Isolated bone marrow gamma-delta T-Cell lymphoma: Another challenge to the WHO lymphoid neoplasm classification

To the editor,

1. Background

Gamma-delta T-cell lymphoma (GD-TCL) constitutes a rare and aggressive subgroup of lymphoma originating from lymphocytes expressing gamma-delta T-cell receptors (TCR) [1]. These lymphocytes develop from CD4-/CD8- (double negative) thymic precursors in the bone marrow, lack histocompatibility complex restriction, function as cytotoxic effectors of the innate immune response, and are enriched in epithelial and mucosal tissue [2]. GD-TCL is a biologically and clinically heterogenous group depending on site of origin, but all share poor response to chemotherapy and a grim prognosis [3,4]. Thus, high suspicion and early detection are extremely important for GD-TCL. The actual incidence of GD-TCL is underestimated due to difficulties in the identification of gamma-delta TCR from routine biopsies, and the entity is poorly represented in clinical studies [5,6].

The 2016 and 2022 revisions of the World Health Organization (WHO) classification of lymphoid neoplasms use cellular, phenotypic, and molecular properties to identify individual lymphoma subtypes [7]. GD-TCLs are recognized as mature cytotoxic TCLs, a group of heterogeneous entities that present with extranodal disease or systemic involvement of the liver, spleen, and bone marrow. There are four GD-TCLs subtypes: Hepatosplenic gamma-delta T-cell lymphoma (HSGDTCL), primary cutaneous gamma-delta T-cell lymphoma (PCGDTCL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITCL), and gamma-delta large granular lymphocytic leukemia (T-LGL). Though the 2016 and 2022 classifications practically describe clinically identifiable disease entities [4,8], other rare TCLs derived from gamma-delta lymphocytes without hepatosplenic, cutaneous, or enteric involvement remain unaccounted for despite their aggressive features. These TCLs are extremely rare and identifying them properly is the necessary first step to allow outcomes research that can guide clinical decisions.

2. Case presentation

A 59-year-old male patient with past medical history of tobacco smoking and chronic obstructive pulmonary disease presented with a 2-month history of fatigue, fever, and generalized weakness. He was diagnosed with hemophagocytic lymphohistiocytosis (HLH) based on severe anemia and neutropenia, elevated inflammatory markers including soluble IL-2 receptor >2400 U/mL and ferritin >6000 ug/L, hypertriglyceridemia, and extensive hemophagocytosis without evidence of infection in the bone marrow. HLH genetic panel demonstrated several variants of uncertain significance: heterozygous missense variant in UNC13D (p.Ala59Thr c.175G>A), a heterozygous missense variant in ITK (p.Arg610Cys c.1828C>T), and a non-coding variant in the 3′ untranslated region of CD27. No pathogenic variants were identified and after thorough work-up for infectious and hematologic etiologies, no triggering cause of HLH was identified. The patient was treated with etoposide and dexamethasone following the HLH-94 protocol and achieved remission.

Severe anemia recurred 3 months later, and a diagnosis of warm autoimmune hemolytic anemia was established through positive antiglobulin test, thus prompting work-up for an underlying condition. Peripheral blood flow cytometry showed an immunophenotypically abnormal lymphocyte population accounting for 54% of lymphocytes as well as loss of regulatory B and T-cells suggesting hematologic malignancy with lymphocyte dysregulation. Repeated bone marrow biopsy showed approximately 20% involvement by atypical lymphocytes of T-cell lineage expressing cytoplasmic CD3, granzyme B, and TCR-Delta (Fig. 1). There was no overt evidence of HLH. Bone marrow aspirate flow cytometry confirmed a similar immunophenotypically abnormal T-cell population, with cytoplasmic CD3, CD45, CD38, and HLA-DR, accounting for approximately 70% of lymphocytes (Fig. 1). These findings were consistent with bone marrow involvement by a CD30-positive mature TCL with gamma-delta phenotype. A complex karyotype with numeric abnormalities including a marker chromosome was identified: 47,XY,+1,add(4)(q31),add(6)(q23),add(9)(p12),−17,+mar. The TCL fluorescence in-situ hybridization (FISH) panel showed no abnormalities in chromosome 7 and no rearrangement of the TP63, DUSP22, or TRAD gene regions.

Fig. 1.

