PRIMARY MALIGNANT LYMPHOMA OF FEivi:ALE URETHRA
phragm and composed of several lobules containing epithelial lined acinio The glands secrete a clear mucus that constitutes a portion of the ejaculateo 10 2 Although Carpenter and Bernardo reported a case of primary adenoid cystic carcinoma of Cowper's gland in 1971, this tumor is more commonly found in the head and neck regiono 3 Also known as a cylindroma, a term coined by Bilroth for the manner in which the cells grow in tubes or cylinders, the tumor is usually slow growing, widely infiltrative and of moderate to low grade malignant potentiaL The tumor can also be found in the breast, cervix, trachea, esophagus and prostate gland" Grossly, the tumor has a grayish-white appearance, while microscopically there are varied patterns of small darkly staining cells with minimal cytoplasmo 4 The natural history of the disease varies but recurrences are frequent even after prolonged followup" The tumor is often locally aggressive, and can metastasize to the lung and braino 5 The natural history of adenoid cystic carcinoma involving the prostate gland is less well known" Only 6 cases have been reported, all with uniformly good outcomes within 1 to 6 yearso 6 Reported treatments include either transurethral resection of the prostate alone or in combination with radiation or a radical operation" The appropriate therapy of adenoid cystic carcinoma of Cowper's gland remains uncertain" Carpenter and Bernardo achieved a 13-year survival after local resection and adjuvant radiation therapy of 3,500 rad in the face of positive surgical margins" 30 7 The patient died of causes unrelated to the primary disease" Most articles discussing the management of adenoid cystic carcinoma involve treatment of the head and neck, particularly the major and minor salivary glands" For tumors in these regions the treatment options include an operation, radiation or a combined approach" Chemotherapy has not been shown to be effective" Complete excision appears to provide the best survivaL Adjuvant radiation therapy is usually administered only when complete surgical excision is not possible but does not appear to benefit patients who have significant residual disease at the surgical marginso 8 Distant metastasis can
occur despite local controL 9 Combined surgical and radiation approaches have achieved survival rates up to 70% ranging from 2 to 17 years after treatment" 10 Accordingly, we recommend a combined surgical and radiation approach for this rare entityo Drso Stephen Sussman and Andrew Salner, Departments of Radiology and Radiation Oncology, respectively, assisted in the preparation of this manuscripto REFERENCES
L Keen, Mo R, Golden, R Lo, Richardson, Jo Fo and Melicow, Mo Mo:
30 40 50 60
Carcinoma of Cowper's gland treated with chemotherapy" Jo UroL, 104: 854, 19700 Coffey, Do So: The biochemistry and physiology of the prostate and seminal vesicles" In: Campbell's Urology, 5th edo Edited by Po Co Walsh, R Fo Gittes, Ao Do Perlmutter and To Ao Stamey" Philadelphia: WO R Saunders Coo, voL 1, secto I, chapL 5, Po 235, 19860 Carpenter, Ao Ao and Bernardo, Jo R, Jro: Adenoid cystic carcinoma of Cowper's gland: case report. Jo UroL, 106: 701, 197L Frankel, K and Craig, Jo R: Adenoid cystic carcinoma of the prostate" Report of a case" Amero Jo Clino Path", 62: 639, 19740 Pellegrino, So Vo: Glossopyrosis due to adenoid cystic carcinoma" Oral Surgo, 43: 521, 19770 Young, RR, Frierson, R Fo, k, Mills, So K, Kaiser, Jo So, Talbot, WO Rand Bhan, Ao K: Adenoid cystic-like tumor of the prostate gland" A report of two cases and review of the literature on "adenoid cystic carcinoma" of the prostate" Amero Jo Clino Patho, 89: 49, 19880 Bernardo, Jo R: Personal correspondence" Shingaki, So, Saito, R, Kawasaki, To and Nakajima, To: Adenoid cystic carcinoma of the major and minor salivary glands" A clinicopathological study of 17 cases" Jo Maxillofaco Surgo, 14: 53, 19860 Matsuba, R Mo, Thawley, So K, Simpson, Jo R, Levine, L Ao and Mauney, Mo: Adenoid cystic carcinoma of major and minor salivary gland origin" Laryngoscope, 94: 1316, 19840 Shidnia, R, Hornback, No R, Hamaker, R and Lingeman, R: Carcinoma of major salivary glands" Cancer, 45: 693, 19800
0022-534 7/92/14 73-0701$03000/0 VoL 147, 701-703, March 1992
THE JOURNAL OF UROLOGY
Printed in US.A.
Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, lNCo
PRIMARY MALIGNANT LYMPHOMA OF THE FEMALE URETHRA: REPORT OF A CASE AND REVIEW OF THE LITERATURE JONATHAN Mo VAPNEK*
CHARLES Wo TURZAN
From the Departments of Urology, University of California School of Medicine, San Francisco and Kaiser Foundation Medical Center, Oakland, California
Primary extranodal lymphoma of the female urethra is rare" We present case 10 and review the literature" Management in the past has varied markedly" Strategies have included simple excision, external beam and intracavitary radiation therapy, and multiple agent chemotherapy. The majority of patients have done well: 7 of 10 are alive with no evidence of disease" Newly diagnosed patients should undergo complete staging with the Ann Arbor staging system and the tumors should be classified histologically according to the Working Formulation for Clinical Usage" Therapy must be individualized but in most cases we recommend that patients be treated as if they have systemic illness, with multimodality therapy" KEY
WORDS: urethra, lymphoma
Accepted for publication August 2, 199L *Requests for reprints: Department of Urology, U-575, University of California, San Francisco, California 94143-07380
Lymphomas rarely present with a primary genitourinary complaint When they do, further evaluation commonly reveals evidence of widespread disease" Primary extranodal lymphoma
VAPNEK AND TURZAN
limited to the lower urinary tract is even rarer. The most common site identified has been the bladder, followed by the prostate and urethra. There have been only 9 cases of primary extranodal lymphoma of the female urethra. We present case 10 and review the pertinent literature. CASE REPORT
A 31-year-old woman presented with a 3-month history of vaginal spotting and urinary urgency. She denied fever, night sweats, fatigue and weight loss. Medical history was noncontributory. At physical examination she had a diffusely thickened, firm urethra. The anterior vaginal wall was otherwise normal. The urethral meatus appeared to be normal and bimanual examination revealed no evidence of a pelvic mass. She had no evidence of§Ystemic lymJ))ladenop_athy. Qy~tm1rethroscopy demonstrated normal urethral and vesical mucosa. Biopsies taken from the anterior urethral wall showed unremarkable squamous mucosa with extensive submucosal infiltration by lymphocytes, plasma cells and histiocytes (part A of figure). In the deeper portions of the specimen there was a diffuse proliferation of atypical large lymphoid cells characterized by large vesicular nuclei, with many demonstrating prominent macronucleoli (part B of figure). In addition, there were numerous mitotic figures and a population of plasma cells, some of which showed features of immaturity. Immunoperoxidase studies demonstrated evidence for cells of B-cell and plasma cell origin. Final pathological diagnosis was malignant
A, at low power unremarkable squamous mucosa shows extensive submucosal infiltration by lymphocytes, plasma cells and histiocytes. H & E, reduced from X40. B, at higher power there is diffuse proliferation of atypical large lymphoid cells characterized by large vesicular nuclei, extensive pleomorphism and frequent mitotic figures. H & E, reduced from X400.
