PERIANAL PAGET\'S DISEASE

Perianal Paget's Disease Report of Three Cases J. TJANDRA, M . B . , B.S. (MELB), F . R . C . S . ( E N G ) , F . R . C . S . ( G L A S )

Tjandra J. Perianal Paget's disease: report of three cases. Dis Colon Rectum 1988:31;462-466. Three cases of perianal Paget's disease are presented. Clinically, three patients had a chronic irritating perianal rash resistant to hydrocortisone cream. One patient had an underlying rectal adenocarcinoma. The controversies in the histogenesis of Paget's cells in perianal Paget's disease remain unresolved, but it appears that perianal Paget's disease probably is more than one disease and is biologically different from mammary Paget's disease. [Key words: Extramammary Paget's disease; Perianal Paget's disease; Paget's cells]

PAGET'S DISEASE OF the n i p p l e w a s first d e s c r i b e d by Sir J a m e s P a g e t i n 1874. t E a c h of t h e 15 p a t i e n t s h e d e s c r i b e d w a s s u b s e q u e n t l y f o u n d to h a v e u n d e r l y i n g i n t r a d u c t a l c a r c i n o m a of the breast. A l t h o u g h P a g e t a l l u d e d to s i m i l a r l e s i o n s i n e x t r a m a m m a r y sites b y des c r i b i n g a s i m i l a r l e s i o n o n the p e n i s , t h a t l e s i o n is n o w t h o u g h t to h a v e b e e n e r y t h r o p l a s i a of Q u e y r a t . 2 T h e first c e r t a i n d e s c r i p t i o n of e x t r a m a m m a r y P a g e t ' s disease w a s m a d e by C r o c k e r i n 1889 i n a p a t i e n t w i t h p e n i l e a n d s c r o t a l i n v o l v e m e n t , s S i n c e t h a t t i m e , P a g e t ' s disease a l s o has b e e n d e s c r i b e d i n o t h e r a p o c r i n e g l a n d - b e a r i n g areas: v u l v a ? p e r i a n a l skin, z a x i l l a , 2 g r o i n , 2 eyelid, 4 e x t e r n a l a u d i t o r y c a n a l , 4 u m b i l i c u s , a n d nose. 5 T h e r e are, h o w ever, b i o l o g i c d i f f e r e n c e s b e t w e e n m a m m a r y a n d extram a m m a r y P a g e t ' s disease. T h r e e i n t e r e s t i n g cases of p e r i a n a l P a g e t ' s disease are p r e s e n t e d to i l l u s t r a t e s u c h differences. Received for publication September 24, 1987. Address correspondence to Dr. Tjandra: Research Centre for Cancer and Transplantation, University of Melbourne, Parkville, Vic. 3052, Australia.

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From the Department o[ Surgery, East Glamorgan Hospital, Upper Church Village, Pontypridd, South Wales, United Kingdom

R e p o r t o f Cases Patient 1: A 76-year-old man, who was well previously, had a twoyear history of pruritus ani and painful defecation of more recent onset. He had been treated by various topical ointments including hydrocortisone cream with no improvement. There were no other gastrointestinal symptoms. On physical examination, an erythematous and indurated area, extending 4 cm circumferentially from the anus, was found (Fig. 1). Digital examination revealed a hard mass at the lower rectum. There were no other abnormal physical findings; in particular, there was no palpable inguinal lymphadenopathy. Proctosigmoidoscopy confirmed the rectal lesion but otherwise showed no other abnormality. Histologic examination of the perianal skin biopsy showed numerous Paget's cells in the epidermis, mainly in the basal portions (Fig. 2). A diagnosis of perianal Paget's disease was therefore made; however, biopsy of the rectal lesion itself revealed an invasive adenocarcinoma of the rectum. Abdominoperineal resection with wide excision of the cutaneous component was performed. Pathology of the resected specimen confirmed a Dukes' A carcinoma of the rectum with total clearance of the perianal Paget's disease, Examination 12 months after surgery revealed no evidence of recurrent disease. Patient 2: A 76-year-old man had a two-year history of perianal irritation and discomfort. There were, however, no associated gastrointestinal symptoms. He also suffered from chronic angina and had a myocardial infarction four years previously. On physical examination, there were extensive erythematous lesions extending 5 to 7 cm circumferentially from the anus (Fig. 3). Rectal examination was normal. Proctosigmoidoscopy to 18 cm failed to reveal any other abnormality. Multiple biopsies of the perianal lesion showed hyperkeratosis with a moderate number of large, clear cells with signet ring appearance in the basal portions of the epidermis. These cells stained strongly blue

