Indolent T-lymphoblastic proliferation in cervical lymph node with synchronous B-acute lymphoblastic leukemia involving bone marrow and hypereosinophilia

INTRODUCTION

Indolent T-lymphoblastic proliferation (iT-LBP) is the extrathymic proliferation of non-clonal TdT+ T cells and may be associated with other hematolymphoid disorders. Although the proliferating lymphocytes express TdT and CD3, patients usually exhibit indolent biological behavior; this disease was thus named as iT-LBP.^[1,2]

The indolent signs of iT-LBP often depend on any associated disorders, such as autoimmune diseases. Patients present with either an isolated mass or lymphadenopathy with or without noticeable symptoms. A specific association has been noted where iT-LBP is more likely to be present in patients who have both follicular dendritic cell sarcoma (FDCS) and paraneoplastic autoimmune multiorgan syndrome.^[3-5]

While rare cases of iT-LBP occurring alongside other malignant hematolymphoid cancers, like B-cell neoplasms, have been documented, its simultaneous presentation with B-acute lymphoblastic leukemia (B-ALL) in the bone marrow and hypereosinophilia (HE) is highly unusual and virtually unprecedented.

CASE REPORT

A 31-year-old male presented to the medical oncology Outpatient Department with low-grade fever, progressive generalized lymphadenopathy, loss of appetite, and significant weight loss along with complaints of fatigue and persistent cough for 6–7 months. On examination, he had palpable cervical and axillary lymph nodes, the largest measuring 3 cm × 2 cm, along with gross splenomegaly.

Laboratory investigations showed hemoglobin 8.8 g/dL, total leukocyte count 15.27 × 10³/uL, platelet count 103 × 10³/uL, and absolute eosinophil count 5340/µL. Peripheral smear revealed 35% mature eosinophils. Radiological investigations showed hypermetabolic enhancing soft tissue thickening along the posterior wall of nasopharynx, enlarged bilateral palatine tonsils, hypermetabolic multiple enlarged supra- and infra-diaphragmatic lymphadenopathy, and diffuse increased fluorodeoxyglucose avidity in bone marrow.

Subsequently, all relevant investigations were ordered, including biopsies from the nasopharynx, cervical lymph node, and bone marrow examination.

The biopsy from the endophytic growth in nasopharynx performed 3–4 months earlier was received for review and it showed features favoring reactive lymphoid hyperplasia which was further confirmed with immunohistochemistry (IHC) showing a mixture of B and T cells highlighted by CD20 and CD3, respectively, in the usual pattern of distribution. BCL2 was not immunoreactive in those follicles. TdT was not performed on this biopsy.

Bone marrow aspirates were partly hemodiluted but showed the presence of blasts constituting 20% of nucleated cells and 12% of eosinophils, rendering a diagnosis of acute leukemia along with eosinophilia. Immunophenotyping of these blasts by flow cytometry was bright positive for CD19 and CD79a; moderately positive for CD10, CD22, and CD34; and dim positive for CD20, CD38, and CD45. The cells were negative for CytoCD3, CD7, and myeloid markers [Figure 1]. Trephine biopsy showed completely disordered architecture with increased cellularity (~70–80%). Marrow spaces showed marked proliferation of eosinophils and an increase in blastoid cells, more in paratrabecular areas. IHC highlighted these blastoid cells accounting for 30–40% which were positive for CD19, CD10, CD34, and TdT, confirming the marrow involvement by B-lymphoblastic lymphoma/ leukemia (B-ALL) [Figure 2]. Karyotyping could not be performed as no metaphases could be grown. BCR::ABL1 reverse transcription-polymerase chain reaction was negative.

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Figure 1: Blasts (red) are moderately positive for CD45, bright positive for CD19, CD20, CD79A, CD22, and CD10, variably positive for CD34 and negative for MPO, cCD3, CD7, CD13, and CD15. The granulocytes are denoted in green which show positivity for MPO and CD15. The eosinophil population is marked by the yellow color. The T-lymphocytes (blue) are bright positive for CD3.

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Figure 2: (a) Hematoxylin and eosin ×200 and (b) Hematoxylin and eosin ×400 showing microsection of bone marrow biopsy with presence of blastoid cells and conspicuous eosinophils. The neoplastic cells are negative for CD3 (c) (×200), and positive for CD19 (d) (×200); CD20 (e) (×200); TdT (f) (×200).

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Histopathology of the cervical lymph node was received for review (performed a few weeks earlier), revealing preserved architecture and proliferation of variable-sized lymphoid follicles in the cortical region. Occasional germinal centers were also seen. The interfollicular areas were composed of lymphoid cells which were small in size, mature-looking with clumped chromatin and scant cytoplasm, admixed with few histiocytes and polymorphs. A proportion of these lymphoid cells showed immunopositivity for CD1a, CD3, CD4, CD8 (CD8>CD4), and TdT. CD19, CD20, and CD10 highlighted the germinal center B cells. CD21 highlighted the FDC meshwork. The overall features of cervical lymph node histopathology and IHC favored a diagnosis of iT-LBP [Figure 3].

