Extramammary Paget's Disease and Anaplastic Basaloid Small-cellCarcinoma of the Anus: Report of a Case* B. RICHARD JACKSON, M . D .
From the Department of Colon and Rectal Surgery, St. Vincent's Hospital, Los Angeles, Calilornia
similar mass appeared in the right groin, and it enlarged in a similar fashion. He had been constipated for five or six years, and recently he had seen bright red blood after straining, and there had been protrusion of hemorrhoids, necessitating manual reduction. In addition, the patient complained of difficulty in starting urination and having a feeling of some urinary retention. Positive physical findings included bilateral hard, matted inguinal nodes as much as 3 cm in diameter, which could be palpated extending up both iliac vessels to the aorta. Rectal examination disclosed a hard, nontender, fixed, submucosal mass anteriorly, beginning just above the anorectal line and extending upward indefinitely, and laterally to the right, and there were prolapsing internal hemorrhoids. At the anal verge posteriorly, there was a small, brownish, eczematous, crusted lesion. Sigmoidoscopic examination disclosed no abnormality to the 20-cm level, and chest and barium-enema x-ray studies were normal. T h e following day a left inguinal node was excised; the submucosal rectal mass was biopsied, and the small, crusted anal lesion was excised. T h e preliminary pathology report on the frozen-section examination of the inguinal node was metastatic carcinoid. After operation there was a difference of opinion among the pathologists who were asked to review the slides. All agreed that the small anal lesion was extramammary Paget's disease. All agreed that the submucosal mass was not prostatic or rectal adenocarcinoma. T h e patient was presented before the T u m o r Board of Saint Vincent's Hospital on December 13, 1957. T h e Board agreed that surgery was not indicated, and recommended that the patient have x-ray therapy to the inguinal nodes with cross-fire to the rectum. From January 10 to February 5, the patient received 5,000 r to these areas through four portals, and there was regression of about 50 per cent in the size of the iliofemoral nodes, with no change in the rectal mass. On February 14 the patient was again presented to the T u m o r Board. He appeared to be in a nearterminal state, with a large, hard liver and a hard,
t~XTRAMAMMARY PAGET'S DISEASE a n d anaplastic basaloid small-cell carcinoma are both rare. In a recent review of medical l i t e r a t u r e , A r m i n s k i a n d P o l l a r d I f o u n d o n l y 31 r e p o r t e d cases o f p e r i a n a l P a g e t ' s d i s e a s e , a n d a d d e d o n e of t h e i r o w n . T h e s e cases w e r e classified as t h o s e a s s o c i a t e d w i t h an apocrine carcinoma, a rectal carcinoma, a m u c i n o u s c a r c i n o m a of i n d e f i n i t e o r i g i n , or a squamous-cell carcinoma, and those not associated with underlying carcinoma. In a study covering a 27-year period at the M a y o C l i n i c , W i t t o e s c h et aIA 2 f o u n d o n l y s e v e n a n a l t u m o r s t h a t t h e y cIassified as b a s a l o i d s m a l l - c e l l c a r c i n o m a s . T h e association of extramammary Paget's disease a n d a n a p l a s t i c b a s a l o i d s m a l l - c e l l carcin o m a of t h e a n u s h a s n o t b e e n r e p o r t e d previously. I n t h e f o l l o w i n g case, t h e p a t h o l o g y of t h e s e n e o p l a s t i c p r o c e s s e s is presented. Report
of a Case
A 52-year-old Caucasian man was admitted to the clinic service of St. Vincent's Hospital on December 4, 1957, with the provisional diagnosis of carcinoma of the prostate with inguinal-node metastases. About eight months prior to admission he had noticed a small, hard, painless lump in the left groin area. It gradually became larger, growing upward and laterally. In several months a * Received for publication November 8, 1974. Address reprint requests to Dr. Jackson, Medical Square, West T h i r d Street, Los Angeles, California 90057. 339 Dis. Col. & Rect. May-June 1975
Volume 18 Number 4
JACKSON
340
enlarged supraclavicular node on the left side, a n d c o m p l a i n e d of e x t r e m e p a i n from a large mass in the region of the coracoid process of the left scapula. H e was relieved of the p a i n after a single dose of 500 r in air to the scapular mass, b u t c o n t i n u e d to h a v e a d o w n h i l l course, a n d died at h o m e , M a r c h 14, 1958, a b o u t a year after the appearance of the first enlarged i n g u i n a l node.
