Non-hodgkin lymphoma arising in lower urinary tract

NON-HODGKIN

LYMPHOMA ARISING IN

LOWER URINARY TRACT JOHN A. HEANEY, M.B.,

F.R.C.S.I.

RONALD

M.D.

A. DELELLIS,

RICHARD

A. RUDDERS,

M.D.

From the Departments of Urology, Pathology, and Medicine (Division of Hematology-Oncology), New England Medical Center Hospital and Tufts University School of Medicine, Boston, Massachusetts

ABSTRACT-Primary involvement of the bladder and prostate by non-Hodgkin lymphoma is exceedingly rare. Usually bladder lymphoma can be cured by aggressive local therapy, but the prognosis of prostatic lymphoma is poor. The devastating clinical course of a young man with primary lymphoma involving the prostate and bladder base is reported to emphasize the heterogeneity of this group of tumors and to encourage precise tumor classification. Prognosis depends on the tumor stage and the specific lymphoma cell-type as defined by conventional histologic and immunologic criteria. Management should be tailored according to tumor grade, stage, and site.

Non-Hodgkin lymphoma usually arises in nodal tissue and subsequently spreads to distant and visceral sites.’ However, extranodal tissue may be involved primarily in a significant portion of cases (lo-58 % ), the head and neck and the gastrointestinal tract (including the liver) being the most prevalent sites. lm4Although secondary involvement of the lower urinary tract occurs in 10 to 20 per cent of patients with widespread lymphoma, it is exceedingly rare for the bladder or prostate to be the primary site.‘m4 Non-Hodgkin lymphoma typically arises in the bladder of elderly women with a long history of recurrent cystitis and in the prostate of younger men. 58 In general, primary nonHodgkin lymphoma of the bladder is associated with a good prognosis whereas prostatic origin is frequently followed by rapid dissemination. Unfortunately, there has been little attempt in the literature to correlate tumor cell type with prognosis in non-Hodgkin lymphoma of the bladder and prostate. Although it is well established that certain histologic and immunolo-

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gic characteristics can be used to place individual tumors in specific prognostic categories,4~7~8 even the most recent case reports have failed to provide adequate pathologic classifications.e-13 In this report, a patient with non-Hodgkin lymphoma, confined at diagnosis to the bladder base and prostate, is presented to emphasize the importance of tumor subcategorization using strict criteria such as those described by The Non-Hodgkin’s Lymphoma Pathologic Classification Project (NHLPCP) .6 Case Report A thirty-year-old man was referred with a diagnosis of a diffuse lymphoma involving the bladder base and prostate. Five months previously he had presented with perineal pain, decreased urinary flow, urinary hesitancy, and urethral burning on urination. He had shaking chills, fever (102”F), and a diffusely enlarged and tender prostate. The peripheral white blood count was 17,OOO/cc, urinalysis showed

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microscopic hematuria, and urine culture was sterile. Gray scale ultrasound confirmed diffuse prostatic enlargement. A diagnosis of abacterial prostatitis was made, and treatment with antibiotics resulted in symptomatic improvement. Over the subsequent three months symptoms were intermittent, and one month prior to referral, hospital admission was needed because of an increase in urinary frequency to every ten minutes, progressive urgency and dysuria, and gross hematuria. There was low-grade fever and further enlargement of the prostate. At cystoscopy a frondular, partially hemorrhagic and necrotic, sessile mass was seen involving the right lateral bladder wall, the bladder neck, the entire right prostatic lobe, the whole trigone, and the medial aspect of the left prostatic lobe. The bladder neck and prostatic urethra were significantly obstructed, and 15 Gm of tumor were resected transurethrally. When evaluated at our institution, the patient’s symptoms had worsened and were associated with strangury, constant perineal pain, and lower abdominal discomfort prior to voiding. There was neither an antecedent history of infectious mononucleosis or genitourinary infection nor a family history of lymphoma or leukemia. He was a physically well-developed man without lymphadenopathy. There was mild lower abdominal distention although a discrete mass was not palpable. On rectal examination there was a variably hard, irregular mass involving the right lobe of the prostate and bladder base extending both beyond the right seminal vesicle and into the left prostatic lobe. The hemoglobin was 12.1 Gm/dl, hematocrit 36.8, white blood count 8,40O/ml (with a normal differential), and platelets 338,00O/ml. Serum creatinine was 0.9 mg/dl, blood urea nitrogen (BUN) 14 mg/dl, and liver enzymes normal. A chest radiograph was normal. Bilateral pedal lymphangiography demonstrated normal lymphatic channels and satisfactory filling of lymph nodes in the para-iliac and para-aortic chains-the texture of some of the nodes raised suspicion of lymphomatous involvement, though no nodes were enlarged. An intravenous urogram showed elevation of the right bladder base and minimal calicectasis and ureterectasis. Computerized axial tomography (CT) of the pelvis and abdomen showed no nodal enlargement. Bilateral posterior ileal crest biopsies showed normocellular bone marrow. Hematoxylin and eosin-stained sections of the biopsy specimens were reviewed and confirmed

