of Dermatology

86 Powell et al

Table 1. Salient features of cases Case No.

Sex

F 2

F

3

F

4

F

5

F

6

F

7

F

8

M

Extent of Paget's disease

Urinary tract rnalignancy (TCC)

Vulva, vagina, periurethral tissue Vulva

Grade 4 TCC, bladder

Sequence

Paget's disease; discovery of TeC 8 yr later

Grade 4 TCC, bladder

TCC of bladder; recurrenee 6 yr later and diagnosis of Paget's disease Vulva, vagina, Grade 3 TCC, TCC of bladder; 18 mo endocervical bladder later, Paget's disease glands of genital mucosa Vulva, vagina, Grade 3 TCC, Paget's disease of geniperineum bladder, uretalia; TCC of bladder ter, urethra 3 yr later Vulva Grade 2 papillary Paget's disease of vulva; TCC, bladder TCC of bladder 13 yr later Vulva, urethra, Paget's disease, Genital Paget's disease vagina, cerurethra for 22 yr; eventual inVIX volvement of urethra Pagetoid extension of Vulva, vagina Grade 4 TCC, TCC of urethra noted (pagetoid urethra histologically extension of TCC) Bladder TCC; urethral Glans penis Grade 3 TCC, (pagetoid bladder, urepagetoid TCC 9 yr extension of later; pagetoid inthra TCe) volvement of glans penis 3 yr after that

2, B). In May, 1983, a small area of erythematous

exudative dermatitis was noted on the lateral margin of the glans penis (Fig. 2, C). Biopsy showed intraepidermal carcinoma or Paget's disease (Fig. 2, D). Local excision of the affected area was carried out. In this patient, TeC of the bladder was followed by the appearance of a similar carcinoma of the urethra, which demonstrated pagetoid spread within the urothelium. Finally, pagetoid cens appeared on genital mucosa. This sequence of events suggests extension of the initial bladder carcinoma to the urethra and subsequently to the glans penis. DISCUSSION

Extramammary Paget's disease may occur alone or in association with other malignancies. The malignancies previously reported to occur with it are summarized in Table II. Probably the most commonly discovered malignant disease is that of adjacent or underlying secretory glands,4,5,7,9-15 and

Follow-up (yr)

25 1

6

4 4

Outcome

Recurrent Paget's disease; death after cystectomy for TCC Death from metastatic TCC of bladder Recurrent Paget's disease; death from metastatic carcinoma of bladder Recurrent Paget's disease of central mucosa; alive and well Recurrent Paget's disease of vulva; alive

15

Recurrent Paget's disease of vulva; alive and well

113

Death from metastatic TCC of urethra

13

Recurrent TCC; alive and well

metastasis may occur from these carcinomas and cause the death of the patient. 14 Rectal carcinoma appears to be the most frequently detected malignancy in patients with perianal Paget's disease. 8 ,16-2J Carcinomas of the breast,7 cervix,22,23 ovary,24,25 pancreas,26 or prostate27-30 have been reported in patients with anogenital extramammary Paget's disease. In several cases of rectal carcinoma, spread of this malignancy in a pagetoid fashion in the epithelium to the perianal skin has been suggested. There have been several previous reports of cases of genital Paget's disease with urinary tract malignancy, although this association has not achieved wide recognition. Some cases represented apparently nonrelated appearance of two malignancies. Four patients had carcinoma of the urethra or bladder not in continuity with Paget's disease of the genital mucosa; both malignancies

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Paget's disease and urinary tract malignancy 87

Fig. 1. Case 6. A, Extensive exudative Paget's disease ofperineuill and vagina. B, Typical Paget cell in biopsy from vulva. C, Paget's disease in urethra. D, Involvement of cervix. (Hematoxylin-eosin stain; B, x 55; C, x 100; D, x 110.)

apparently arose spontaneously.7,22,31,32 Another patient with multiple recurrent and apparently benign bladder papillomas, who eventually required cystectomy, developed Paget's disease of the vulva 14 years after the initial bladder lesion was diagnosed. 33 In two cases of long-standing Paget's disease of the genital region, apparent extension of pagetoid cells into the urethra was documented histologically.24,27 In another series of eighteen cases of genital Paget's disease, there was his to-

logic evidence of involvement of the urethra by the disease in nine. 24 A patient with long-standing Paget's disease of the vulva had apparent extension of the process into the urethra, bladder, and uterus; eventually, lymphatic and hematogenous dissemination produced metastatic lesions in the lymph nodes, vertebral column, and liver, causing death of the patient. 34 Intraepithelial spread can occur with malignancy of the bladder,35,36 and pagetoid spread from

88

Powell et at

Journal of the American Academy of Dermatology

.

