Correspondence *Sisli Etfal Egitim ve Arastirma Hastanesi, 2 Uroloji Klinigi, Sisli 34360, Istanbul, Turkey

Email khorasanli@gmail.com

The case

A 65-year-old Caucasian woman was admitted to a urology department after presenting with macroscopic hematuria, dysuria, urinary frequency and urgency. She did not have a history of weakness, fatigue, night sweating, fever, weight loss or recurrent urinary infection. Physical examination found no organomegaly or lymphadenopathy. One year earlier, she had experienced a 1-month episode of hematuria, dysuria, urinary frequency and urgency, which was treated with antibiotic and antimuscarinic agents. The patient had subsequently undergone simultaneous surgeries for resection of a basal cell carcinoma of the nasal skin and lymphoma of the bladder; no lymph node involvement had been observed at this time. Furthermore, no recurrence of the carcinoma was seen following the surgery. At presentation, the patient's serum levels of urea, creatinine and electrolytes were normal, as was her peripheral blood film.

Ultrasonography and intravenous pyelography demonstrated a mass involving the right lateral wall of the bladder and the right ureteral orifice (Figure 1). An abdominal ultrasound scan revealed hydronephrosis of the right kidney, asymmetric hypoechoic diffuse thickening of the bladder wall and a large solid mass, with the dimensions 10 mm 45 mm 30 mm, involving the right ureteral orifice on the right wall of the bladder. The mass was lobular and hypo–hyperechoic. Clinical and radiographic examinations, including CT of the upper abdomen and chest, did not identify any other tumors. Bone marrow aspirate and a bone biopsy sample were also normal, indicating no systemic disease.

Figure 1 Intravenous pyelogram demonstrating a mass within the urinary bladder.

The image depicts a filling defect on the right lateral wall and dilatation of the right upper urinary tract.

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Cystoscopy showed an irregular lobular, solid and ulcerative mass arising from the right wall of the bladder. The vesical tumor was transurethrally resected, and histopathologic examination showed a diffuse, dense infiltration of a highly pleomorphic population of large cells, a few of which had prominent nucleoli (Figure 2A). Tumor cells were strongly positive for leukocyte common antigen (LCA) and CD20, markers indicative of a B-cell-derived lymphoma (Figure 2B). Immunohistochemical analyses were negative for cytokeratin, cytokeratin 7 and CD45RO, ruling out the possibility of carcinoma. The tumor was diagnosed as primary lymphoma of the bladder.

Figure 2 Histopathologic appearance of the primary lymphoma of the bladder.

(A) Light microscopy of a diffuse large cell lymphoma infiltrating the vesical wall ( 4 magnification; hematoxylin and eosin stain).The arrows show the prominent nucleoli ( 40 magnification). (B) Immunohistochemical staining with anti-CD20 antibody, a marker of B-lymphoid cells ( 100 magnification).

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Three months after resection of the tumor, follow-up cystoscopy indicated no mass or suspicious areas in the bladder. A CT scan of the whole abdomen and pelvis performed 5 months after resection, however, identified multiple lymph nodes with diameters of around 25 mm in the common iliac, parauterine and para-aortacaval regions. The patient was administered cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy to prevent the progression of the disease (four 5-day cycles [weeks 1, 4, 7 and 10 after CT] of cyclophosphamide 1,000 mg/m², doxorubicin 100 mg/m², vincristine 2 mg/m² and prednisolone 100 mg). Subsequently, radiotherapy was applied with a total of 46 Gy delivered in 23 equal fractions. After chemotherapy and radiotherapy, a CT scan of the pelvis and upper abdomen showed complete resolution of the disease. Tumor recurrence was monitored by cystoscopy and urinary immunocytologic examination on four occasions during the following year. The cystoscopic evaluations at months 3, 6, 9 and 12 after resection were normal, as were the results of immunocytologic analyses of urine samples that assessed reactivity to LCA and CD20. Furthermore, a biopsy specimen obtained from the site of resection after 12 months showed no sign of disease recurrence. Subsequently, the patient was monitored by cystoscopy and urinary immunocytologic examination every 6 months, with no evidence of recurrence.