lymphoma, large cell type, with malignant plasma cell component. Conventional chest radiographs and bone marrow biopsy revealed no evidence of metastatic disease. A computerized tomography (CT) scan of the pelvis showed no evidence of pelvic masses or of enlarged lymph nodes. After consultation with our Department of Hematology-Oncology, the patient underwent 4 cycles of methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone chemotherapy. She remained in complete remission 9 months after diagnosis. DISCUSSION
Malignant lymphomas may involve the genitourinary tract either pr-imar-ily or -secondarily. W-atson et al first noted the marked discrepancy between the clinical incidence of genitourinary involvement by lymphoma versus that found at autopsy. 1 Higher stage tumors are more likely to cause clinically significant symptoms, and the most common presentation appears to be ureteral obstruction from retroperitoneal lymphadenopathy. 2 Autopsy studies demonstrate that 7 to 62% of the patients dying of advanced lymphoma have pathological evidence of genitourinary organ involvement, and the organs involved in decreasing order of frequency are the kidney, adrenal, bladder and testis. 3- 5 Most but not all studies have confirmed that nonHodgkin's lymphoma is more likely to affect the genitourinary tract than Hodgkin's disease. In some cases the primary site of origin of a lymphoma may appear to be within the genitourinary tract, since extensive evaluation fails to reveal evidence of distant disease. These tumors are referred to as primary extranodal lymphomas. By far the most common site within the genitourinary tract is the testis. 6 In fact, testicular lymphomas account for 1 to 7% of all testis tumors, and they are the most common testicular malignancy in men more than 50 years old. Further evaluation of these patients often reveals evidence of widespread disease. Therefore, they are treated with systemic chemotherapy. On the other hand, primary lymphomas of the lower urinary tract itself are much rarer, with fewer than 50 cases of bladder,7 fewer than 40 cases of prostate8 and only 9 cases of urethral9-16 lymphoma reported. Histologically, the majority of primary genitourinary lymphomas, including those of the female urethra, are of the nonHodgkin's type. Historically, there were multiple, competing classifications for nonHodgkin's lymphomas, including that of Rappaport, Kiel, Dorfman, the World Health Organization, and Lukes and Collins. In 1982 the National Cancer Institute published a new Working Formulation for Clinical Usage with division of all nonHodgkin's lymphomas into 10 major types, and this has become the most widely used and comprehensive system. 17 Further classification by means of immunohistochemical staining may identify the cell of origin as either the B-cell or T-cell type. Review of the literature. All 9 cases of primary urethral lymphoma have been reported in women, 1· 9-16 and the most common presentation is a painless mass resembling a caruncle or a polyp. Less often there is spotting, hematuria, dysuria, vulvar pruritus or an infiltrating vaginal mass. In rare cases there are systemic symptoms, including fatigue, weight loss and generalized weakness. The table shows the presenting symptoms, staging, treatment and followup of the 9 previously reported cases and our own. All patients with lymphoma should undergo careful staging for metastatic disease with conventional chest radiographs, pelvic CT scan or magnetic resonance imaging and bone marrow biopsy. Because of the rarity of primary lymphomas of the urethra staging has not been uniform. The Grabstald staging system, which categorizes tumors by the depth of invasion (mucosal, submucosal, muscular, periurethral and distant), is commonly used for staging female urethral tumors of other
PRIMARY MALIGNANT' LYMPHOMA OF FEMALE URETHRA
Summary of reported cases of primary urethral lymphoma Reference Watson et al 1 Grabstald et al' Melicow et al 10
62 70-75 76
Caruncle, spotting, vaginal nodules
Allen and Nelson 11 Pak et al 12 Chaitin et al' 3
53 83 77
Touhami et al 14
Nabholtz et al'' Simpson et al 16 Present case
Caruncle (fleshy mass), hematuria
Stage Disseminated ? Locally invasive
Followup Dead of disease, 5 mos. No evidence of disease, 9 mos. No evidence of disease, 1 yr.
Disseminated Local (probably) Disseminated
Excision Radiation Transurethral resection, radiation Palliative None Biopsy, chemotherapy
Dead, 2 mos. Dead of unrelated cause No evidence of disease, 9 mos.
No evidence of disease, 4 yrs.
Caruncle Dysuria, meatal mass Vaginal mass, hematuria, decreased stream, fatigue, weakness Vulvar pruritus, dysuria, urethral mass Urethral polyp
No evidence of disease, 10 yrs.