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with the alcian blue-PAS technique, indicating the presence of acid mucin. The diagnosis was perianal Paget's disease. The pathologic process was limited to the epidermis and there was no associated invasive carcinoma in any of the biopsies. The patient refused further treatment and was therefore followed in the clinic. There was no clinical deterioration or development of invasive carcinoma clinically until his death two years later from a massive myocardial infarction. Patient 3: A 90-year-oldwoman presented with a two-year history of pruritus ani and perianal discomfort. She was otherwise well with no other symptoms. She had been treated with various topical dermatologic ointments with no improvement. On examination, the involved skin was erythematous and finely papular, extending 3 to 5 cm circumferentially from the anus (Fig. 4). Rectal and proctosigmoidoscopic examinations were normal. Multiple biopsies were taken that again confirmed perianal Paget's disease with no invasion or associated carcinoma. The patient refused surgery and was treated with topical I percent 5-fluorouracil ointment. Four months after treatment there was some symptomatic improvement and the involved skin was not as weepy and inflamed. Discussion

P e r i a n a l Paget's disease is a n u n c o m m o n entity. I n 1893, Darier a n d C o u i l l a r d reported the first case of e x t r a m a m m a r y p e r i a n a l Paget's disease. 6 A review of the literature i n 1977 by G r o w et al. revealed o n l y 38 cases of the c o n d i t i o n a n d they added a n o t h e r of their own. 7 Since then, Jones et al., 2 M a c L a u g h l i n a n d M a n s o n ? L a n g s ford a n d Kermode, 4 S u b b u s w a m y a n d Ribeiro, 9 P i t m a n et al., TM Secco et al., 11 a n d G i l t m a n et al. 1~ were able to c o n t r i b u t e a d d i t i o n a l cases a n d at the present time, it appears that there are o n l y 55 cases of p e r i a n a l Paget's disease reported i n the E n g l i s h medical literature. Since some cases are u n r e p o r t e d or unrecognized, the true incidence is u n k n o w n . Of these 55 reported cases, 38 (69 percent) cases were associated w i t h u n d e r l y i n g m a l i g n a n c y (Table 1). T w e n t y (36 percent) were associated w i t h u n d e r l y i n g c a r c i n o m a

Fig. 2 (Patient 1). Photomicrograph showing Paget's cells in the anal mucosa with underlying infiltratingadenocarcinoma (hematoxylin and eosin X 100).

FIG. 1 (Patient 1). Perianal Paget's diseaseappearing as erythematous rash.

of a p o c r i n e or eccrine origin, 12 (22 percent) w i t h carcinom a of the rectum, six (11 percent) w i t h c a r c i n o m a of the a n u s , three of w h i c h were s q u a m o u s - c e l l carcinoma, two of cloacogenic c a r c i n o m a , a n d o n e of colloid c a r c i n o m a of the a n a l glands. I n 17 cases (31 percent), however, there was n o evidence of a n y u n d e r l y i n g malignancyY,4, 7-t2 T h e present cases b r i n g to 13 the n u m b e r associated w i t h rectal c a r c i n o m a a n d to 19 the n u m b e r n o t associated with underlying malignancy. Conceivably, however, some of the cases reported to have n o u n d e r l y i n g m a l i g n a n c y m a y have a small, sweatg l a n d c a r c i n o m a overlooked o n r o u t i n e histologic seo

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TABLE1. Case Reports of Perianal Paget's Disease in the Literature2d-13,1~

Associated With

Number (percent)

Apocrine or eccrine carcinoma Rectal carcinoma Anal carcinoma No carcinoma TOTAL

FIG. 3 (Patient 2). Extensive perianal Paget's disease appearing as erythematous plaque.