DiscussIon of Diagnosis

Although the bladder is secondarily involved in 10–20% of terminal non-Hodgkin's lymphoma cases,¹ primary lymphomas of the bladder are very uncommon and represent less than 1.0% of vesical tumors and less than 0.2% of extranodal lymphomas.^{2, 3} The most common sites of primary extranodal malignant lymphoma are the stomach, connective tissues and skin. Primary lymphoma of the bladder was first described by Eve in 1885.⁴ Approximately 100 cases have been reported in the literature. The etiology of primary lymphoma of the bladder has not been elucidated, partly because of the rarity of the condition. According to one theory, lymphoma follows chronic cystitis and an associated increase in the amount of lymphoid tissue found in the lamina propria.^{2, 5, 6, 7} As a number of cases have been reported in the literature in the absence of chronic cystitis, we postulate that the tumor might originate in the lymphoid tissue derived from the embryonic cloaca.⁶ Among primary terminal lymphomas, low-grade lymphomas—including the subtypes of mucosa-associated lymphoid tissue (MALT)—are common.^{8, 9} Primary lymphoma of the bladder affects 6.5 times more women than men, and the tumor typically appears in patients between the ages of 20 and 85 years (at a median of 64 years).¹⁰

The major symptoms of primary lymphoma of the bladder are intermittent hematuria, urinary frequency and dysuria. This disease presents as a solitary tumoral mass. A history of chronic cystitis has been shown to be a preceding feature in some cases of primary bladder lymphoma;^{10, 11} approximately 20% of patients present with such a history.^{10, 12} The current patient did not have a history of recurrent urinary infection. Hydronephrosis is an uncommon feature of the tumor. The tumor does not typically involve the ureteral orifices, and involvement of the entire bladder wall is also a rare phenomenon.^{13, 14} The current patient's tumor involved the right ureteral orifice and caused hydronephrosis of the right kidney; this is a very uncommon presentation of primary lymphoma of the bladder.

At presentation, the patient was hemodynamically stable; there were no signs of clinical anemia, and findings on abdominal examination were normal. Microscopic analysis of her urine showed the presence of erythrocytes but not lymphocytes. No evidence of malignant cells was found on cytologic assessment. Serum levels of urea, creatinine and electrolytes were measured and were found to be normal, indicating that the patient's hydronephrosis had not resulted in impaired renal function. CT of the upper abdomen and chest showed no evidence of systemic disease. There was also no evidence of lymphadenopathy or hepatosplenomegaly on CT. Bone marrow aspirate and a bone biopsy sample showed no sign of lymphoma infiltration.

This patient had hematuria, dysuria, urinary frequency and urgency. Other possible causes of these symptoms are cystitis, interstitial cystitis, bladder carcinoma and urinary stones. Ultrasonography and CT of the abdomen showed no sign of urinary stones. No growth of organisms was observed on midstream urine culture, ruling out cystitis. Cystoscopy showed an irregular lobular, solid and ulcerative mass arising from the right wall of the bladder.

Histopathological and immunohistochemical studies are absolutely necessary for the diagnosis of bladder lymphoma, as the clinical and radiological features of this tumor are similar to those of urothelial carcinomas of the bladder. The most common macroscopic findings are solitary masses located in the lateral walls of the bladder.¹⁵ The most common primary malignant lymphomas of the bladder are low-grade B-cell-derived non-Hodgkin's lymphomas of the MALT type, including Burkitt's and plasmacytoid lymphomas,³ which are associated with good prognoses. Approximately 20% of primary bladder lymphomas are high-grade neoplasms.¹⁰ High-grade primary bladder lymphomas are mostly of the diffuse large-B-cell type.^{1, 3, 16} In this patient, strong positive staining for LCA and CD20 (Figure 2B) indicated a B-cell-derived lymphoma, while immunohistochemical analyses negative for cytokeratin, cytokeratin 7 and CD45RO ruled out the possibility of carcinoma.