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the diagnosis of malignant lymphoma. In all areas, the tumor showed a diffuse pattern of growth which essentially obliterated the architecture of the prostate. The neoplastic lymphocytes had round to ovoid nuclei with moderately condensed chromatin and two to three distinct nucleoli. Occasional tumor cells had nuclei with single prominent nucleoli. The nuclei of the tumor cells were approximately the same size as those of the non-neoplastic histiocytes which were scattered throughout the tumor in a “starry-sky” pattern. Overall mitotic activity was high with up to 5 mitoses per single high-power microscopic field. On immunologic phenotyping the tumor cell surface membrane was positive for IgM (lambda) confirming a Bcell origin. Chemotherapy was started with intravenous cyclophosphamide, vincristine, and doxorubitin hydrochloride (Adriamycin), and oral prednisone. Within two days there was dramatic resolution of both urinary symptoms and perineal pain. One week later, intravenous and intrathecal methotrexate was given in conjunction with Leucovorin “rescue.” Three further courses were given but, fifteen weeks after commencement of chemotherapy, symptoms rapidly returned and physical examination and CT confirmed massive local tumor recurrence. External beam radiation using twice daily fractionation to a tumor dose of 4,453 rad resulted in prompt symptomatic palliation which was short-lived. In four weeks, azotemia resulting from ureteral obstruction by massive retroperitoneal nodal disease required placement of percutaneous nephrostomy tubes bilaterally. No response followed further intensive combination chemotherapy with BCNU, bleomycin, VM26, dexamethasone, and cis-platinum, and within two weeks a loop colostomy was necessitated because of rectosigmoid obstruction. Meningeal involvement developed, causing death eleven months after the onset of symptoms. Comment Malignant tumors of the bladder and prostate are usually epithelial in origin. Transitional cell (urothelial) carcinoma predominates in the bladder while adenocarcinoma is most common in the prostate. Non-epithelial tumors (usually sarcomas) are rare (about 1% of bladder tumors and less than 0.1% of malignant prostate tumors) and have a predilection for the young and old.i1J4 Rhabdomyosarcoma, leiomyosarcoma, and fibrosarcoma are common cell

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TABLEI.

Age/Sex

Details of 9 patients with primary bladder lymphoma treated by local therapy alone

Lymphoma Histology

69F 34F

Follicular Mixed

37M 72F 70F 69F 75F 74M 64F

Reticulum cell Mixed Lymphoblastic Nodular reticulum Diffuse lymphocytic Histiocytic Poorly differentiated lymphocytic

*TUR =

Treatment * Pt Cx + 3000R Anterior exenteration TUR + 4000R Pt Cx + 5600R TUR + 4000R TUR + 4000R TUR + 5280R TUR + 3800R PT Cx

Disease-Free Survival Reference (MO) (#) 19 (19) 108 (20) 62 f: 60 54 24 72

[?ij’ ;;:I I::; (24)

transurethral resection; Pt Cx = partial cystectomy.

types. Historically, primary extranodal lymphoma has been included in discussions of lower urinary tract sarcomas under the classification of lymphosarcoma and reticulum cell sarcoma.11,14 However, with increased understanding of the heterogenicity, potential systemic nature, etiology, and cells of origin of lymphomas has rendered such classification obsolete, although it is regrettably still in common use. Primary lymphomas of the bladder and prostate are exceedingly rare. Rosenberg et al. l reviewed 1,269 cases of primary lymphoma and found primary involvement of the bladder in 2 and the prostate in 1, while among 1,467 similar cases, Freeman, Berg, and Cutler3 found 3 and 2, respectively. In contrast, Richmond et aL2 believe that lower urinary tract lymphoma may occur secondarily in up to 20 per cent of cases, emphasizing the importance of accurate staging prior to planning local therapy. The clinical presentation of primary lymphoma of the lower urinary tract is similar to that of other malignant tumors. In the bladder, the trigone and adjacent lateral walls are usually involved by a sessile mass which, though covered by normal urothelium, causes periodic hematuria (84 % of cases), urinary frequency (65 %), and dysuria (52 %).5J5 Indeed, hematuria combined with frequency and/or dysuria occurs in 77 per cent of patients with bladder lymphoma, in contrast to only 12 per cent of patients with other bladder malignancies.5 Women over the age of forty years are most commonly affected, and often there has been preceding cystitis. However, it is unlikely that cystitis is a precipitating event in developUROLOGY i MAY1985 / VOLUMEXXV,NUMBER5