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Figure 3: (a) Hematoxylin and eosin ×100 and (b) Hematoxylin and eosin ×400 show cervical lymph node with preserved architecture and proliferation of variable-sized lymphoid follicles in the cortical region. These lymphoid cells showed immunopositivity for CD1a (c), CD3 (d), CD4 (e), CD8 (f), CD10 (g), CD19 (h), CD20 (i). CD34 highlighted the blood vessels (j). CD79A (k) highlighted the germinal center B cells. TdT (l) highlighted scattered and few clusters of cells in interfollicular areas.

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However, whether the eosinophilia was clonal or reactive could not be established as further molecular studies could not be done. The anti-nuclear antibody panel was negative. There were no skin lesions.

A final diagnosis of synchronous iT-LBP (cervical node) with B-ALL (bone marrow) with HE was made. The patient was treated with ALL-BFM 2002 protocol. The patient has responded well. His post-induction marrow showed morphologic remission; however, B-ALL measurable residual disease (MRD) by flow cytometry was positive (0.016%) post-induction.

Unfortunately, the patient was subsequently lost to follow-up. Therefore, further MRD assessment, subsequent treatment response, status of the lymphadenopathy/iT-LBP-like proliferation, eosinophil counts, and long-term clinical outcome could not be evaluated.

DISCUSSION

iT-LBP is a T-lymphoblastic proliferation predominantly affecting the head-and-neck region and is defined by an indolent trajectory, localized persistence, local recurrence, and a notable absence of distant dissemination.^[6] Bone marrow involvement has not been described so far. The pathogenesis of this entity is currently not well elucidated. These cases usually present TdT-positive T cells in the paracortical region forming confluent clusters. Immunophenotypically, the immature cells are T-lineage positive, demonstrating the expression of TdT, CD3, and co-expression of CD4/CD8. This phenotype mirrors an intermediate thymocyte developmental stage within the lymph node microenvironment.^[7]

Demonstration of T-cell receptor gene rearrangement analysis is an important supportive feature in the diagnosis of iT-LBP and is particularly valuable in its distinction from T-lymphoblastic lymphoma (T-LBL). T-cell receptor gene rearrangement studies could not be performed for our patient due to financial constraints. However, several morphological and immunophenotypic findings in the cervical lymph node strongly favored iT-LBP, including mature-looking lymphoid cells, preservation of lymph-node architecture, preservation of follicles rather than destructive replacement, and interfollicular/paracortical distribution.

Yuanyuan et al. have reported a previously diagnosed case of peripheral T-cell lymphoma, not otherwise specified achieved remission, presenting with bilateral cervical lymph node enlargement showing polyclonal precursor T-cells consistent with iT-LBP. No clonal rearrangement of the TR gene was observed. Bone marrow aspiration showed involvement of B-cell lymphoblastic lymphoma/leukemia expressing PAX-5, CD34, and TdT, similar to our case.^[2]

Our patient demonstrated significant peripheral-blood and bone-marrow eosinophilia in association with B-ALL. An important differential diagnosis here is B-ALL associated with IGH::IL3 rearrangement, classically t (5;14)(q31;q32.3).

This rare genetic abnormality results in dysregulated IL-3 overexpression that drives the leukemic clone in an autocrine manner and can induce eosinophil maturation in bone marrow and reactive eosinophilia in peripheral blood. The possibility of B-ALL with IGH: IL3 which shows HE, organomegaly, and organ dysfunction, could not be ruled out, as the karyotype in this case failed to reveal metaphases.

In view of eosinophilia, splenomegaly, lymphadenopathy, and negative ANA panel results, the differential diagnosis also includes myeloid/lymphoid neoplasms with eosinophilia and tyrosine-kinase gene fusions such as platelet-derived growth factor receptor alpha (PDGFRA), PDGFR Beta, FGFR1, JAK2, FLT3 rearrangements, and ETV6::ABL1 fusion. However, these molecular tests were not available in-house, and the patient could not afford to get them done from outside because of financial constraints.

Therefore, the lack of tests for classifying the eosinophilia as reactive or part of a clonal process is a limitation in our case report.

The WHO 5^th edition for hematolymphoid tumors suggests an association of iT-LBP with other tumors and lymphoma; however, synchronous association like our case has seldom been reported.

Guo et al., reported a novel case of indolent T-LPD with synchronous DLBCL.^[8]

Ohgami et al., recommend several key criteria for diagnosing iT-LBP. Immature T-cells (positive for TdT and CD3) forming confluent groups primarily within the interfollicular regions, without damaging the normal lymphoid follicles. Morphologically, the T-cells show minimal irregularity, lacking features of significant atypia, and are negative for cytokeratin, ruling out the possibility of ectopic thymus. The cells must show an absence of aberrant antigen expression and be established as non-clonal, confirming they do not arise from a single, identical mutated cell line.^[3] Our case meets almost all of these above criteria. However, TR gene rearrangement study from the lymph node could not be performed.

Arzu Saglam, et al., reviewed 45 cases of iT-LBP. Their literature review found that 51% of the described iTLBPs involved lymph nodes that also showed changes consistent with Castleman disease (CD), CD-like features, follicular dendritic cell tumor/sarcoma, or both. The next most frequent co-occurring condition was hepatocellular carcinoma (20% of cases).^[9,10]

Summary of literature review is given in Table 1

CONCLUSION

This case highlights that awareness of iT-LBP as a benign mimic of T-LBL helps in timely identification and treatment which helps in a good response for the patient. Its cooccurrence along with B-ALL has been reported only once previously, and co-occurrence with HE is not reported in the literature.