Female Paraurethral Primary Burkitt’s Lymphoma presenting with symptoms of bladder outlet obstruction, successfully treated with chemoimmunotherapy

Burkitt’s lymphoma (BL) is an aggressive B-cell lymphoma characterized by a high degree of proliferation of malignant cells and deregulation of c-myc expression.  Primary genitourinary lymphomas are uncommon, and, in particular, primary BL of the bladder or genitourinary tissue is extremely rare [1] [2]. Most frequently, genitourinary lymphoma reflects widespread metastasis caused by a systemic haematological disease [3].

We report a case of inoperable, primary paraurethral female BL successfully treated with chemoimmunotherapy with remission.

A 27-year-old female presented to the Bayless Healthcare institution with acute urinary retention. The gynaecological examination revealed a 30x40x30-mm widely pedunculated, firm, smooth, paraurethral mass without discharge, arising close to the external urethral orifice. Past medical and surgical history was otherwise unremarkable, with no history of previous urinary tract symptoms. A voiding cystourethrogram (VCUG) and computed tomography (CT) scan showed a paraurethral mass.  Pelvic magnetic resonance imaging (MRI) was performed as a supplementary diagnostic tool and confirmed the presence of a large, well-circumscribed, paraurethral mass (Figure 1A).

Cystoscopy was performed and confirmed the urethral protrusions at the bladder neck region. A provisional diagnosis of paraurethral leiomyoma was initially established on the basis of the cystoscopic examination, as well as radiological and clinical findings.

Proposed treatment involved surgical removal of the mass. An open vaginal approach was selected, the paraurethral tissue was diffusely infiltrated and the mass was partially removed.  Intra-operative frozen section showed a small cell lymphoproliferative tumor, so the surgical procedure was discontinued. The postoperative course was uneventful, and the urethral catheter was left inserted for three weeks. After removal of the urethral catheter, the patient developed mild stress urinary incontinence.

Histology of the haematoxylin-eosin-stained tissue revealed a highly cellularized tumor displaying a diffuse, infiltrating pattern, a medullary, cohesive proliferation of medium-sized neoplastic cells, monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and a basophilic cytoplasm.  A “starry-sky” pattern was observed with frequent mitotic figures (Figure 1B).

Immunohistochemical stains were negative for antibodies against CD23, CD3, CD5, bcl2, bcl6,TdT and p53. Tumour cells were positive for CD79a, CD20, CD43, CD10, MUM1 and Ki67 (100%). Fluorescence in situ hybridization (FISH) for MYC/IGH/CEP8 revealed t(8;14)(q24;q32).  However, Epstein-Barr virus RNA was not detectable. Polymerase chain reaction (PCR) analysis was used to analyze the rearrangement of VH region genes.  By amplifying the complementarity-determining region III using PCR, it was discovered that CDRIII, CDRII and CDRI showed a clonal pattern. All of the phenotypic features mentioned support the diagnosis of Burkitt’s lymphoma.

Based on the presumptive diagnosis of primary paraurethral  BL, the patient had a full workup that included  a bone marrow aspirate/biopsy, viral serologies, MRI evaluation and PET/CT  to rule out metastatic origin of the paraurethral BL. The bone marrow aspirate and biopsy revealed normocellular haematopoiesis, and no tumour cells were detected based on negative immunohistochemical analysis (CD79a, CD20, CD3). Tumour markers and a screening test for Epstein-Barr virus, human immunodeficiency virus, hepatitis virus and cytomegalovirus were all negative. MRI showed a T2-weighted hypersignal at the fifth lumbar vertebra. The F-2-fluoro-D-deoxyglucose positron emission tomography CT (FDG-PET/ CT) revealed increased FDG uptake in pelvic, bilateral iliac internal/ external lymph nodes, and significant activity in the fifth lumbar vertebra (Figure 2A).

The patient was referred for six cycles of immunochemotherapy: anti-CD20 (Rituximab) combined with chemotherapy (high doses of methotrexate and cytarabine with conventional cystostatics and prophylactic administration of G-CSF after chemotherapy cycles).

After completing the third cycle of treatment, the patient achieved near-complete remission as well as a nearly complete regression of the paraurethral tumor and lesion of the 5th lumbar vertebra. Haematological grade 2 toxicity and gastrointestinal grade 1 toxicity were reported (Figure 2B).

Follow-up was uneventful, and at the nine-month follow-up a total body CT scan revealed no evidence of clinical progression (either local recurrence or other distant metastasis, Figure 3).

The patient is still alive with a good quality of life and without clinical evidence of tumour progression.