ment of bladder lymphoma as lymphoid aggregation seen in chronic cystitis is usually on the luminal aspect of the lamina propria (cystitis follicularis) whereas the most florid lymphomatous involvement is in the deeper layers of lamina propria and the muscle.5 Primary prostatic lymphoma presents with symptoms of bladder outlet obstruction and is often only diagnosed following prostatectomy for suspected benign prostatic hyperplasia.B,Q-11J3J6 Other patients do have inflammatory phenomena such as fever, perineal pain, dysuria, and strangury, as in the man we.described.6J7 The latter presentation may mimic that of a prostatic abscess, and incision and drainage has been attempted in some patients6 Prostatic lymphoma occurs in all ages, but tends to be more aggressive in young men.6~14~17 Lymphoma of the bladder manifests lethality by virtue of local disease rather than by dissemination. Bhansali and Cameron in 19605 reviewed 23 previously published cases finding that the majority of patients died of local disease; at the time of death there was disseminated disease in only 2. PartonlB subsequently reviewed a total of 22 cases in the English literature estimating survival to be 68 per cent at one year and 27 per cent at five years, even with concomitant regional lymph node involvement. However, only 1 of 19 patients who had aggressive local therapy-cystectomy (partial or total) or radiotherapy, alone or in combination-died of lymphoma.5J8 Recent reports confirm that aggressive local therapy alone produces long-term survival for patients with varying tumor histology (Table I).15J9-24

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TABLE II.

Details of

5

patients with primary prostatic lymphoma

diagnosed incidentally at prostatectomy Reference

Age

Prostatectomy*

Lymphoma

Clinical Course

Histology

(f)

71

SPP

Lymphocytic

4 mo. widespread adenopathy. Radiotherapy and cyclophosphamide. Died 22 mo. after diagnosis.

72

RPP

Reticulum cell

4 mo. recurrent obstruction. TUR bladder neck-no lymphoma in specimen. Well 2l12 years later.

79

TURP

Lymphocytic

Interstitial irradiation. Died 8 years later with no evidence of disease.

(II)

71

RPP (subtotal)

Lymphoblastic

Radiotherapy-3,000 R. 5 mo widespread adenopathy. Chemotherapy. Died 7 mo. after diagnosis.

(IO)

57

TURP

Lymphocytic

Diffuse adenopathy within months. Chemotherapy with partial response. No follow-up.

(13)

*SPP = suprapubic prostatectomy;

RPP = retropubic prostatectomy;

In contrast, survival from primary prostatic lymphoma is limited by dissemination to distant nodes and viscera. Waller and Schullenberger6 from their research of 20 cases concluded that metastases had taken place in 45 to 50 per cent at diagnosis, and that the prostatic primary was often only recognized at autopsy. Smith and Dehner14 searched the files of the Armed Forces Institute of Pathology finding 55 primary sarcomas of the prostate gland of which 8 were classified as non-Hodgkin lymphoma. Five patients with reticulum cell sarcoma had a median survival of nine months (2 months to 5 years), while none of 3 patients with small cell lymphoma survived beyond twelve months. Table II shows the details of 5 patients in whom the diagnosis of primary prostatic lymphoma was made on examination of specimens surgically removed for treatment of prostatic obstructionQ-r1J3J6 One patient was apparently cured of minimal local disease by transurethral resection alone, no tumor being found in a subsequent resection.e A second patient was without disease at death eight years after prostatectomy and adjuvant interstitial irradiation. l1 Disseminated lymphoma developed soon after diagnosis in the other 3 patients in spite of regional radiotherapy and systemic chemotherapy. Recently, Boe, Nilsen, and RyttoG described a case similar to ours: a twenty-fouryear-old man with a clinical presentation mimicking prostatitis had rapid resolution of

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TURP

(16)

(9)

= transurethral prostatectomy.

