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Subspecialties Hematology, Training and education, Oncology

Low-Grade Follicular Lymphoma with Increased Proliferation Index

Clinical history 

73-year-old with a history of follicular lymphoma, presenting with palpable inguinal lymphadenopathy.

Complete blood count and differential (reference range)

Serum lactate dehydrogenase 

272 (135–214 U/L) 

Lymph node morphology

Core biopsy of an abdominal mass shows fragments of lymphoid tissue involved by lymphoma. The neoplasm has a follicular/nodular pattern of growth (A and B; H&E 40x and 200x, respectively). Cytologically, the neoplastic follicles are composed predominantly of centrocytes with few admixed centroblasts in the range of histologic grade 2 (C; H&E 400x). Dual-stain immunohistochemistry shows that the lymphoma cells are positive for PAX5 (brown); residual small, admixed CD5+ T cells are seen in the interfollicular regions (red) (C). The neoplastic cells are positive for LMO2, supporting germinal center derivation (D). The Ki-67 proliferation index is ~40 percent (E). Photomicrographs courtesy of Francisco Vega-Vasquez, MD Anderson Cancer Center.


A PET/CT study showed hypermetabolic adenopathy above and below the diaphragm and widespread osseous lesions.

Flow cytometry

Flow cytometric immunophenotyping of a concurrent fine needle aspirate sample showed an expanded population of CD19+ B cells that were positive for CD10 (dim), predominantly negative for CD20, negative for CD5, and lacked surface light chain expression. These cells lacked expression of CD43 and CD200 and showed moderate/dim expression of CD38 and bright expression of CD45.

Immunohistochemical characterization of neoplastic lymphoid cells

Final diagnosis

Follicular lymphoma, grade 2, with high Ki-67 proliferation index.

Case Discussion

The pathologist’s view
Follicular lymphoma (FL) is a mature B cell lymphoma of germinal center cell origin, usually easy to diagnose when the biopsy specimen is adequate because the neoplasm exhibits typical morphologic, immunophenotypic, and cytogenetic findings. Common FL presents with a nodular expansion of malignant lymphoid follicles. Underlying the clonal expansion is constitutive overexpression of the anti-apoptotic protein BCL-2, most often as a result of the presence of t(14;18)/IGH-BCL2. The resultant monoclonal B cells typically show CD10/BCL6 expression, aberrant expression of BCL2 by immunohistochemistry, and surface immunoglobulin light chain restriction by flow cytometry.

An important prognostic indicator of FL is grading of malignant follicles wherein the number of centroblasts per high power field (hpf) distinguishes low-grade FL (grade 1–2, <15 centroblasts/hpf) from high-grade FL (grade 3, >15 centroblasts/hpf). The WHO classification scheme for lymphoid neoplasms recommends evaluating 10 follicles and calculating average centroblasts/hpf (1). In reality, most tissue biopsies we evaluate in our practice are small core needle biopsy specimens; we rarely have 10 neoplastic follicles available for evaluation. Nevertheless, distinction between low- and high-grade FL is often critical for treatment decisions, and grade 3B FL is biologically and clinically distinct from other forms and more akin to diffuse large B cell lymphoma (2,3).

In this patient with a previous history of follicular lymphoma, with an elevated serum LDH level and marked fatigue, a tissue biopsy was pursued to evaluate for possible transformed disease. However, morphologically the neoplasm is still in the low-grade spectrum (grade 2), with a predominance of small centrocytes and occasional admixed centroblasts. Of note, the Ki-67 proliferation index is higher than expected for typical low-grade FL.

Along with morphologic grading, the Ki-67 proliferation index (PI) serves as an additional prognostic biomarker (4). In most cases, histologic grade and Ki-67 index are concordant; however, in a subset of cases, there is morphologic evidence of low-grade FL, but the neoplastic follicles demonstrate a high Ki-67 (>30 percent). Low-grade FL with high PI appears to be a subgroup of FL with clinical behavior more akin to grade 3 FL, and some investigators believe these neoplasms should be treated as grade 3 neoplasms (5). Although Ki-67 PI evaluation is not formally required by the WHO, they advocate for its inclusion in the FL diagnostic workup. We believe there is sufficient evidence available to support the specific inclusion of routine Ki-67 assessment in the pathology report.