Primary genitourinary lymphomas are uncommon, and, in particular, primary BL of the bladder or genitourinary tissue is extremely rare [1-2]. Most frequently, genitourinary lymphoma reflects widespread metastasis caused by a systemic haematological disease [3]

BL was first described in 1958 in Uganda by a surgeon who observed children with rapidly enlarging tumors involving the jaw. Since then, BL has been categorized by the World Health Organization into three types: endemic, sporadic and immunodeficiency-associated types [4]. The endemic form is found mostly in equatorial Africa and Papua New Guinea and is associated with the Epstein-Barr virus in 95% of cases. The sporadic (or American) form is found in North America, Northern and Eastern Europe, and the Far East and is associated with the Epstein-Barr virus in 15% of patients. The immunodeficiency associated form occurs mainly in patients with HIV but can also occur in allograft recipients and patients with congenital immunodeficiencies or X-linked lymphoproliferative disease [4-5].Although BL can involve the head and neck in children, the gastrointestinal tract, genitourinary tract, gonads, mesentery, peritoneum and retroperitoneum also represent potentially affected sites.Lymphomas arising in the male genitourinary tract are relatively uncommon.  Malignant lymphoma involving the prostate is rare and accounts for less than 0.1% of newly diagnosed lymphomas. The most frequent presentation forms are obstructive urinary symptoms. [6-8].

Bladder outlet obstruction in women is an infrequently diagnosed urological condition.  A combination of history taking; physical examination; and diagnostic tests provides a consistent way to accurately recognize and diagnose bladder outlet obstruction. Causes of obstruction are varied and numerous but generally fall within two broad categories: functional and anatomic. In a fertile female the most likely anatomic causes of bladder outlet obstruction symptoms are bladder and urethral leiomyoma, and an association with female hormone expression has been suggested previously [9-10]. Other differential diagnoses include urethral caruncle, urethral diverticulum [11], malignant lymphoma, sarcoma, extravesical leiomyoma of the bladder, Gartner’s duct cyst, and ectopic urethral orifice.

The diagnosis of BL relies on morphological findings, immunophenotyping results, and cytogenetic features. Because this lymphoma is one of the most rapidly proliferating neoplasms and is often associated with tumor lysis syndrome, a prompt diagnosis is required. Treatment of BL includes high doses of alkylating agents, frequent administration of chemotherapy, and attention to CNS prophylaxis with high doses of systemic chemotherapy, intrathecal therapy, or both. There is no role for radiation therapy in the modern treatment of BL- even for localized disease or paraspinal presentations, which respond very quickly to chemotherapy.

To our knowledge, this is the first case of primary paraurethral female Burkitt´s Lymphoma not related to Epstein-barr virus that is reported in the literature. Intensive chemotherapy regimens are required to treat BL [12].  Although several reports utilized initial excision, radiotherapy, chemotherapy or some combination thereof, the case report here suggests that the use of intensive immunochemotherapy should be considered as a possible treatment modality.

[1] Mearini E, Zucchi A, Costantini E. et al. Primary Burkitt’s lymphoma of bladder in patient with AIDS. J Urol 2002;167(3):1397–8.

[2] R. H. W. Simpson, R. S. Amin and R. D. Pocock. Malignant Lymphoma of the Bladder and Female Urethra. Int Urogynecol J 1994;5(2):102-105.

[3] Dahm P, Gschwend J. Malignant non-urothelial neoplasms of the urinary bladder: a review. Eur Urol 2003;44(6):672-681.

[4] Ferry JA. Burkitt’s lymphoma: clinicopathologic features and differential diagnosis. Oncologist 2006;11(4):375-383.

[5] Shad A, Magrath IT. Non-Hodgkin’s lymphoma in children. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology, 3rd ed. Philadelphia, PA: Lippincott-Raven, 1997:545-548.

[6] Choi WW, Yap RL, Ozer O, et al. Lymphoma of the prostate and bladder presenting as acute urinary obstruction. J Urol 2003;169(3):1082-1083.

[7] Singh I, Joshi M, Agarwal S, et al. Extra-nodal small cell lymphocytic lymphoma of prostate: an unusual cause of lower urinary tract symptoms. Urology 2008;71(3):547.e7-9.

[8] Schniederjan D and Osunkoya A. Lymphoid neoplasms of the urinary tract and male genital organs: a clinicopathological study of 40 cases. Mod Pathol 2009;22(8):1057-1065.

[9] Shield DE, Weiss RM. Leiomyoma of the female urethra. J Urol 1973;109(3):430-431

[10] Yusim IE, Neulander EZ, Eidelberg I, Lismer LJ, Kaneti J. Leiomyoma of the genitourinary tract. Scand J Urol Nephrol 2001;35(4):295-299.

[11] Gómez Gallo A, Valdevenito Sepúlveda JP, San Martín Montes M. Giant lithiasis in a female urethral diverticulum. Eur Urol  2007;51(2):556-8.

[12] Thomas DA, Cortes J, O’Brien S, et al. Hyper-CVAD program in Burkitt’s-type adult acute lymphoblastic leukemia. J Clin Oncol 1999;17(8):2461-70.

We would like to thank the team members from the Departments of Pathology, Haematology, Radiology and Nuclear Medicine at the Hospital del Mar, Barcelona.