A Retired Teacher With a Constant Headache and Vomiting

Discussion

CSF flow cytometry revealed 48% kappa-restricted CD5-positive B-cell population, consistent with involvement of mantle cell lymphoma. These cells express CD20, CD19, CD5, and CD38. Bone marrow biopsy performed showed low-normocellular marrow with active trilineage hematopoiesis and no morphologic or immunophenotypic (flow cytometry) evidence of a B-cell lymphoma. CT of the chest, abdomen, and pelvis with contrast were negative for any suspicious lymphadenopathy. The CSF was the only site of recurrence.

Mantle cell lymphoma was diagnosed in this patient 2 years before this presentation. At the time, he had surveillance abdominal ultrasonography owing to his history of hepatitis C. A complete blood cell count at the time revealed leukocytosis/lymphocytosis. Flow cytometry on peripheral blood revealed a 32% abnormal B-cell population, which express CD20, CD19, and CD5. It also revealed surface kappa light-chain restriction. The cells did not express CD10, CD23, and CD38.

At the time of diagnosis, bone marrow biopsy revealed 50% involvement of mantle cell lymphoma. Immunohistochemistry was positive for CD19, CD20, CD5, and cyclin Dl; Ki-67 was not increased. PET at diagnosis revealed splenomegaly with a standard uptake value of 4.6 and mildly fluoro-D-glucose (FDG)–avid, nonenlarged lymph nodes diffusely in his cervical, thoracic, and abdominal/pelvic regions.

He was initially observed for approximately 6 months off treatment and was then treated with rituximab-lenalidomide for 2 months; however, he could not tolerate this treatment owing to a grade 3 rash. He completed six cycles of rituximab-bendamustine, with cytarabine (500 mg) added to cycles 5 and 6 owing to a plateau in response (size of spleen). His end-of-treatment scan showed a complete response. He was started on rituximab maintenance every 2 months, which he maintained for 1.5 years before his presentation with hydrocephalus.

Mantle cell lymphoma is a rare form of non-Hodgkin lymphoma (NHL). It is a mature B-cell neoplasm of small to medium-sized cells with a variable disease course. It is associated with poor long-term survival compared with other mature B-cell cancers. Mantle cell lymphoma represents about 7% of NHLs, with a median age at diagnosis of 60 years, male predominance, and median survival of 3-5 years.^[1] Mantle cell lymphoma usually responds to initial treatment with chemoimmunotherapy; however, most patients have relapse and have poor outcomes.^[2] A small number of patients have indolent disease; however, this population remains difficult to predict.

Mantle cell lymphoma is classically defined by the acquired translocation(11;14)(q13;q32) of pre-B cells in the bone marrow, which results in the constitutive expression of cyclin D1; this leads to cell cycle dysregulation.^[3] This translocation transposes the CCDN1 gene under control of immunoglobulin heavy chain locus (14q32), which leads to the constitutive expression of cyclin D. This translocation alone is not responsible for the development of mantle cell lymphoma; however, it leads to genetic instability and subsequent genetic aberrations, which are implicated in the aggressive disease course.

Two different forms of mantle cell lymphoma are recognized. Classical mantle cell lymphoma is generated from B cells that express SOX11 and is characterized by minimal IgVH somatic hypermutation and genetic instability. SOX11 is a transcription factor usually absent in B cells that affects cell cycle regulatory genes, DNA repair mechanisms, and cell survival mechanisms, leading to arrest of B-cell differentiation and proliferation of abnormal cells.^[3] Classical mantle cell lymphoma tends to be more aggressive, and patients are more symptomatic at diagnosis. Lymph node involvement is noted, and extranodal involvement is typically present, often in the gastrointestinal tract.

The second form of mantle cell lymphoma is known as the leukemic non-nodal variant and accounts for 10%-20% of cases.^[4] It is generated from post-germinal center, SOX11-negative B cells that are IgVH hypermutated and is more genetically stable. The leukemic variant of mantle cell lymphoma typically involves the peripheral blood and spleen, sparing the lymph nodes. This form is often clinically indolent but can involve further mutations (TP53) that can lead to a more aggressive disease course.^[3] As more mutations are acquired, this may lead to the blastoid and pleomorphic variants. The blastoid variant is classified by medium-sized lymphocytes, with indistinct cytoplasm and dispersed chromatin. Classical mantle cell lymphoma generally has morphologically smaller lymphocytes and condensed chromatin.^[5]

On the basis of our patient's initial presentation with splenomegaly and lymphocytosis with nonenlarged, mildly FDG-avid lymphadenopathy, he may have the leukemic variant that is theoretically associated with indolent disease. A pathology review of the SOX11 and p53 IHC status in the bone marrow was requested.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.