Co-occurrence of thymoma and acute T-lymphoblastic leukemia/lymphoma: a case report and literature review
Case Report

Co-occurrence of thymoma and acute T-lymphoblastic leukemia/lymphoma: a case report and literature review

Nicholas Frazzette, Jeffrey Ordner, Navneet Narula, Andre L. Moreira, Christopher Y. Park, Nicholas D. Ward

Department of Pathology, NYU Langone Medical Center, New York, NY, USA

Contributions: (I) Conception and design: J Ordner, AL Moreira, ND Ward; (II) Administrative support: N Frazzette, AL Moreira, ND Ward; (III) Provision of study materials or patients: J Ordner, N Narula, AL Moreira, CY Park, ND Ward; (IV) Collection and assembly of data: N Frazzette, J Ordner, AL Moreira, ND Ward; (V) Data analysis and interpretation: N Frazzette, J Ordner, AL Moreira, ND Ward; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Nicholas D. Ward, MD. Department of Pathology, NYU Langone Medical Center, 550 1st Avenue, New York, NY 10016, USA. Email: Nicholas.Ward@nyulangone.org.

Background: A thymoma is a tumor originating from thymic epithelial cells variably associated with non-neoplastic lymphocytes. T-lymphoblastic leukemia/lymphoma (T-LBL) is thought to arise from precursor T-cells from bone marrow-derived hematopoietic stem cells that migrate to the thymus. While the association of secondary hematopoietic malignancies in thymoma is well established, only rarely in the literature have T-LBL and thymoma been seen in association and the relationship is poorly understood. Occasionally, distinction between the two can be difficult as immature lymphocytes in thymoma resemble T-LBL both morphologically and immunophenotypically. An accurate diagnosis is essential as treatments vary between these two entities.

Case Description: We present the interesting case of a 64-year-old male, former smoker, originally from Uzbekistan, with a mediastinal mass diagnosed as small cell carcinoma in his home country and treated with chemotherapy. After immigrating to the United States, a positron emission tomography (PET) scan demonstrated a large, metabolically active mediastinal mass. He presented to our institution where a biopsy with histomorphologic and immunohistochemical analysis was diagnostic of type B1 thymoma. He was lost to follow-up, but represented months later with B symptoms. Flow cytometry, cytogenetics, and bone marrow biopsy were diagnostic of T-LBL. Although he was started on chemotherapy, his disease progressed and he expired 6 months after initial presentation. Post-mortem analysis of the mediastinal mass revealed the co-occurrence of benign thymocytes and neoplastic T-LBL lymphoblasts, further confirmed as two distinct entities by T-cell receptor (TCR) sequencing.

Conclusions: Co-occurrence of thymoma and T-LBL is a well-documented, though poorly understood, phenomenon. Literature review for this phenomenon reveals that type B thymoma is most commonly associated with T-LBL in these co-occurrences. Most cases are diagnosed synchronously, though in metachronous cases, the diagnosis of thymoma has always preceded the diagnosis of T-LBL. Of note, recently developed LMO2 immunohistochemical stain is positive in malignant lymphoblasts but negative in benign thymocytes, allowing for post-mortem evaluation of this case to be determined as a synchronous presentation. These entities are difficult to distinguish and require a multimodal diagnostic approach including histology, immunohistochemistry, flow cytometry, cytogenetics, and TCR sequencing.

Keywords: Thymoma; T-lymphoblastic leukemia/lymphoma (T-LBL); T-lymphoblastic lymphoma; T-lymphoblastic leukemia; case report

Received: 30 May 2024; Accepted: 29 August 2024; Published online: 25 February 2025.

doi: 10.21037/med-24-23

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Key findings

• Co-occurrence of thymoma and T-lymphoblastic leukemia/lymphoma (T-LBL) can occur in any type of thymoma and may present synchronously or metachronously.

• Here we present a case of type B1 thymoma and T-LBL synchronous co-occurrence. Literature review suggests that in cases of co-occurrence, type B1 thymoma is the most common subtype observed and synchronous presentation is more common than metachronous presentation.

What is known and what is new?

• Co-occurrence of thymoma and T-LBL is well-documented, though rare and diagnostically challenging, phenomenon because benign thymocytes and malignant lymphoblasts share varies morphologic and immunophenotypic characteristics.