Extramammary Paget's Disease Paget's disease of the breast represents a well-known skin manifestation of an underlying in-situ or infiltrating carcinoma of the superficial or deep mammary ducts. It has a low incidence, occurring in about 2 per cent of mammary cancers in women. When Sir James Paget 10 described it 100 years ago, he predicted that the disease would also occur in other parts of the body in association with underlying carcinomas. ~vge know this phenomenon today as extramammary Paget's disease and, while the lesion is rare, it is found in locations rich in apocrine glands, i.e., in the anogenital, groin, and axillary areas. Extremely rare locations such as the umbilicus, nose, ear, mucous membrane of the mouth~ thigh, and buttocks have been reported. 9 T h e disease is said to occur twice as frequently in women, with most cases affecting the vulva. T h e anogenital incidences in male and female patients are about equal. T h e r e is one report of familial occurrence 7 in father and son, in both instances affecting the right scrotal area. Clinically, these patients manifest, in the early stages, an erythematous, scaling, weeping lesion with a fairly well-defined border, and complaints of itching and occasionally, pain. With chronicity, the lesion may assume a brownish, papillary or a leukoplakia-like appearance. Bleeding, ulcerated areas may be present. Diagnosis is suggested by these findings and confirmed by biopsy. Histologic findings (Fig. 1) show the presence of large, deformed, ballooned cells with pale, vacuolated cytoplasm (Fig.
Dis. Col. &Rect. May-June 1975
2), and eccentric, large, hyperchromatic nuclei. T h e cells are confined to the epidermis, scattered through the granular layer, and occasionally replace the basal layer. While the histologic findings in mammary and extramammary disease are the same, there is continuing controversy concerning the pathogenesis of the extramammary lesion. W h e t h e r this lesion arises as a type of in-situ epithelial carcinoma or whether an underlying sweat gland or other subjacent carcinoma is always present has not been determined. Subjacent carcinomas are by no means u n c o m m o n when the lesion is e n c o u n t e r e d : In other instances, however, despite the most painstaking investigation, an underlying carcinoma is not found, and the origin of the Paget's cells is believed to be in the apocrine structures normally present in the surface epithelium. 11 T h e r e is also the belief that the disease may have more than one site of origin, all sites being effected by the same carcinogenic stimuli. A comprehensive review of the literature on pathogenesis has been published by Liiders.S New evidence on the pathogenesis has been disclosed by the ultrastructural studies of Koss and Brockunier 6 and by Demopoulos. 2 Koss and Brockunier interpreted their investigations to suggest that the extramammary Paget's cells are derived from clear eccrine ceils. Demopoulous reports that although she found minor differences in her studies, the Paget's cells more closely resemble the secretory cells of the apocrine glands. She concludes that the differences may represent two basically different forms of extramammary Paget's disease or different degrees of dedifferentiation. It seems apparent from these conclusions that the studies with the electron microscope clearly demonstrate the glandular nature of Paget's cells.
Volume 18 Number 4
EXTRAMAMMARY PAGET'S DISEASE
Fie. 1 (above). Large, deformed, ballooned cells of extramammary Paget's disease dispersed among granular and basal layer at epidermis (hematoxylin and eosin; • FiG. 2 (below). Higher magnification, with arrow showing Paget cell with scanty, pale, vacuolated cytoplasm and eccentric large nucleus (hematoxylin and eosin; • 100).
341
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JACKSON
Fig. 3.
Dis, CoL & Rect. May-June 1975
T r a n s i t i o n a l zone of e p i t h e l i u m where the rarer t u m o r s h a v e their origin.
