Case study 41.1

A 64-year-old male presents to his primary care physician with weight loss and anemia. Physical exam reveals splenomegaly. A colonoscopy reveals grossly nodular mucosa, and biopsy shows an extensive infiltrate of medium-sized lymphocytes, lambda-restricted and positive for CD5, CD20, and cyclin D1, but negative for CD23 by immunohistochemistry. Fluorescence in situ hybridization shows translocation 11;14. The patient is referred for evaluation and management.

1. What additional studies are required for evaluation and disease staging?

No further workup, as diagnosis and stage have been established
Splenectomy, bone marrow aspirate, and biopsy
Physical exam, contrast-enhanced computed tomography (CT) scan, bone marrow aspirate, and biopsy
Upper endoscopy and positron emission tomography (PET)–CT scan

This patient’s sex, age, and presentation are typical of MCL, and the combination of immunophenotype and genetic findings is diagnostic. MCL has a unique predilection for leukemic involvement and infiltration of bone marrow and the gastrointestinal (GI) tract, and it may present with splenomegaly without nodal involvement. On endoscopy, polyps, nodules, or ulcers may be seen in the upper or lower GI tract (including a minority with diffuse “multiple lymphomatous polyposis”)—but grossly normal colonic mucosa is common. Even in such patients, MCL is commonly found on immunohistochemical analysis. In series of newly diagnosed MCL patients (mostly without GI symptoms), about 90% will have GI involvement by lymphoma on biopsy. Such patients appear not to face higher risk of complications during therapy (e.g., bleeding), and management or surveillance is not affected by endoscopic data. Therefore, routine endoscopic staging evaluation for all MCL patients—or performing an upper endoscopy in this case—is unwarranted. Endoscopy may be useful when other staging studies are equivocal, or to investigate diarrhea, GI bleeding, or iron deficiency anemia in newly diagnosed MCL patients.

As with other non-Hodgkin’s lymphomas, radiographic imaging is useful for identifying the extent and size of nodal masses, splenomegaly, or organ involvement by lymphoma. PET is sensitive in pretreatment staging of MCL, but it adds little to standard staging including bone marrow aspirate and biopsy, and any role in guiding therapy remains investigational. Based on available data, CT scan remains the reasonable standard imaging test in the modern era.

Case study 41.2

A 54-year-old male presents with adenopathy and night sweats, and he has become fatigued to the point of spending most of the time resting at home. Lymph node biopsy reveals MCL with a classical growth pattern and a Ki-67 proliferation index of 40%, and he is found to have leukemic involvement of the peripheral blood. Total white blood cell (WBC) count is 20 × 106/μL, and serum lactate dehydrogenase is 320 IU/L (normal 100–220).

1. What favorable prognostic feature does this patient have?

LDH level
Stage
Performance status
Ki-67 proliferation index
Age

MCL has been historically marked by a poor long-term prognosis, with standard regimens offering remissions lasting 1–2 years and a median survival of under 5 years—although survival appears to be improving. This patient’s only favorable prognostic feature is his age. A number of studies have demonstrated age over 60 (or 70) to be an adverse prognostic feature in MCL, affecting relapse risk and survival.

This patient falls into the high-risk category using the Mantle Cell International Prognostic Index (MIPI) score, which is calculated using age, LDH level, performance status, and total WBC count. The MIPI has been validated in several data sets and has been proven superior to the International Prognostic Index in some series.

A further refinement to the MIPI incorporates the Ki-67 proliferation index, the so-called biologic MIPI. Mitotic index has long been identified as an adverse prognostic factor in mantle cell lymphoma, supplanted by Ki-67 as the standard marker of tumor cell proliferation. The median Ki-67 index in mantle cell lymphoma is about 20–30%, with values above the median range adversely prognostic. Efforts to harmonize measurement of Ki-67 have been proposed, given challenges in its reproducibility. The role and prognostic impact of the SOX11 transcription factor, expressed in most MCL but reported absent in some MCL with nonnodal presentation, are under study. Absent nuclear sox11 staining may predict an indolent clinical course, particularly among MCL cases with hypermutated IGHV genes, and may be useful as a diagnostic marker for the uncommon, cyclin-negative MCL cases. The evolution of prognostication in MCL is outlined in Figure 41.1.

Figure 41.1 Evolution of prognosis in MCL.

Case study 41.3

A 68-year-old schoolteacher presents in the autumn with a history of two episodes of bronchitis, a peripheral lymphocytosis without anemia, and total WBC 9 × 10⁶/μL. He has a palpable spleen 2 cm below the left costal margin, and bone marrow biopsy shows involvement by mantle cell lymphoma in an interstitial pattern. He has no other symptoms related to his lymphoma, and asks about the role of observation so that he may complete his scheduled year of teaching.

1. Is observation an appropriate option in newly diagnosed mantle cell lymphoma?

Although mantle cell generally behaves in an aggressive manner, cases of indolent mantle cell lymphoma are well described. Such cases may present with leukemic blood involvement and no (or low-level) lymphadenopathy, with or without splenomegaly; some show unique features, including kappa light-chain restriction (as opposed to lambda, which is more typical for MCL), hypermutated immunoglobulin heavy-chain genes (seen in a minority of MCL cases), and absent nuclear staining for the transcription factor SOX11.

Clinical data suggest that observation is acceptable for a proportion of MCL patients. Some data show no survival decrement for those initially observed with mantle cell lymphoma. In this case, there is certainly a concern that his episodes of bronchitis are a disease-related phenomenon, but lacking other MCL-specific high-risk features or symptoms, one may opt to observe this patient while evaluating (by measuring his immunoglobulin G level) and treating his pulmonary infection as needed.