".

I"'.

",-

Fig. 2. Case 8. A, Grade 3 TCC of bladder. B, Nine years after biopsy of bladder, TCC is found in urethral lining. Note pagetoid appearance of cells. C, Appearance of glans penis, showing eczematoid reaction, typical clinically of Paget's disease. D, Biopsy from glans penis, showing typical Paget cells. (Hematoxylin-eosin stain; A, x 50; Band D, x 100.)

the bladder to the urethra and to genital mucosa has been documented. 37 •38 In one case, intraepithelial pagetoid extension of a grade 1 papillary epidermoid bladder carcinoma occurred about a suprapubic cystectomy site. 39 Similar pagetoid extension has been documented with prostatic carcinoma spreading to the urethra and bladder. 27.29.30 Thus it appears from previously reported cases that Paget's disease of the genital mucosa may appear simultaneously with, but is apparently otherwise unrelated to, carcinoma of the urinary tract. However, Paget's disease of genital mucosa may extend into the urethra and possibly even the bladder, and malignancy originating in the bladder and urethra can extend in a pagetoid fashion to involve the genital mucosa and so produce the clinical and histologic features of Paget's disease.

The cases we have described here seem to be consistent with these three patterns. Cases 1 to 5 appear to represent the concurrence·of two separate malignancies without continuity and with clearly distinctive histologic patterns. In Case 6, longstanding and recurrent Paget's disease of the vulva appears to have extended to the cervical epithelium and into the distal urethra. The anatomic continuity, the histologic appearance, and the use of mucin stains suggest that this was a continuous process. In Cases 7 and 8, however, extension of urothelial carcinoma in a pagetoid fashion to genital mucosa is the most likely sequence of events. In Case 7 a grade 4 TCC of the urethra extended in continuity to the epithelium of the vulva. Case 8 demonstrates the sequential appearance of TCC of the bladder followed by pagetoid extension into

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Table II. Malignancies reported in patients with extramammary Paget's disease Apocrine gland carcinoma Eccrine gland carcinoma Carcinoma of Moll's glands Ceruminal gland carcinoma Carcinoma of Bartholin's gland Perianal gland carcinoma Adenocarcinoma of rectum Carcinoid of ileum Adenocarcinoma of br~ast Carcinoma of ureter, bladder, and urethra Adenocarcinoma of prostate Carcinoma of cervix Adenocarcinoma of ovary Carcinoma of pancreas

the urethra and followed, finally, by a histologically similar eruption on the penis, with the typical clinical appearance of genital Paget's disease. The precise nature and origin of the Paget cells of extramammary Paget's disease remain an enigma. Multiple theories of origin have been advanced. Electron microscopic studies have supported both an apocrine 40 and an eccrine origin 41 .42 for these cells. Histochemical studies showing staining of extramammary Paget's disease cells for carcinoembryonic antigen43 ,44 and apocrine epithelial antigen45 have also supported an adnexal secretory gland origin for these cells. Indeed, metastatic Paget's disease of the genitalia recently has been associated with an increased serum level of carcinoembryogenic antigen. 46 We think that the cases reported here and those in the literature indicate that the cells in Paget's disease of genital mucosa may have multiple origins. In some cases these cells appear to arise in the epidermis without any underlying or associated malignancy. However, an exhaustive search of underlying secretory glands in these cases may reveal a malignant change, and malignancy of secretory glands is probably the most commonly associated malignancy. In some cases, as may be seen in perianal Paget's disease, the pagetoid cells may represent an intraepithelial extension of an adenocarcinoma of the rectum. On the genital mucosa, Paget's disease also may represent the outward pagetoid extension of a urothelial malignancy. Although this appears to occur rarely, it