Anaplastic Basaloid Small-cell Carcinoma
Malignant tumors of the anus are un. common, and vary in pathologic features. T h e most common of these neoplasms are of ectodermal origin, squamous-cell and basal-cell carcinomas. Rare tumors include adenocarcinomas, mucoepidermoid carcinomas, melanomas, sarcomas, and transitional-cell carcinomas. These neoplasms have their origins in the upper anal canal in the transitional membranous zone of epithelium, and in the submucosal anal ducts and intramuscular anal glands (Fig. 3). Much of the disagreement of the pathologists reviewing the slides in the case presented here resulted from argument regarding the nomenclature of these rarer tumors, particularly those transitional-cell carcinomas having certain morphologic resemblance to basal-cell carcinoma. Klotz et al.S collected a series of 373 cases of this type of carcinoma from many hospitals, and believes that although there are various histologic patterns, they are only variants of the basic transitional-cell neoplasm. H e calls all of these variants "transitional cloacogenic" carcinomas. Wittoesch
et al. 12 reported 28 cases of anal tumors having basal-cell features and classified them into five groups: basal-cell carcinoma, basaloid small-cell carcinoma, basaloid squamous-cell carcinoma, papillary squamous-cell carcinoma and adnexal tumor. This group of tumors consitutes less than 10 per cent of primary malignant tumors of the anus. T h e basaloid small-cell type arises near the pectinate line, and in this location presents a bizarre anaplastic cellular pattern, is rapidly disseminated, and is lethal.3 In each of the affected inguinal nodes in our patient (Fig. 4), only a small perimeter of a few islands of residual lymphoid tissue remained. T h e bulk of the node was replaced by islands of small cells separated by a firm fibrous stroma, and it is understandable that a preliminary diagnosis of metastatic carcinoid was made. Carcinoid tumors may prove troublesome in the differential diagnosis. 5 T h e cells (Fig. 5) in these islands have a basaloid character, with scanty, clear cytoplasm and indefinite cytoplasmic membranes. T h e nuclei are ovoid and hyperchromatic. T h e r e are
Volume 18 Number 4
EXTRAMAMMARY PAGET'S DISEASE
F1G. 4 (above). Section of inguinal node completely replaced by islands of small, neoplastic cells with firm, fibrous stroma (hematoxylin and eosin; Xl0). gio. 5 (below). Island of cells in lymph node, showing basaloid character of cells with ovoid, hyperchromatic nuclei and indefinite cytoplasmic membranes (hematoxylin and eosin;
X40).
343
344
JACKSON
Dis. CoL &Rect. May.June 1975
FIG. 6 (above). Biopsy of rectal submucosal mass. Nests and sheets of anaplastic cells showing lack of palisading (hematoxylin and eosin; • FIC,. 7 (below). Submucosal tumor cells, showing irregular, small size and nuclear anaplasia (hematoxylin and eosin; )
From the Department of Colon and Rectal Surgery, St. Vincent's Hospital, Los Angeles, Calilornia
similar mass appeared in the right groin, and it enlarged in a similar fashion. He had been constipated for five or six years, and recently he had seen bright red blood after straining, and there had been protrusion of hemorrhoids, necessitating manual reduction. In addition, the patient complained of difficulty in starting urination and having a feeling of some urinary retention. Positive physical findings included bilateral hard, matted inguinal nodes as much as 3 cm in diameter, which could be palpated extending up both iliac vessels to the aorta. Rectal examination disclosed a hard, nontender, fixed, submucosal mass anteriorly, beginning just above the anorectal line and extending upward indefinitely, and laterally to the right, and there were prolapsing internal hemorrhoids. At the anal verge posteriorly, there was a small, brownish, eczematous, crusted lesion. Sigmoidoscopic examination disclosed no abnormality to the 20-cm level, and chest and barium-enema x-ray studies were normal. T h e following day a left inguinal node was excised; the submucosal rectal mass was biopsied, and the small, crusted anal lesion was excised. T h e preliminary pathology report on the frozen-section examination of the inguinal node was metastatic carcinoid. After operation there was a difference of opinion among the pathologists who were asked to review the slides. All agreed that the small anal lesion was extramammary Paget's disease. All agreed that the