The hematologist’s view

The management of follicular lymphoma (FL), the most common indolent B cell lymphoma, has evolved rapidly in the past few years. As a result, patients and clinicians have many more treatment options, but lack predictive biomarkers to inform treatment selection. Navigating this expanding therapeutic landscape without a map to guide treatment selection can be challenging.

This 73-year-old man with no significant comorbidities has excellent performance status. He presents with palpable inguinal lymphadenopathy. Unfortunately, this is not his first such presentation; his history dates to 2002, when he first presented with axillary lymphadenopathy and was diagnosed with low-grade follicular lymphoma. At that time, he had lymphadenopathy above and below the diaphragm (>4 nodal sites) with bone marrow involvement indicating stage IV disease. Serum lactate dehydrogenase (LDH) was elevated; hemoglobin and beta-2 microglobulin were within normal limits. He had some poor prognostic features: a high-risk follicular lymphoma international prognostic index (6) and high tumor burden as defined by the GELF criteria (7). He was treated with six cycles of chemoimmunotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), achieving a complete response. He had a durable remission, lasting six years. With his first relapse, he received rituximab monotherapy and achieved a complete remission that lasted several years. In 2014, he relapsed once again with bulky disease, this time in the abdomen, and was treated with R-bendamustine. He achieved remission, but developed persistent, mild cytopenias. This time, the patient has significant fatigue, but also notes he is in his early 70s and is still more active than his friends. He has no fever or significant weight loss. Laboratory workup is notable for elevated serum LDH and mild leukopenia and thrombocytopenia. Biopsy showed recurrent follicular lymphoma, grade 2. He is in need of therapy. How do I approach a fit 73-year-old with relapsed FL who has had meaningful responses to three prior lines of therapy?

My first approach is to risk-stratify the patient. Based on observational data, he should anticipate a normal life expectancy despite his FL as a result of durable remission (>24 months) following frontline chemoimmunotherapy (8). Therefore, the toxicity of a regimen and impact on quality of life should factor into the treatment decision. Historically, outcomes generally decline dramatically after two prior lines of therapy (9), so efficacy is also an important consideration. The success of prior therapy in this situation raises the question: should we repeat any of the prior treatments, such as bendamustine, in combination with a CD20 antibody? The GADOLIN study reported favorable outcomes with obinutuzumab – a type II, fully humanized anti-CD20 antibody – in combination with bendamustine, albeit in patients refractory to rituximab (10). The potential concern would be the risk for worsening cytopenias. Would cytopenias worsen given the underlying mild cytopenias already present? How do the recently approved agents compare to this efficacy and safety profile?

Lenalidomide, an oral immune modulator, is approved in combination with rituximab for relapsed FL based on the AUGMENT study, which demonstrated a significant improvement in PFS over rituximab monotherapy (11). The most common adverse events were neutropenia, diarrhea, constipation, and fatigue. How confident am I that a non-chemotherapy approach will adequately address the disease burden in this patient? High-tumor-burden patients were just as likely to respond to lenalidomide as those with low tumor burden. The potential advantage to this approach is a fixed duration of therapy. Lenalidomide is given for 12 cycles (days 1–21 of a 28-day cycle) and rituximab administered once per week for four weeks during cycle 1 and day 1 of cycles 2–5. It is important to remember to dose adjust the lenalidomide in elderly patients with creatinine clearance <60 mL/min. The favorable efficacy and manageable toxicity profile make lenalidomide and rituximab an attractive option for the next treatment strategy.