Paget's disease and urinary tract malignancy 89

must also be remembered that long-standing genital Paget's disease can extend inward to the cervix and urinary tract. When treating a patient who has genital Paget's disease, the dermatologist must consider the possible origins of these cells, and appropriate investigations, depending on the clinical circumstances, must be undertaken. The ability of the Paget cells of the external genital mucosa to spread inward and invade urothelium reinforces the importance of a thorough clinical evaluation of vaginal, cervical, and urothelial tissue. In view of the high frequency of recurrence and ability to invade tissue, wide surgical excision is the treatment of choice for this form of dermatosis. REFERENCES 1. Paget J: Disease of the mammary areola preceding cancer

2. 3. 4. 5.

6. 7. 8. 9. 10.

11. 12. 13.

14.

of the mammary gland. St Bartholomew's Hosp Rep 10:87-89, 1874. Miki Y, Kawatsu T, Kawatsu T, et al: Axillary involvements in genital Paget's disease. J Dermatol (Tokyo) 6:25-29, 1979. Imai S, Nitto H, Imai R: Axillary Paget's disease. J Dennatol (Tokyo) 8:245-252, 1981. Whorton CM, Patterson JB: Carcinoma of Moll's glands with extramammary Paget's disease of the eyelid. Cancer 8:1009-1015,1955. Fligiel Z, Kaneko M: Extramammary Paget's disease of the external ear canal in association with ceruminous gland carcinoma: A case report. Cancer 36:1072-1076, 1975. Belcher RW: Extramammary Paget's disease: Enzyme histochemical and electron microscopic study. Arch PathaI 94:59-64, 1972. Helwig EB, Graham JH: Anogenita1 (extramammary) Paget's disease: A clinicopathological study. Cancer 16:387-403, 1963. Williams SL, Rogers LW, Quan SHQ: Perianal Paget's disease: Report of seven cases. Dis Colon Rectum 19:3040, 1976. Rosser EI, Hamlin 1MB: Paget's disease of the vulva. J Obstet Gynaecol Br Empire 64:127-130, 1957. Plachta A, Speer FD: Aprocrine-gland adenocarcinoma and extramammary Paget's disease of the vulva: Review of the literature and report of a case. Cancer 7:910-919, 1954. Becker SW Jr, Brennan B, Weichse1baum PK: Genital Paget's disease. Arch Dennato1 82:857-862, 1960. Murrell TW Jr, McCullan FH: Extramammary Paget's disease: A report of two cases. Arch Dermatol 85:8292, 1962. Roth LM, Lee SC, Ehrlich CE: Paget's disease of the vulva: A histogenetic study of five cases including ultrastructural observations and review of the literature. Am J Surg Pathol 1: 193-206, 1977. Mitsudo S, Nakanishi I, Koss LG: Paget's disease of the

90

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

30.