submucosal mass was not prostatic or rectal adenocarcinoma. T h e patient was presented before the T u m o r Board of Saint Vincent's Hospital on December 13, 1957. T h e Board agreed that surgery was not indicated, and recommended that the patient have x-ray therapy to the inguinal nodes with cross-fire to the rectum. From January 10 to February 5, the patient received 5,000 r to these areas through four portals, and there was regression of about 50 per cent in the size of the iliofemoral nodes, with no change in the rectal mass. On February 14 the patient was again presented to the T u m o r Board. He appeared to be in a nearterminal state, with a large, hard liver and a hard,
t~XTRAMAMMARY PAGET'S DISEASE a n d anaplastic basaloid small-cell carcinoma are both rare. In a recent review of medical l i t e r a t u r e , A r m i n s k i a n d P o l l a r d I f o u n d o n l y 31 r e p o r t e d cases o f p e r i a n a l P a g e t ' s d i s e a s e , a n d a d d e d o n e of t h e i r o w n . T h e s e cases w e r e classified as t h o s e a s s o c i a t e d w i t h an apocrine carcinoma, a rectal carcinoma, a m u c i n o u s c a r c i n o m a of i n d e f i n i t e o r i g i n , or a squamous-cell carcinoma, and those not associated with underlying carcinoma. In a study covering a 27-year period at the M a y o C l i n i c , W i t t o e s c h et aIA 2 f o u n d o n l y s e v e n a n a l t u m o r s t h a t t h e y cIassified as b a s a l o i d s m a l l - c e l l c a r c i n o m a s . T h e association of extramammary Paget's disease a n d a n a p l a s t i c b a s a l o i d s m a l l - c e l l carcin o m a of t h e a n u s h a s n o t b e e n r e p o r t e d previously. I n t h e f o l l o w i n g case, t h e p a t h o l o g y of t h e s e n e o p l a s t i c p r o c e s s e s is presented. Report
of a Case
A 52-year-old Caucasian man was admitted to the clinic service of St. Vincent's Hospital on December 4, 1957, with the provisional diagnosis of carcinoma of the prostate with inguinal-node metastases. About eight months prior to admission he had noticed a small, hard, painless lump in the left groin area. It gradually became larger, growing upward and laterally. In several months a * Received for publication November 8, 1974. Address reprint requests to Dr. Jackson, Medical Square, West T h i r d Street, Los Angeles, California 90057. 339 Dis. Col. & Rect. May-June 1975
Volume 18 Number 4
JACKSON
340
enlarged supraclavicular node on the left side, a n d c o m p l a i n e d of e x t r e m e p a i n from a large mass in the region of the coracoid process of the left scapula. H e was relieved of the p a i n after a single dose of 500 r in air to the scapular mass, b u t c o n t i n u e d to h a v e a d o w n h i l l course, a n d died at h o m e , M a r c h 14, 1958, a b o u t a year after the appearance of the first enlarged i n g u i n a l node.
Extramammary Paget's Disease Paget's disease of the breast represents a well-known skin manifestation of an underlying in-situ or infiltrating carcinoma of the superficial or deep mammary ducts. It has a low incidence, occurring in about 2 per cent of mammary cancers in women. When Sir James Paget 10 described it 100 years ago, he predicted that the disease would also occur in other parts of the body in association with underlying carcinomas. ~vge know this phenomenon today as extramammary Paget's disease and, while the lesion is rare, it is found in locations rich in apocrine glands, i.e., in the anogenital, groin, and axillary areas. Extremely rare locations such as the umbilicus, nose, ear, mucous membrane of the mouth~ thigh, and buttocks have been reported. 9 T h e disease is said to occur twice as frequently in women, with most cases affecting the vulva. T h e anogenital incidences in male and female patients are about equal. T h e r e is one report of familial occurrence 7 in father and son, in both instances affecting the right scrotal area. Clinically, these patients manifest, in the early stages, an erythematous, scaling, weeping lesion with a fairly well-defined border, and complaints of itching and occasionally, pain. With chronicity, the lesion may assume a brownish, papillary or a leukoplakia-like appearance. Bleeding, ulcerated areas may be present. Diagnosis is suggested by these findings and confirmed by biopsy. Histologic findings (Fig. 1) show the presence of large, deformed, ballooned cells with pale, vacuolated cytoplasm (Fig.