What other options are there? Three phosphatidylinositol-3-kinase (PI3K) inhibitors are available for relapsed FL, with more on the horizon. These agents differ in their selectivity against the four isoforms and potentially, as a result, in their toxicity profiles. Idelalisib is an oral PI3Kd inhibitor approved based on a single-arm, phase II study with an objective response rate (ORR) of 57 percent and median PFS of 11 months in patients with disease refractory to rituximab and an alkylating agent (12). The most common severe adverse events were neutropenia, elevations in aminotransferase levels, diarrhea, and pneumonia. Copanlisib is an intravenous pan-PI3K inhibitor with most of its clinical activity against the a and d isoforms. The ORR in a slightly less refractory patient population was 60.6 percent, with a median PFS of 14.1 months (13). Common adverse events were transient hyperglycemia, diarrhea, transient hypertension, and neutropenia. Duvelisib, an oral g-d PI3K inhibitor had an ORR of 47.3 percent and median PFS of 9.5 months (14). The most common severe adverse events were neutropenia, diarrhea, anemia, and thrombocytopenia. All PI3K inhibitors are continued until disease progression or intolerance. The toxicity profiles, though manageable, can lead to intolerance over time and can be reserved for higher-risk situations, given the chronicity of therapy and potential for toxicity. Schedule-finding studies with intermittent dosing strategies are underway and may address these concerns. The efficacy of PI3K inhibitors warrants consideration and may be more attractive in earlier lines of therapy if toxicity can be mitigated with intermittent dosing.

Tazemetostat, an oral EZH2 inhibitor, is now approved for relapsed FL patients with an EZH2 mutation (approximately 10-20 percent) (15) after two prior lines of therapy, or for those without an acceptable standard of care in which the mutation is not present or unknown. The ORR of tazemetostat was 69 percent in the EZH2 mutant cohort and 35 percent in the wild-type cohort (16). Interestingly, the median PFS was 13.8 months in the EZH2 mutant cohort and 11.1 months in the wild-type cohort. Grade 3 or higher adverse events were infrequent and included thrombocytopenia, neutropenia, and anemia. Tazemetostat has a favorable toxicity profile and the efficacy as measured by PFS suggests it is a reasonable consideration even in the absence of the EZH2 mutation.

As more therapies emerge, so too will questions as to the most effective sequencing of therapy.

Additional therapies are on the horizon, including bispecific antibodies targeting tumor antigens and T cell engagement. Mosunetuzumab is a fully humanized IgG1 CD20/CD3 bispecific antibody with preliminary reports of an ORR of 67.7 percent in FL patients who have failed at least two prior therapies (17). Dose ramp-up and subcutaneous administration are strategies under exploration to mitigate the cytokine release syndrome observed in 23 percent of patients. Chimeric antigen receptor (CAR) T cell therapy has transformed the management of refractory large B cell lymphoma (18). The interim analysis of ZUMA-5, a phase II study of axicabtagene ciloleucel (autologous CD19/CD28), reported an ORR of 95 percent in patients with relapsed/refractory FL (19); longer follow-up is needed to assess durability. The toxicity profile compares favorably with other large B cell lymphoma treatments, suggesting that this agent will be approved for high-risk patients. As more therapies emerge, so too will questions as to the most effective sequencing of therapy. Either way, these new developments will provide additional options for patients.

What would I advise for this patient? At this point, I would pursue lenalidomide and rituximab based on the fixed duration of treatment, efficacy, and manageable safety profile. I would also explore EZH2 mutation status to inform my next treatment approach, recognizing that the number of therapies will likely be even more expansive by that time.

Read on to discover our other lymphoid cases...

Case 1: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma – Accelerated Phase
Case 2: Lymphoma-Driven Hemophagocytic Lymphohistiocytosis
Case 3: High-Grade B Cell Lymphoma with Leukemic Presentation

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About the Authors
Sanam Loghavi

Assistant Professor of Hematopathology, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Kamran Mirza

Professor of Pathology and Director of the Division of Education Programs, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, United States.

Loretta J. Nastoupil

Associate Professor, Director of the Lymphoma Outcomes Database, and Section Chief of New Drug Development in the Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

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