• We present an interesting case of co-occurrence that required histomorphologic, immunohistochemical, flow cytometric, cytogenetic, and genomic analysis to fully distinguish and confirm co-occurrence.

What is the implication, and what should change now?

• A multimodal diagnostic approach should be utilized when evaluating new diagnoses of thymoma, T-LBL in the mediastinum, or a suspected co-occurrence.

Introduction

Thymomas are a unique set of epithelial derived tumors that represent the most common neoplasm in the anterior mediastinum (1). Thymomas can vary drastically in histology, but generally have a lobulated architecture, and further classified based on the histologic appearance of the neoplastic epithelial cells; nuclei that have a spindle or oval shape and uniformly bland (Type-A thymoma) or whether they have a predominately round/polygonal appearance (Type-B thymoma) (2). The extent of infiltration of mature or immature non-neoplastic lymphocytes further subdivides type-B thymomas; B1-richest in lymphocytes, while B3-richest in epithelial cells. T-lymphoblastic leukemia/lymphoma (T-LBL) is a neoplasm of immature T-lymphoblasts that also presents frequently with mediastinal involvement (3). Distinguishing T-LBL from thymoma can be on occasion difficult, requiring a multimodality diagnostic approach incorporating histologic, immunohistochemical, flow cytometric and molecular data for an accurate diagnosis. Herein, we demonstrate diagnostic evidence for a rare phenomenon of a concurrent type-B1 thymoma and T-LBL and review the literature of this unusual phenomenon. We present this case in accordance with the CARE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-24-23/rc).

Case presentation

A 64-year-old male, former smoker, from Uzbekistan, was evaluated at our institution for dyspnea and right sided abdominal and chest pain. Significant medical history includes a previous large lung occupying mass diagnosed as small cell carcinoma in his home country for which he received chemotherapy with 2 cycles of etoposide/cisplatin and 2 cycles of docetaxel/cisplatin before he moved to the United States in late 2021 (per clinical note; histology and pathology report not reviewed). Imaging at an outside institution by positron emission tomography-computed tomography (PET-CT) demonstrated a 14.3 cm × 10.2 cm × 14.0 cm isolated mediastinal/lung mass occupying the right middle lobe extending into the lung hilum with increased uptake (standard uptake values of 4.5–10.6) (Figure 1A). No lymphadenopathy or other foci of disease were noted at this time. Core biopsy of the mass was performed at our institution and revealed bland epithelioid cells positive for cytokeratins (AE1/AE3, CAM5.1), PAX8, and p40, associated with copious immature lymphocytes positive for CD3 and TdT, diagnostic of a World Health Organization (WHO) type B1 thymoma (Figure 1B-1F). The patient was subsequently lost to follow-up.

Figure 1 Thymoma. Radiologic and histologic imaging of mediastinal mass. (A) Positron emission tomography-computed tomography scan of chest reveals a large mediastinal mass. (B) Hematoxylin and eosin-stained core biopsy reveals diffuse lymphocyte population with occasional epithelial cells (×40). (C) p40 immunostain highlights malignant epithelial cells (×20). (D) Cytokeratin AE1/AE3 immunostain highlights malignant epithelial cells (×20). (E) TdT immunostain highlights lymphoblasts (×20). (F) LMO2 immunostain differentiates malignant lymphoblasts (positive) from benign thymocytes (negative) (×20).