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penis and adjacent skin: Its association with fatal sweat gland carcinoma. Arch Pathol Lab Med 105:5 18-520, 1981. Paget GE, Rowley HA, Woodcock AS: Paget's disease of the vulva: Report ofa case. J PathoI67:256-259, 1954. Dockerty MB, Pratt JH: Extramammary Paget's disease: A report of four cases in which certain features of histogenesis were exhibited. Cancer 5:1161-1169, 1952. Foraker AG, Miller CJ: Extramamrnary Paget's disease of perianal skin. Cancer 2:144-152, 1949. Grow JR, Kshirsagar V, Tolentino M, et al: Extramammary perianal Paget's disease: Report of a case. Dis Colon Rectum 20:436-442, 1977. Pinkus H, Gould SE: Extramammary Paget's disease and intraepidermal carcinoma. Arch Dermatol Syph 39:479502, 1939. Grimes OF: Extramammary Paget's disease. Surgery 45:569-574, 1959. Arminski TC, Pollard RJ: Paget's disease of the anus secondary to a malignant papillary adenoma of the rectum. Dis Colon Rectum 16:46-55, 1973. Lee SC, Roth LM, Ehrlich C, Hall JA: Extramammary Paget's disease of the vulva: A clinicopathologic study of 13 cases. Cancer 39:2540-2549, 1977. Jones RE Jr, Austin C, Ackerman AB: Extramammary Paget's disease: A critical reexamination. Am J Dermatopatholl:101-132, 1979. Taylor PT, Stenwig JT, Klausen H: Paget's disease of the vulva: A report of 18 cases. Gynecol Oncol 3:46-60, 1975. Sonck VCE: Ein Fall von Paget'scher Erkrankung der Vulva. Dermatologica 102:151-160,1951. Fardal RW, Kierland RR, Clagett QT, Woolner LB: Prognosis in cutaneous Paget's disease. Postgrad Med 36:584593, 1964. Chierego F, Fabris P: Sulla (propagazione intraepitheliale) del carcinoma prostatico alIa vescica. Tumori 43:203-209, 1957. Oka M, Saita B, Nakashima K: Simultaneous prostatic carcinoma and genital Paget's disease associated with subjacent adenocarcinoma. Br JUral 51:49, 1979. Ortega LG, Whitmore WF Jr, Murphy AI: In situ carcinoma of the prostate with intraepithelial extension into the urethra and bladder: A Paget's disease of the urethra and bladder. Cancer 6:898-923, 1953. Salazar G, Frable WJ: Extramammary Paget's disease: A case involving the prostatic urethra. Am J Clin Pathol 52:607-612, 1969.

Journal of the American Academy of Dermatology 31. Pitman GH, McCarthy JG, Perzin KH, Herter FP: Extramammary Paget's disease. Plast Reconstr Surg 69: 238-244, 1982. 32. Fenn ME, Morley GW, Abell MR: Paget's disease of vulva. Obstet Gynecol 38:660-670, 1971. 33. Koss LG, Ladinsky S, Brockunier A Jr: Paget's disease of the vulva: Report of 10 cases. Obstet GynecoI31:513525, 1968. 34. Kay JM, Southwood WFW: Paget's disease of the vulva associated with an unusual bladder tumour. Br J Cancer 18:233-237, 1964. 35. Krumerman MS, Katatikam V: Rhabdomyosarcoma of the urinary bladder with intraepithelial spread in an adult. Arch Pathol Lab Med 100:395-397, 1976. 36. Iwasaki H, Enjoji M, Kano M: Nonpapillary carcinoma in situ of the urinary bladder: A histopathologic study and mapping of the urothelial lesions. Acta Pathol Jpn 29:623-633, 1979. 37. Gowing NFC: Urethral carcinoma associated with cancer of the bladder. Br J Urol 32:428-438, 1960. 38. Turner AG: Pagetoid lesions associated with carcinoma of the bladder. J UroI123:124-126, 1980. 39. Eversole JW: Extra-mammary Paget's disease: Discussion of pathogenesis. South Med J 45:28-30, 1952. 40. Demopoulos RI: Fine structure of the extramammary Paget's cell. Cancer 27:1201-1210, 1971. 41. Koss LG, Brackunier A Jr: Ultrastructural aspects of Paget's disease of the vulva. Arch Pathol 87:592-600, 1969. 42. Ferenczy A, R,ichart RM: Ultrastructure of perianal Paget's disease. Cancer 29:1141-1149,1972. 43. Nadji M, Morales AR, Girtanner RE, et al: Paget's disease of the skin: A unifying concept of histogenesis. Cancer 50:2203-2206, 1982. 44. Mazoujian G, Pinkus GS, Haagensen DE Ir: Extramammary Paget's disease-evidence for an apocrine origin: An immunoperoxidase study of gross cystic disease fluid protein-15, carcinoembryonic antigen, and keratin proteins. Am J Surg Pathol 8:43-50, 1984. 45. Kariniemi A-L, Forsman L, Wahlstrom T, et al: Expression of differentiation antigens in mammary and extramammary Paget's disease. Br J DermatolllO:203-210, 1984. 46. Oji M, Fume M, Tamaki K: Serum.carcinoembryonic antigen level in Paget's disease. Br J DermatolllO:211213, 1984.