symptoms with antibiotic therapy. Within five weeks unremitting symptoms and progressive tender prostatic enlargment prompted biopsy which disclosed Burkitt lymphoma. Despite complete response with multiagent chemotherapy and pelvic irradiation, relapse was rapid and unremitting causing death within six months of diagnosis. From the preceding discussion it is evident that patients with non-Hodgkin lymphoma involving the bladder have a good prognosis if local control is achieved. Conversely, patients with prostatic involvement generally have a poor prognosis despite aggressive therapy. It is important to consider the factors involved in this dichotomy and why some patients have a clinical course which is different from the norm for that organ site. Obviously, the number of cases is too small to provide conclusive answers to these questions, but relevant information can be obtained by reviewing the overall experience with extranodal non-Hodgkin lymphoma. The specific site of extralymphatic involvement does not appear to affect prognosis, and most authorities consider that the factors which impact most strongly on survival are (1) the stage and bulk of disease at diagnosis and (2) the histologic classification of the tumor.1,3,4*25The correlation of tumor cell type with prognosis was pioneered by Rappaport,’ and subsequently other classifications have been developed using cytologic and immunologic criteria (Lukes and

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Collins).’ Recently, these classifications have been synthesized into a working formulation for clinical usage by the NHLPCP8 Tumor categories of low, intermediate, and high grade correlate well with prognosis. It is pertinent that the tumors of both our patient and the patient described by Boe et al. l’ (i.e., small noncleaved follicular center cell lymphoma and Burkitt lymphoma, respectively) are included in the J subtype of high-grade tumors comprising 5 per cent of non-Hodgkin lymphoma and having the worst prognosis with a median survival of only 0.7 years8 Although the tumor showed some features of Burkitt lymphoma, the individual-cells showed more nuclear pleomorphism than is usual for that tumor type. Accordingly, the tumor was classified in the Rappaport system as an undifferentiated malignant lymphoma of the nonBurkitt type. In the NC1 working formulation of the non-Hodgkin lymphomas, the tumor corresponded to a high-grade, malignant lymphoma, small noncleaved follicular center cell type (non-Burkitt). Recently, Grogan, Warnke, and Kapla@ studied a series of 9 patients with undifferentiated lymphomas of Burkitt and non-Burkitt types. Morphologically, these two groups of cases differed in the degree of nuclear pleomorphism and in the numbers of nucleoli. Thus, the Burkitt cases showed a predominance of cells with 3-5 basophilic nucleoli while the non-Burkitt cases showed a slightly greater nuclear variability with a greater portion of nuclei containing l-2 eosinophilic nucleoli. Immunologically, all cases of Burkitt and non-Burkitt tumor stained for a single immunoglobulin light chain indicating a monoclonal B-cell proliferation. Clinically, the Burkitt cases were adults with a median age of fifty-four years. The site of presentation in both groups was predominantly extranodal and intra-abdominal. Oviatt et aLz7 have concluded that the small noncleaved follicular center cell lymphomas (non-Burkitt) should be treated in a manner similar to that used for Burkitt lymphomas and that this approach is likely to produce better clinical results than inclusion of these patients in routine diffuse “histocytic” lymphoma treatment protocols. It is tempting to conclude that three factors influence prognosis in non-Hodgkin lymphoma of the bladder and prostate. First, tumor subtype is vitally important as in other organ sites. Second, in published reports, tumor bulk appears to be greater at diagnosis in the prostate

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than in the bladder. Third, regional factors may facilitate dissemination more rapidly from a primary focus in the prostate than from one in the bladder. There is no doubt that local radical treatment can cure patients with localized extranoda1 non-Hodgkin lymphoma; but if there is recurrence, salvage is often difficult.4,25,2s Spread of extranodal lymphoma is usually to the regional lymph nodes prior to wide dissemination, but a “skip” to distant sites may occur especially with aggressive histological cell types4 Consequently, Rosenbergz5 recommends that highgrade tumors should be considered systemic at diagnosis and be treated primarily with chemotherapy. Accordingly, certain guidelines for the management of apparently primary bladder and prostate lymphomas are presented. Initially, the tumor should be precisely categorized. Then accurate staging is imperative to exclude distant or regional dissemination to nodal or extranodal sites, including the bone marrow. Multiagent chemotherapy should be used initially for a high-grade tumor, a bulky tumor, or for disseminated disease. For a small localized lower grade tumor, aggressive regional therapy is indicated-transurethral or segmental resection followed by external beam radiotherapy to the whole pelvis for bladder involvement, and radical radiotherapy to the whole pelvis for prostatic involvement. Currently, there is no place for exenterative pelvic surgery in the management of bladder or prostate lymphomas. Early diagnosis as a result of awareness of this disease entity, especially in younger males with “prostatitis” who have a tender enlarged prostate not responding rapidly to antibiotic therapy, may lead to an improved prognosis. St, Vincent’s