Two months later the patient represented to our institution with persistent dyspnea and abdominal pain, but now with night sweats. Peripheral blood counts at this time revealed leukocytosis of 86.7×109–124×109cells/L with peripheral blasts (5–22%), hemoglobin of 11.6–13.4 g/dL and platelets of 30×109–57×109/L. Computed tomography (CT) of chest/abdomen/pelvis revealed the pre-existing mediastinal/lung mass with additional mediastinal, axillary, and intra-abdominal lymphadenopathy and hepatosplenomegaly. The patient underwent a bone marrow aspiration which revealed an excess population morphologically consistent with lymphoblasts (Figure 2A), and concurrent flow cytometry demonstrated a correlate population exhibiting an immunophenotype of CD45dim+, CD1a+, cytoplasmicCD3+, CD4+, CD5+, CD7+, CD8+ and TdT+, consistent with an aberrant cortical-stage T-lymphoblast population (Figure 2B). Cytogenetics revealed a complex karyotype (46,XY, add(Jeny1)(p13), del(Jeny5)(q15q33), t(Jeny6;8)(q21;q13), t(Jeny10;14)(q24;q11.2), del(Jeny12)(p11.2p13)[7]/46,XY[13]). Molecular studies regarding T-cell clonality were performed on both the mediastinal mass and bone marrow biopsy, which showed identical T-cell receptor (TCR) gamma chain monoclonal gene rearrangements (Figure 2C). We further evaluated both the bone marrow process and the mediastinal/lung mass by whole exome sequencing, with the following pathogenic mutations detected in both sites: NOTCH1 p.L1678P (33% mass, 36% bone marrow; exon 27), CDKN2A p.Y129X (78% mass, 93% bone marrow; exon 2) and PHF6 p.Q308X (95% mass, 93% bone marrow; exon 9). He was started on outpatient hyper-CVAD chemotherapy (cyclophosphamide, vincristine, doxorubicin and dexamethasone).

Figure 2 T-lymphoblastic lymphoma. Histologic, flow cytometric, and genomic data of bone marrow biopsy. (A) Hematoxylin and eosin-stained bone marrow aspirate reveals diffuse population of lymphoblasts (×100). (B) Flow cytometry demonstrates aberrant CD45dim+, CD1a+, cytoplasmicCD3+, CD4+, CD5+, CD7+, CD8+ and TdT+ cell population. (C) TCRG clonality sequencing demonstrates identical monoclonal populations in bone marrow biopsy (top) and mediastinal mass (bottom). TCRG, T-cell receptor gene.

The clinical course was complicated by cerebral spinal fluid involvement by T-LBL, which required intrathecal methotrexate and cytarabine. In addition, shortly after starting chemotherapy the patient was found to be profoundly neutropenic with bacterial endocarditis, which required cessation of systemic chemotherapy after 1 cycle. After multiple hospital admissions due to persistent endocarditis as well as methicillin resistant Staphylococcus aureus-pneumonia and midbrain cerebrovascular accident, the patient transitioned to hospice care and died 6 months after initial presentation to our institution.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

The incidence of thymoma and T-LBL, whether synchronous (herein defined as diagnosed within 6 months of each other) or metachronous (defined as diagnosed greater than 6 months apart), is a rare and poorly described process. In reviewing the literature, we identified 13 cases of T-LBL arising in association with thymoma, summarized in Table 1 (4-13), with a median age of 61 (20–95 years) and a male predominance (10/13). Of those cases, most (9/13, 69%) occurred synchronously (diagnosed within 6 months of the first primary tumor), with metachronous cases showing a median interval from initial diagnosis to their second malignancy diagnosis of 8 years (6–30 years). Most patients (8/13, 62%) were diagnosed with a type-B thymoma, and of that subset most (5/8, 62%) were diagnosed with a type B1 thymoma. With the data available and based on when both diagnoses were established, most patients succumbed to their disease (7/13, 54%), with metachronous cases with notably poorer survival outcomes. Of note, we found no cases in the literature of a diagnosis of T-LBL preceding a diagnosis of thymoma.

Table 1

Summary of reported cases of concurrent thymoma and T-LBL reported in the literature and the present case

