December 2018 Case

Michelle Don, MD (Hematopathology fellow), Jean Lopategui, MD (Attending) and Sumire Kitahara, MD (Attending)

This case is that of a 78 year old male with a history of angioimmunoblastic T-cell lymphoma (AITL) diagnosed on lymph node biopsy, status 5 years post chemotherapy. He had disease recurrences at 4 years and 5 years after diagnosis. Past medical history was also significant for history of treated tuberculosis several decades ago. He presented again, in the fifth year after diagnosis, with recurrent fevers and pulmonary effusions and was admitted to the hospital. Upon admission, he was noted to have pancytopenia and a bone marrow examination was performed.

PCR for mycobacterium (aspirate clot and core biopsy; performed at the Centers for Disease Control, Atlanta, GA):

• Negative

Next generation sequencing (NGS)

• DNMT3A p.PHE608Serfs*43, VAF 6.77%
  

Consistent with persistent/recurrent angioimmunoblastic T-cell lymphoma

This case demonstrates the utility of abnormalities found by next generation sequencing (NGS) in making a diagnosis of angioimmunoblastic T-cell lymphoma (AITL) presenting as bone marrow granulomas in a patient with remote history of tuberculosis (TB). Patients with AITL are immunodeficient due to immune dysregulation caused by the lymphoma's interaction with its microenvironment. This case posed a diagnostic dilemma in determining whether the bone marrow granulomas were secondary to TB recurrence or a granulomatous manifestation of persistent/recurrent lymphoma. We briefly discuss below lymphoma pathogenesis, clinical and histologic features, and the diagnostic approach taken in this case.

AITL is a rare subtype of peripheral T-cell lymphoma, accounting for 1-2% of all non-Hodgkin lymphoma, with an overall poor prognosis and a median survival of less than 3 years. It is a neoplasm of follicular helper T (TFH) cells which release factors (such as CXCL13, IL21, IL10, TGF-beta, VEGF) that contribute to expansion of TFH cells, B-cells, production of IL-6, follicular dendritic cells and vascular proliferation (figure 1). As a consequence, patients present with any combination of symptoms including generalized lymphadenopathy, hepatosplenomegaly, B-symptoms (fever, weight loss, night sweats), polyclonal hypergammaglobulinemia, skin rash, pruritus, pleural effusion, arthritis, ascites, hemolytic anemia, circulating immune complexes and cold agglutinins. Immunodeficiency occurs secondary to the neoplastic process. Reactivation of EBV frequently occurs (75%) in the context of a dysregulated immune system.

Microscopically, AITL can cause partial or total effacement of the lymph node architecture with a neoplastic proliferation of TFH cells within a mixed inflammatory background (reactive lymphocytes, histiocytes, plasma cells and eosinophils), proliferation of high endothelial vessels, and expanded follicular dendritic meshworks. The lymphoma cells are small to medium in size with clear to pale cytoplasm, distinct cell membranes, and without cytological atypia. Some cases may exhibit an infiltrate of reactive epithelioid histiocytes which can mimic a granulomatous reaction. The lymphoma cells demonstrate an immunophenotype of TFH cells, expressing CD4, CD10, CXCL13, ICOS, BCL6 and PD1. Pan-T-cell antigen expression is usually maintained. They are often arranged in clusters, surrounded by dendritic processes highlighted by CD21 stain. Most cases are associated with EBV-infected B-cells.

Positive T-cell receptor gene rearrangement studies are seen in 75-90% of cases of AITL. Recent studies utilizing next generation sequencing have identified recurrent mutations that help to unify AITL and other follicular T-cell lymphomas. Common mutations seen in AITL include RHOA (60-70%), TET2 (50- 80%), IDH2 (20-30%), and DNMT3A (20-30%). Frequent mutations in epigenetic modifiers (TET2, IDH2, DNMT3A) suggest that aberrant DNA methylation contributes to AITL pathogenesis. Additionally, since both IDH2 and TET2 are associated with promoter hypermethylation, there is strong consideration for utilizing hypomehtylating agents as well as IDH2 inhibitors as targeted therapy of AITL to improve outcome. There is speculation as to whether AITL arises from a common progenitor as myeloid malignancies.

In this case presenting a diagnostic dilemma due to bone marrow presentation of granulomatous infiltrates in a patient with history of recurrent AITL and TB, we utilized various ancillary tests to exclude TB and rule in AITL. AFB stains were negative for acid fast bacilli; Auramine O/Rhodamine B fluorescent stains were inconclusive; and polymerase chain reaction testing for mycobacterium was negative. Immunohistochemistry was non-contributory in establishing a diagnosis of AITL due to lack of significant staining for PD1 and CXCL13. T-cell receptor gene rearrangement studies were negative, though the aspirate was scanty and likely unrepresentative. NGS testing showed a DNMT3A mutation (frameshift mutation; p.PHE608Serfs*43). DNMT3A mutations are not specific, commonly seen in myeloid malignancies, and notably in age-related clonal hematopoiesis. Additionally, in the setting of AITL, it has been shown that DNMT3A mutations occur concurrently with TET2 mutations. Despite limitations in sensitivities and specificities of the testing which we performed, in the current setting with a relatively high pretest probability of recurrent AITL, this positive NGS result with a negative mycobacterium workup supported the clinical suspicion of involvement by AITL in the bone marrow. In fact, subsequent bone marrow biopsies were additionally performed, demonstrating more overt morphologic involvement by lymphoma (Image 3) with positive T-cell receptor gene rearrangement studies.

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