Hospital Elm Park Dublin 4, Ireland (MR. HEANEY)

References 1. Rosenberg SA, Diamond HD, Vaslowitz B, and Craver LF: Lymphosarcoma: a review of 1,269 cases, Medicine (Baltimore) 40: 31 (1961). 2. Richmond 1, Sherman RS, Diamond HD, and Craver LF: Renal lesions asskiated with malignant lymphomas, Am J Med 32: 184 (1962). 3. Freeman C, Berg IW, and Cutler ST: Occurrence and uroenosis of extranodal ly@homas, Cancer i9: 252 (1972). _ 4. Rudders RA, Ross ME. and DeLellis RA: Primarv i extranoda1 lymphoma, Cancer 42: 406 (1978). 5. Bhansali SK, and Cameron KM: Primary malignant lymphoma of the bladder, Br J Urol32: 440 (1960).

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6. Waller JI, and Schullenberger WA: Lymphosarcoma of the prostate, J Uro162: 480 (1949). 7. Rappaport H: Tumors of the hematopoietic system, in: Atlas of Tumor Pathology, Section 3, Washington, D.C., U.S. Armed Forces Institute of Pathology, fast 8, 1966. 8. The Non-Hodgkin’s Lymphoma Pathologic Classification Proiect: National Cancer Institute Soonsored Studv of Classificati0n.s of Non-Hodgkin’s Lymphomg. Summary and description of a working formulation for clinical usage, Cancer 49: 2112 (1982). 9. Cartagena R, Baumgartner G, Wajsman Z, and Merrin C: Primary reticulum cell sarcoma of the prostate gland, Urology 5: 815 (1975). 10. Hampel N, Richter-Levin D, and Gersh I: Primary lymphosarcoma of prostate, ibid 9: 461 (1977). 11. Narayana AS, Loening S, Weimar GW, and Culp DA: Sarcoma of the bladder and prostate, J Urol 119: 72 (1978). 12. Winter CC, Puente E, and Wall RL: Bladder involvement with lymphoma, Urology 14: 151 (1979). 13. Hamburger S, and Woods K: Non-Hodgkin’s lymphoma of the prostate, J Kans Med Sot 81: 457 (1980). 14. Smith BH, and Dehner LP: Sarcoma of the prostate gland, Am J Clin Path01 58: 43 (1972). 15. Santino AM, Shumaker EJ, and Games J: Primary malignant lymphoma of the bladder, J Urol 103: 310 (1970). 16. West WO: Primary lymphosarcoma of the prostate gland, Arch Intern Med 109: 469 (1962). 17. Boe S, Nielsen H, and Ryttov N: Burkitt’s lymphoma mimicking prostatitis, J Urol 125: 891 (1981).

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18. Parton I: Primary lymphosarcoma of the bladder, Br J Urol 34: 221 (1962). 19. Pontius EE, Nourse MH, Pax L, and Mac&hum DC: Primarv maliarrant lvmnhoma of the bladder. 1 Urol90: 58 (1963). 29. Wagg CC, SC&Y RE, and Leadbetter-WF: Primary’malignant lymphoma of the urinary bladder, Cancer 24: 772 (1969). 21. Aquilina JN, and Bugeja TJ: Primary malignant lymphoma of the bladder: case report and review of the literature, J Urol 112: 64 (1974). 22. Makinen J, Alfthan 0, and Vuori J: Malignant lymphoma of the urinary bladder. A report of 2 cases, Eur Urol5: 45 (1979). 23. Cato AR: Primary histiocytic lymphoma of the bladder, Aust NZ J Surg 51: 496 (1981). 24. Mincione GP: Primary malignant lymphoma of the urinary bladder with a positive cytologic report, Acta Cytologia 26: 69 (1982). 25. Rosenberg SA: Current concepts in cancer: non-Hodgkin’s lymphoma-selection of treatment on the basis of histiologic type, N Engl J Med 301: 924 (1979). 26. Grogan TM, Warnke RA, and Kaplan HS: A comparative studv of Burkitt’s and non-Burkitt’s “undifferentiated” malignant lymphoma: Immunological, cytochemical, ultrastructural, cytologic, histopathologic, clinical and cell culture features, Cancer 49: 1817 (1982). 27. Oviatt DL, et nl: Malignant lymphoma of follicular center cell origin in humans. IV Small transformed (non-cleaved) cell lymphoma of the non-Burkitt’s type, ibid 52: 1196 (1983). 28. Reddy S, Pellettiere E, Saxena V, and Hendrickson FR: Extranodal non-Hodgkin’s lymphoma, ibid 46: 1925 (1980).

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