Dis. Col. &Rect. May-June 1975
2), and eccentric, large, hyperchromatic nuclei. T h e cells are confined to the epidermis, scattered through the granular layer, and occasionally replace the basal layer. While the histologic findings in mammary and extramammary disease are the same, there is continuing controversy concerning the pathogenesis of the extramammary lesion. W h e t h e r this lesion arises as a type of in-situ epithelial carcinoma or whether an underlying sweat gland or other subjacent carcinoma is always present has not been determined. Subjacent carcinomas are by no means u n c o m m o n when the lesion is e n c o u n t e r e d : In other instances, however, despite the most painstaking investigation, an underlying carcinoma is not found, and the origin of the Paget's cells is believed to be in the apocrine structures normally present in the surface epithelium. 11 T h e r e is also the belief that the disease may have more than one site of origin, all sites being effected by the same carcinogenic stimuli. A comprehensive review of the literature on pathogenesis has been published by Liiders.S New evidence on the pathogenesis has been disclosed by the ultrastructural studies of Koss and Brockunier 6 and by Demopoulos. 2 Koss and Brockunier interpreted their investigations to suggest that the extramammary Paget's cells are derived from clear eccrine ceils. Demopoulous reports that although she found minor differences in her studies, the Paget's cells more closely resemble the secretory cells of the apocrine glands. She concludes that the differences may represent two basically different forms of extramammary Paget's disease or different degrees of dedifferentiation. It seems apparent from these conclusions that the studies with the electron microscope clearly demonstrate the glandular nature of Paget's cells.
Volume 18 Number 4
EXTRAMAMMARY PAGET'S DISEASE
Fie. 1 (above). Large, deformed, ballooned cells of extramammary Paget's disease dispersed among granular and basal layer at epidermis (hematoxylin and eosin; • FiG. 2 (below). Higher magnification, with arrow showing Paget cell with scanty, pale, vacuolated cytoplasm and eccentric large nucleus (hematoxylin and eosin; • 100).
341
342
JACKSON
Fig. 3.
Dis, CoL & Rect. May-June 1975
T r a n s i t i o n a l zone of e p i t h e l i u m where the rarer t u m o r s h a v e their origin.
Anaplastic Basaloid Small-cell Carcinoma
Malignant tumors of the anus are un. common, and vary in pathologic features. T h e most common of these neoplasms are of ectodermal origin, squamous-cell and basal-cell carcinomas. Rare tumors include adenocarcinomas, mucoepidermoid carcinomas, melanomas, sarcomas, and transitional-cell carcinomas. These neoplasms have their origins in the upper anal canal in the transitional membranous zone of epithelium, and in the submucosal anal ducts and intramuscular anal glands (Fig. 3). Much of the disagreement of the pathologists reviewing the slides in the case presented here resulted from argument regarding the nomenclature of these rarer tumors, particularly those transitional-cell carcinomas having certain morphologic resemblance to basal-cell carcinoma. Klotz et al.S collected a series of 373 cases of this type of carcinoma from many hospitals, and believes that although there are various histologic patterns, they are only variants of the basic transitional-cell neoplasm. H e calls all of these variants "transitional cloacogenic" carcinomas. Wittoesch
et al. 12 reported 28 cases of anal tumors having basal-cell features and classified them into five groups: basal-cell carcinoma, basaloid small-cell carcinoma, basaloid squamous-cell carcinoma, papillary squamous-cell carcinoma and adnexal tumor. This group of tumors consitutes less than 10 per cent of primary malignant tumors of the anus. T h e basaloid small-cell type arises near the pectinate line, and in this location presents a bizarre anaplastic cellular pattern, is rapidly disseminated, and is lethal.3 In each of the affected inguinal nodes in our patient (Fig. 4), only a small perimeter of a few islands of residual lymphoid tissue remained. T h e bulk of the node was replaced by islands of small cells separated by a firm fibrous stroma, and it is understandable that a preliminary diagnosis of metastatic carcinoid was made. Carcinoid tumors may prove troublesome in the differential diagnosis. 5 T h e cells (Fig. 5) in these islands have a basaloid character, with scanty, clear cytoplasm and indefinite cytoplasmic membranes. T h e nuclei are ovoid and hyperchromatic. T h e r e are
Volume 18 Number 4
EXTRAMAMMARY PAGET'S DISEASE
F1G. 4 (above). Section of inguinal node completely replaced by islands of small, neoplastic cells with firm, fibrous stroma (hematoxylin and eosin; Xl0). gio. 5 (below). Island of cells in lymph node, showing basaloid character of cells with ovoid, hyperchromatic nuclei and indefinite cytoplasmic membranes (hematoxylin and eosin;
X40).
343
344
JACKSON
Dis. CoL &Rect. May.June 1975
FIG. 6 (above). Biopsy of rectal submucosal mass. Nests and sheets of anaplastic cells showing lack of palisading (hematoxylin and eosin; • FIC,. 7 (below). Submucosal tumor cells, showing irregular, small size and nuclear anaplasia (hematoxylin and eosin; )
