Primary Urinary Tract Lymphoma: Rare but Aggressive

Discussion

To our knowledge, this is the first large-scale population study of PUTL with >1,000 cases from several registries across the USA. Although the urinary tract does not have any organized lymphoid tissue, PUTL may originate from lymphoid cells attracted to the area from recurrent infections (4, 5). This hypothesis is supported by regression of some lymphomas in other parenchymal organs after the use of antibiotics, particularly MALT-associated lymphomas (13). In addition, the observation that bladder lymphomas occur more frequently in women than men could support the above theory since women experience cystitis more frequently than men. Moreover, higher frequency of MALT-associated lymphoma, which is commonly associated with bacterial infections (13), was noted in the bladder. A previous study failed to demonstrate an association between kidney lymphoma and Epstein-Barr virus infection (14). The most frequent symptoms in patients with kidney lymphoma are fever, weight loss, flank or abdominal pain, and hematuria (4), whereas the most frequent symptoms in bladder lymphomas are hematuria and recurrent urinary tract infections (5). Patients can have a flank mass on physical examination and may often present with acute kidney injury from renal parenchymal involvement or obstruction (15). While the differential diagnosis of lymphoma from other more common malignancies of the urinary tract can be difficult based solely on imaging, a small-scale study with 12 patients suggested that in contrast to most types of renal cell carcinoma, lymphoma usually has a high fludeoxyglucose uptake on positron-emission tomography scan (16). The use of percutaneous biopsy can safely and accurately provide histological diagnosis (17) and lead to early identification of kidney lymphoma. For bladder masses, cystoscopy with tissue biopsy can provide an accurate diagnosis (18).

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Figure 4.

Cancer-specific survival of patients with stage I-II (N=19173, p<0.001) (A) and stage III-IV diffuse large B-cell lymphoma (N=28,731, p=0.03) (B) stratified by site. Five-year cancer-specific survival for patients with nodal and urinary tract diffuse large B-cell lymphoma was 69% and 59% for those with stage I-II and 46% and 39%, respectively, for those with stage III-IV disease.

Our data suggest that surgical treatment may be beneficial in patients with PUTL. This is notable, given that the mainstays of nodal DLBCL therapy are chemotherapy and radiation therapy (19). Surgery was most likely implemented for diagnostic purposes in the majority of patients, but it is possible that tumor debulking may produce survival benefit. Of note, Kim et al. similarly found that intestinal lymphoma benefits from surgery (20). Another study found that the most likely lymphoma to respond to local therapies is MALT-associated lymphoma of the bladder, which can recede even with administration of antibiotics (21). Surgery is occasionally used for MALT-associated lymphomas (22) but given that the analysis was multivariable and that DLBCL was the predominant form, the benefit should have been shared across all cases.

With regards to radiation therapy, it should be noted that the limitations of SEER radiation data can confound interpretation. The International Lymphoma Radiation Group includes in their guidelines “pelvic lymphoma involving bladder or gynecologic organs” and advises in favor of the use of radiation therapy. However, it does not outline any specific indications for lymphomas originating from the kidneys (23). In terms of chemotherapy, based on an analysis of the SEER database, Olsewski et al. argued that the location of extranodal NHL is critical for the effect of rituximab on the therapy, and that survival of patients with genitourinary lymphomas has not shown an improvement in the rituximab era (24). Our data are in agreement with this finding, however, the assumptions that after 2000 almost everybody received rituximab and that only the introduction of rituximab affected the survival are significant limitations.

Extranodal lymphoma has been shown to have worse prognosis than nodal (especially for DLBCL) depending on the tumor location. Castillo et al. demonstrated that gastrointestinal, pulmonary and liver/pancreas DLBCL carry a worse prognosis than nodal (6). In our analysis, after controlling for gender, patient age and race, disease stage and year of diagnosis, we showed for the first time that PUTL of DLBCL type is associated with worse CSS compared with primary nodal DLBCL in both early (I-II) and late (III-IV) stages. This could potentially be explained by the comorbidities that are caused by mass effect in the urinary tract (hydronephrosis) and infiltration of the renal parenchyma which leads to acute kidney injury. Any type of kidney injury in patients with cancer is associated with worse outcomes (25).

When comparing kidney with bladder lymphoma, a few differences were noted. Patients with bladder lymphoma were mainly female whereas those with kidney lymphoma were mainly male. Moreover, a higher frequency of MALT-associated lymphoma was noted in the bladder, which according to the literature is most commonly associated with bacterial infections (13). Contrary to kidney lymphoma, the majority of the bladder lymphomas were diagnosed at stage I. A possible explanation is the fact that bladder lymphoma gives rise to symptoms faster, mainly hematuria (5). More patients with bladder lymphoma underwent surgery and received radiation, which can be interpreted as being a result of the greater accessibility of the area for excisional biopsy when compared to the kidney. After controlling for multiple variables, no mortality difference was noted between the two sites. Finally, our data clearly disagree with the literature on the most common lymphoma of the bladder as it was found to be DLBCL and not MALT-associated as mentioned before (26).

Among the three most prevalent PUTL histology subtypes in our analysis, DLBCL carried the worse prognosis, whereas patients diagnosed with MALT-associated lymphoma had the best prognosis. Female gender was also independently associated with better survival. Similar data have been reported for B-cell lymphomas in the era of rituximab but were not noticed before supporting the fact that women may respond better to rituximab (27, 28). Age as categorized by NCCN-IPI (9) also has prognostic value for patients with PUTL.

The major strength of our study is the large number of patients (>1,000) from a multi-institutional database that spans more than 30 years, minimizing selection bias. Limitations include the lack of information about chemotherapy regimens and the low quality of information on radiation treatment. Moreover, due to the lack of central pathology review, possible tumor misclassification cannot be excluded. It should be noted that the distinction between advanced-stage primary extranodal and nodal lymphoma can be challenging given that nodal disease can involve extranodal sites as it progresses (29). Different definitions can often alter the results of these studies (30). We propose the creation of an international multi-center clinical database that can further elucidate and verify our findings. Already, efforts from the International Extranodal Study Group have delineated the behavior and clarified the treatment of other rare types of extranodal lymphomas (31-33).

In summary, our study is the first to provide a detailed description of the demographic and clinical characteristics of patients with PUTL. We found that primary urinary tract DLBCL carries a worse prognosis than nodal DBLCL in both early and late stages. In addition, surgery may be beneficial for patients with PUTL. The survival of patients with PUTL in the past two decades has not improved significantly despite the introduction of modern therapies such as rituximab. Therefore, better therapies are needed.