Large urethral mass Spotting, firm urethra
Excision, chemotherapy Excision Biopsy, radiation, chemotherapy
histological types. 9 The Ann Arbor system forms the standard staging criteria for most adult nonHodgkin's lymphomas, and is applicable to tumors of nodal and extranodal origin. 18 Of the 10 reported cases of primary urethral lymphoma, including our own, 7 appear to have been localized and 3 were widespread. Because of the rarity of these tumors there is no consensus on treatment. Local excision, radical excision, external beam radiotherapy, intracavitary radiotherapy and chemotherapy have all been used with success. Of the 10 reported patients (including our own) 7 had no evidence of disease after intervals of 9 months to 10 years (see table). Because the majority of other lymphomas are systemic, either at diagnosis or subsequently, our bias is to treat as if the disease were widespread using combinations of surgery, radiation and chemotherapy. The prognosis in primary lymphoma of the female urethra appears to be favorable, with 7 of 10 patients having no evidence of disease. If we generalize from the experience gained from management of other lymphomas the prognosis appears to depend on the stage of the tumor as well as the histology. According to the Rappaport grading system nodular is more favorable than diffuse histology, and according to the Working Formulation intermediate grade tumors have a better prognosis than high grade tumors. Dr. Ronald Dorfman, Stanford University, performed the immunoperoxidase studies. REFERENCES
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
1. Watson, E. M., Sauer, H. R. and Sadugor, M. G.: Manifestations
of the lymphoblastomas in the genito-urinarytract. J. Urol., 61: 626, 1949. 2. Whitmore, W. F., III, Skarin, A. T. and Rosenthal, D.S.: Urological presentations of nonHodgkin's lymphomas. J. Urol., 128: 953, 1982. 3. Weimar, G., Culp, D. A., Loening, S. and Narayana, A.: Urogenital involvement by malignant lymphomas. J. Urol., 125: 230, 1981. 4. Sufrin, G., Keogh, B., Moore, R.H. and Murphy, G. P.: Secondary
No evidence of disease, 2 yrs. No evidence of disease, 9 mos.
involvement of the bladder in malignant lymphoma. J. Urol., 118: 251, 1977. Miyake, 0., Namiki, M., Sonoda, T. and Kitamura, H.: Secondary involvement of genitourinary organs in malignant lymphoma. Urol. Int., 42: 360, 1987. Freeman, C., Berg, J. W. and Cutler, S. J.: Occurrence and prognosis of extranodal lymphomas. Cancer, 29: 252, 1972. Aigen, A. B. and Phillips, M.: Primary malignant lymphoma of urinary bladder. Urology, 28: 235, 1986. Hampel, N., Richter-Levin, D. and Gersh, I.: Primary lymphosarcoma of prostate. Urology, 9: 461, 1977. Grabstald, H., Hilaris, B., Henschke, U. and Whitmore, W. F., Jr.: Cancer of the female urethra. J.A.M.A., 197: 835, 1966. Melicow, M. M., Lattes, R. and Pierre-Louis, C.: Lymphoma of the female urethra masquerading as a caruncle. J. Urol., 108: 748, 1972. Allen, R. and Nelson, R. P.: Primary urethral malignancy: review of22 cases. South. Med. J., 71: 547, 1978. Pak, K., Takayama, H., Tomoyoshi, T. and Takeoka, 0.: Reticulum cell sarcoma of the female urethra: report of a case. Acta Urol. Jap., 26: 599, 1980. Chaitin, B. A., Manning, J. T. and Ordonez, N. G.: Hematologic neoplasms with initial manifestations in lower urinary tract. Urology, 23: 35, 1984. Touhami, H., Brahimi, S., Kubisz, P. and Cronberg, S.: NonHodgkin's lymphoma of the female urethra. J. Urol., 137: 991, 1987. Nabholtz, J. M., Friedman, S., Tremeaux, J. C., Cuisenier, J., Mansoni, H., Douvier, S., Arnalsteen, C., Collin, F. and Guerrin, J.: Non-Hodgkin's lymphoma of the urethra: a rare extranodal entity. Gynec. Oncol., 35: 110, 1989. Simpson, R. H., Bridger, J.E., Anthony, P. P., James, K. A. and Jury, I.: Malignant lymphoma of the lower urinary tract. A clinicopathological study with review of the literature. Brit. J. Urol., 65: 254, 1990. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas. Summary and description of a working formulation for clinical usage. Cancer, 49: 2112, 1982. Magrath, I.: The Non-Hodgkin's Lymphomas. Baltimore: Williams & Wilkins, p. 184, 1990.