A. Bone marrow biopsy (H&E 40X) showing hypercellularity; B. Bone marrow biopsy (H&E 400X) showing a lymphoid infiltrate; C. CD3 (400X) staining background T-cells and cells of interest; D. CD2 (400X) staining background T-cells, cells of interest are negative; F. Granzyme B (400X) staining cells of interest; G. TCR delta (400X) staining cells of interest, background T-cells are negative; TCR beta (400X) staining background T-cells, cells of interest are negative. I. Flow cytometry showing an immunophenotypically aberrant T-cell population accounting for 60–70% of lymphocytes. The cells of interest do not express lineage specific markers such as CD2, CD3, or CD5. They express only dim CD8, CD38, CD11c, HLA-DR, and variable CD57.

Extensive work up to determine TCL involvement and pattern was conducted. Detailed exam revealed no cutaneous lesions. Laboratory results showed normal organ function. Computerized tomography (CT) of chest, abdomen and pelvis showed no hepatosplenomegaly or lymphadenopathy, and positron emission tomography (PET) confirmed the absence of other sites of hypermetabolic nodal or extranodal disease. Cerebrospinal fluid analysis showed no central nervous system involvement. No focal signs suggesting gastrointestinal involvement were identified and the patient's main symptoms were explained by severe cytopenia. Thus, no evidence of systemic TCL was identified outside bone marrow and peripheral blood. Despite absence of hepatosplenomegaly, HSGDTCL was considered part of the differential, though the lack of prominent intrasinusoidal distribution of the abnormal T-cells and lack of abnormality in chromosome 7 did not support this diagnosis. In correlation with clinical features, a diagnosis of peripheral TCL (PTCL) with gamma-delta phenotype isolated to the bone marrow was established. The patient was treated with combination chemotherapy including cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone (CHOP) with transient improvement in marrow involvement by GD-TCL after 2 cycles. Unfortunately, his clinical condition deteriorated with progressive deconditioning and persistent cytopenia, and he passed away due to infectious complications.

3. Commentary

GD-TCLs are rare but aggressive neoplasms arising from a small subset of T-cells that express gamma-delta TCR [2]. The WHO classification of lymphoid neoplasms has established clinically distinct subtypes harboring a predominant gamma-delta T-cell phenotype [7]. These definitions have allowed efforts to gather case series within small clinical trials to describe the presentation, clinical behavior, prognosis, and response to treatments of some subtypes, especially the two main entities, HSGDTCL and PCGDTCL [4,5,8]. However, there are increasing reports in the literature of aggressive GD- TCLs not accounted for in this classification, all with extensive extranodal or diffuse systemic involvement and an aggressive clinical course with extremely poor prognosis [9,10]. The clinical heterogeneity and rarity of these mature TCLs makes them difficult entities to diagnose and study, however there are substantial clinical arguments to suggest they should be differentiated from other not-otherwise-specified PTCL cases (PTCL-NOS). Proper classification is the necessary first step to encourage research efforts as these PTCLs with gamma-delta phenotype are currently poorly represented in PTCL-NOS studies and data about their clinical presentations and patterns are limited.

In this letter, we highlight a case which cannot be perfectly categorized according to the current WHO classification of lymphoid neoplasms. This difficult and challenging case of a biopsy-confirmed GD-TCL does not fit into any of the available subgroups and would be classified as PTCL-NOS. Nevertheless, based on laboratory and histologic findings, our patient had a distinct diagnosis of a GD-TCL isolated to the bone marrow and peripheral blood. He had no hepatosplenomegaly, cutaneous manifestations, evidence of bowel, respiratory tract, thyroid, or nasal cavity involvement. Malignant lymphocytes did not have a particular morphology (large lymphocytes with abundant cytoplasm and conspicuous azurophilic granules) to suggest gamma-delta T-LGL. Notwithstanding, this lymphoma case was not classifiable according to the current 2016 or 2022 WHO lymphoma classifications for GD-TCL.

This unique case is the first documented in the literature, to the best of our knowledge, of a patient with GD-TCL and absence of any nodal or extranodal involvement outside the bone marrow and peripheral blood, thus adding to the list of the likely underreported atypical GD-TCLs. Using this case, we aim to illustrate the need for a new classification that includes a spectrum of aggressive cytotoxic GD-TCLs, without hepatosplenic or cutaneous involvement, but with aggressive extranodal presentations. Currently, these cases are extremely hard to identify and a dedicated morphologic category may result in increased reporting. Furthermore, patients are treated with combination chemotherapeutic regimens extrapolated from other malignancies and data are sparse regarding the dedicated induction and consolidation treatment strategy for these unclassifiable lymphomas. Given their extremely poor prognosis and our limited knowledge partly caused by poor recognition and reporting, future studies to better understand, diagnose, classify, and manage these patients may be supported by a clearer classification category of extranodal GD-TCLs.

Declaration of Competing Interest

The authors confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.