20 (36) 12 (22) 6 (11) 17 (31) 55 (100)

tioning of the specimen and the usual pathologic reports are based on "representative sections." A true serial sectioning is necessary to avoid this but to do so would be highly uneconomical because of the size of the specimen. In contrast, the entire nipple can be studied easily with just a few sections. 1~ 13 Such a wide spectrum of presentation indicates that perianal Paget's disease is probably more than one disease with different pathologic processes, with or without underlying malignancy. It is, therefore, not analogous biologically to m a m m a r y Paget's disease, which invariably is associated with underlying ductal carcinoma, despite their similar clinical and histopathologic appearances.Z, 7,15 Clinically, perianal Paget's disease tends to occur in the elderly as a slowly enlarging erythematous, eczematous, and often sharply demarcated perianal skin rash that may be oozing or scaling. There is often intractable pruritus. T h e m a j o r differential diagnoses include Bowen's disease, m a l i g n a n t melanoma, basal-cell anal carcinoma, cloacogenic transitional-cell carcinoma, dermatitis, psoriasis, Crohn's disease, and hidradenitis suppurativa. 5,15 There is often a delay in diagnosis due to clinical error. T h e duration between onset and biopsy in the reported cases has varied from one m o n t h to 31 years. 5 Perianal

FIG.4 (Patient 3). Patient with perianal Paget's disease. Note raw and weeping surfaces.

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Paget's disease probably is best regarded as a histopathologic entity and the diagnosis confirmed histologically.2, ~2,~4 The physician must maintain a high index of suspicion, especially in cases with characteristic lesions unresponsive to conventional dermatologic therapy. 15 Although Sir James Paget first described Paget's disease, he did not describe the Paget's cells that are so essential in its pathologic diagnosis. George Thin, in 1881, was the first to describe the cytologic features of Paget's cells that appear microscopically as large, rounded cells with abundant pale staining cytoplasm and a large nucleus that often is displaced to the periphery of the cell, giving a signet-ring appearance3,16 Paget's cells stain positive for mucin with PAS (diastase resistant), mucicarmine, and alcian blue at p H 2.5. It is generally agreed that Paget's cells are secretory epithelial cells with glandular differentiation.15,17 The histogenesis of Paget's cells in perianal Paget's disease is highly controversial. There are four main theories that would explain the four different patterns of presentation (Table 1)3 ,4,5, 7-10,12-15,is, 19 First, it was suggested that Paget's cells in the epidermis arise from underlying carcinoma of the apocrine or eccrine sweat glands by continuity and are, therefore, analogous to mammary Paget's disease, a, a5 Second, Paget's cells may be metastatic from underlying rectal adenocarcinoma. Wood and Culling, is the major proponents of such a theory, stress the histochemical similarity of the mucin in Paget's cells and the underlying carcinoma cells in one case. It is difficult to accept this explanation in every case, however, as perianal Paget's disease may be associated with a wide variety of different types of carcinoma, including squamous-cell carcinoma of the anus, with the Paget's cells appearing different from the underlying carcinoma cells.2, 9 A third theory was therefore put forward, suggesting that there is a simultaneous multicentric reaction in the epidermis, apocrine structures, and the glandular elements of the rectum due to an unknown neoplastic stimui n s . a , 1,t, 19

Finally, it was suggested that Paget's cells arise in situ in the epidermis, probably from faulty development of the pleuripotential ectodermal basal cells. They have a long preinvasive phase and, with time, may infiltrate into adnexa and dermis. Paget's disease therefore behaves initially as an adenocarcinoma in situ and, as such, would explain those cases reported with no underlying malignancy3, 7,14 Whatever the theories of its histogenesis, perianal Paget's disease is probably best regarded as an intraepithelial adenocarcinoma, irrespective of its site of origin. This understanding of its biology is essential if therapy is to be rational and effective3 A logical approach to managing patients suspected of