Primary malignant lymphoma of the bladder usually exhibits a silent course with a favorable prognosis. The prognosis is associated with the tumor grade and stage at presentation. If a high-grade lymphoma of the bladder is diagnosed by pathological examination, systemic lymphoma should be excluded via clinical and radiographic examinations, including CT of the abdomen and chest. Also, bone marrow aspirate and bone biopsy samples should be analyzed to exclude the possibility of systemic lymphoma. In the current patient, clinical and radiographic examinations excluded systemic lymphoma and confirmed a focused lymphoma of the bladder.

Treatment and Management

The treatment for bladder lymphomas is the same as that for nodal lymphomas. Chemotherapy, radiotherapy and surgery, as well as combinations of these therapies, are the treatment options for primary lymphoma of the bladder.^{1, 5, 8} Patient characteristics, such as age, tumor grade and the coexistence of systemic disease, should be considered when selecting treatment modalities. Patients with a high-grade lymphoma should be considered to have systemic disease, which requires chemotherapy. Systemic chemotherapy should be considered as a first-line treatment for high-grade lymphomas, and also in cases in which radiotherapy is not sufficient to cure the disease.¹⁷ Surgery can be beneficial for the alleviation of intractable irritative urinary symptoms. In the current patient, resection of the lesion was associated with cessation of both irritative symptoms and hematuria. Radiotherapy can be used if the patient's tumor is of low grade and small size. This modality can also be used for local control of the disease after surgical intervention. Some authors have, however, considered radiotherapy alone to be the treatment of choice for this neoplasm.¹⁸ All usable treatment modalities have shown efficacy in the treatment of this rare disease. The current patient presented with irritative urinary symptoms and hematuria. Ultrasonography and CT revealed the tumor to be small; therefore, cystoscopy and transurethral resection of the tumor were performed after the exclusion of other potential causes of the presenting symptoms. The histopathologic diagnosis of high-grade primary lymphoma of the bladder indicated the use of chemotherapy as a first-line treatment.

The most frequently applied chemotherapy regimen is CHOP for four cycles: cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² and prednisolone 100 mg for 5 days. As a result of the rarity of the disease, no consensus exists regarding the optimum chemotherapy regimen. In the patient presented here, the treating radiation oncology department considered the tumor to be a recurrence, and consequently administered chemotherapy at an increased dose.

The optimum follow-up protocol for patients treated for primary lymphoma of the bladder has yet to be determined. Follow-up evaluations should take place every 3 or 6 months for the first 2 years and yearly thereafter,¹⁹ as is the case for transitional cell carcinoma. Primary lymphoma of the bladder usually exhibits an indolent course with a favorable prognosis. The risk of recurrence remains unknown. The current patient was evaluated with abdominal ultrasonography and cystoscopy every 3 months for the first year and every 6 months for the second year. The most important aspect of monitoring with cystoscopy is surveillance for a mass in the bladder.

Conclusions

If a bladder tumor with uncommon histopathological features is found, lymphoma should be excluded. In the presented case, the diagnosis of primary bladder lymphoma was made after excluding a systemic hematological malignancy. Primary lymphoma of the bladder with hydronephrosis is a very rare condition that exhibits a silent course and a favorable prognosis.

There is no consensus regarding the treatment of primary lymphoma of the bladder, owing to the lack of large patient series. A variety of therapies, including chemotherapy, radiotherapy and surgery, have been favored for primary bladder lymphoma. Patients with high-grade lymphoma should be considered to have systemic disease, and, therefore, require chemotherapy. Surgical approaches can be beneficial for patients with irritative urinary symptoms. In the current patient, following resection, radiation therapy and four cycles of chemotherapy, the tumor and its related symptoms did not reappear.

Acknowledgments

We thank the patient for giving consent to publish this case report.

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