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having perianal Paget's disease would first include a careful clinical assessment including pelvic, rectal, and proctosigmoidoscopic examinations to assess the extent of involvement and the possible underlying malignancy. Barium enema may also be indicated. Preliminary diagnostic biopsy should be performed to confirm the diagnosis and to detect any underlying carcinoma. 1~ Surgical excision offers the only chance for cure. The treatment of choice, therefore, is wide local excision because microscopic spread of Paget's disease may extend within the epidermis horizontally beyond clinically apparent disease. One would require precise histologic guidance by multiple biopsies from the periphery of the lesions to define the resection margin several days preoperatively, because traditional frozen section without histochemical staining has repeatedly shown false negatives. Wide local excision also helps to determine if a subjacent carcinoma is present3,10 Paget's disease involving the rectal mucosa can be excised with a sphincter-saving technique if there is no invasion. If invasive disease is present or if the rectal mucosa cannot be reestablished, abdominoperineal resection is indicated.10 When perianal Paget's disease is associated with underlying anorectal carcinoma, the treatment is that of the underlying disease, that is abdominoperineal resection with wide excision of the cutaneous lesion.4 Groin lymph node dissection might be considered if they are involved or if Paget's cells are present throughout the dermis, bearing in mind that patients are often elderly and frail and that reactive lymphadenopathy may occur with perianal sepsis3,10, x~ Unfortunately local recurrence is a problem and often requires repeated excisions. Many are directly related to inadequate excision or associated invasive carcinoma but some may be due to a general "field effect." Therefore patients who are affected should be kept under lifelong surveillance for recurrences3, ~o,~5 After adequate excision, the prognosis is good when there is no underlying carcinoma. When there is an underlying carcinoma of the sweat glands, the prognosis is worse because of the likelihood of metastases to regional lymph nodes and to visceral organs. The prognosis is worst in patients with underlying rectal adenocarcinoma. 7 Other treatment modalities in cases with no underlying carcinoma have included topical bleomycin, topical 1 percent 5-fluorouracil, chemotherapy, radiotherapy, and cryosurgery with variable results. However, experiences with such treatments are very restricted.11,15 It is hoped that these three cases will emphasize the existence of this uncommon condition with its different patterns of presentation. They further illustrate the biologic differences of perianal Paget's disease from mammary Paget's disease.

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Acknowledgments The author thanks Mr. G. Davies and Dr. T. Dauncy for their helpful suggestions, and Mr. B. Rees, and Dr. C. Long for giving permission for their cases to be reported.

References 1. PagetJ. On disease of the mammary areola preceding cancer of the mammary gland. St Bartholomew Hosp Res London 1874;10: 87-9. 2. Jones RE, Austin C, Ackerman AB. Extramammary Paget's disease: a critical reexamination. Am J Dermatopathol 1979;1:10132. 3. Crocker HR. Paget's disease affecting the scrotum and penis. Trans Pathol Soc London 1889;40:187-91. 4. Langsford G, Kermode D. Perianal Paget's disease: a case report. Aust NZ J Surg 1980;50:181-3. 5. Kavlie H, Stevenson JK, Gould VE. Perianal Paget's disease. Am Surg 1971;37:485-9. 6. Darier J, Couillard P. Sur un cas de maladie de Paget de la r6gion perin6o-anale scrotale. Soc Franc Dermatol Syph 1893;4:25- 31. 7. Grow JR, Kshirsagar V, Tolentino M, Gramling J, Schutte AG. Extramammary perianal Paget's disease: report of a case. Dis Colon Rectum 1977;20:436-42. 8. MacLaughlin WS, Manson RR. Perianal Paget's disease with and without infiltrating carcinoma: report of two cases. Maine Med Assoc 1979;70:149-51. 9. Subbuswamy SG, Ribeiro BF. Perianal Paget's disease associated

10. 11.

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with cloacogenic carcinoma: report of a case. Dis Colon Rectum 1981 ;24:535-8. Pitman GH, McCarthy JG, Perzin KH, Herter FP. Extramammary Paget's disease. Plast Reconstr Surg 1982;69:238-44. Secco GB, Lapertosa G, Sertoli MR, Scarpati D, Riboli EB. Perianal Paget's disease: case report of an elderly patient treated with polychemotherapy and radiotherapy. Tumori 1984;70:3813. Gihman LI, Osborne PT, Coleman SA, Uthman EO. Paget's disease of the anal mucosa in association with carcinoma demonstrating mucoepidermoid features. J Surg Onco11985;28:27780. Grodsky L. Extramammary Paget's disease of the perianal region. Dis Colon Rectum 1960;3:502-9. Arminski TC, Pollard RJ. Paget's disease of the anus secondary to a malignant papillary adenoma of the rectum. Dis Colon Rectum 1973;16:46-55. Brenden LD, Schwartz RA. Extramammary Paget's disease. Am Fam Physician 1983;28:159-61. Thin G. Malignant papillary dermatitis of the nipple and the breast tumors with which it is found associated. Br Med J 1881;1:760-3. Morson BC, Dawson IMP. Extramammary Paget's disease. In: Gastrointestinal pathology. Oxford: Blackwell Scientific Publications, 1979:739-40. Wood WS, Culling CF. Perianal Paget's disease: histochemical differentiation utilizing the borohydride-KOH-PAS reaction. Arch Pathol 1975;99:442-5. Helwig EB, Graham JH. Anogenital (extrammary) Paget's disease: a clinicopathological review. Cancer 1963;16:387-403.