Reference Age (years)/sex Presenting symptom(s) Distribution of T-LBL* Thymoma & T-LBL diagnostic interval Thymoma type T-LBL immunophenotype Outcome
Macon et al. (4) 64/F Acute pulmonary edema Mediastinum, pleural fluid 30 years B1 Positive for CD43, CD45, CD45RO, TdT; negative for CD75 Expired 24 days after 2nd presentation
Friedman et al. (5) 95/M Back pain, cough, anorexia Abdomen Synch. A Positive for CD2, CD3, CD4, CD5, CD7, CD45, CD45RO; negative for CD8, CD10, CD19, CD20, CD22, CD43, CD68, kappa, lambda Expired 10 days after presentation
Rovera et al. (6) 65/M Dyspnea, fever, weakness, rash Cutaneous, followed by hepatic and cerebral metastasis 3 months AB Positive for CD1a, CD3, TdT Expired 8 months after 2nd presentation
Mizrahi et al. (7) 67/M B symptoms Mediastinum, diffuse lymph nodes, liver, kidney, skeleton 8 years B1 Positive for CD1a, CD3, TdT Expired 6 months after 2nd presentation
Boddu et al. (8) 50/F Chest pain Mediastinum Synch. B1 Positive for CD1a, CD3, CD5, CD10, CD99, TdT Alive at least 2 years
Boddu et al. (8) 45/M Weight loss, cough Mediastinum, bone marrow Synch. A Positive for CD3, CD7, CD33, CD34, CD45(dim), CD56, CD117, HLA-DR, TdT; negative for CD1, CD2, CD3, CD4, CD5, CD8, CD10 Not reported
Boddu et al. (8) 60/F Chest discomfort Mediastinum Synch. B1 Positive for CD2, CD3, CD4, CD5, CD7, CD8, TdT Alive at least 8 months
Boddu et al. (8) 20/M Referred Mediastinum Synch. AB/B1/B2 Positive for CD1a, CD2, CD3, CD4, CD5, CD7, CD8, CD24, CD38, CD45(dim), CD52, TdT; negative for CD10, CD13, CD19, CD33, CD56, CD117, HLA-DR, MPO Alive at least 1.5 years
Nishioka et al. (9) 43/M Fatigue, blepharoptosis, then malaise dyspnea Mediastinum, bone marrow 6 years Type 1 Positive for CD2, CD3, CD5, CD7, CD8 Expired weeks after 2nd presentation
Ito et al. (10) 62/M Fever, chest pain Mediastinum Synch. AB Positive for CD1a, CD3, CD4, CD5, CD7, CD8, CD99; negative for CD20 Alive at least 1 year
Le Clef et al. (11) 46/M Pleural effusion, then diffuse lymphadenopathy Diffuse lymphadenopathy 10 years B2 Positive for CD2, CD3(dim), CD7, CD8(dim), TdT; negative for CD1a, CD4, CD5 Not reported
Ertel et al. (12) 62/M None/incidental Thorax 8 years B1/B2 Positive for CD1a, CD3, CD99, TdT; negative for CD10, CD34 Expired 1 year after T-LBL diagnosis
Yılmaz et al. (13) 47/M Fever, weakness, dyspnea Mediastinum Synch. B2/B3 Not reported Not reported
Present case 64/M Chest and abdominal pain, then dyspnea, night sweats Mediastinum, bone marrow, lymph nodes, liver, spleen 3 months B1 Positive for CD1a, CD3, CD4, CD5, CD7, CD8, TdT Expired 3 months after 2nd presentation

*, all cases include mediastinal mass positive for thymoma and as such when mediastinum is listed in this table; T-LBL is observed in the thymus/thymoma. M, male; F, female; T-LBL, T-lymphoblastic leukemia; Synch., synchronous (within 6 months).

While a molecular basis or conclusive evidence for a direct transformation from thymoma into T-LBL is lacking, other possibilities for a causative association exist. The risk for secondary malignancies in patients with thymoma has been described, though studies vary widely on the specific associated neoplasia. Some studies suggest non-Hodgkin lymphoma as one of the most frequent associated neoplasms (1,14,15), however other studies find solid tumors such as colorectal, lung, prostate and breast to much more common (16,17). Regardless, thymoma is known to alter immune function and leads to susceptibility to perturbations in T-cell immunity that can lead to paraneoplastic conditions such as pure red cell aplasia, myasthenia gravis, and hypogammaglobulinemia. Thus, it would seem plausible that altered immune function related to disturbed T-cell immunity caused by thymoma may lead to a predisposition to neoplasia, including T-LBL. Another possibility is that our patient, based on a presumed, though unconfirmed, diagnosis of thymoma possibly incompletely resected in his home country, received multiple cycles of adjuvant chemotherapy years prior, including alkylating and platinum-based agents that have been well described in association with secondary cancers. The genotoxic effect on hematopoietic progenitor cells from cytotoxic chemotherapy has been typically associated with clonal myeloid disorders such as a myelodysplastic syndrome or an acute myeloid leukemia, however acute lymphoblastic leukemias have also been described in this setting (18,19). In addition, there appears to be an increased incidence of thymoma among Asians and Pacific Islanders which may suggest an underlying genetic component.

Management for almost all thymomas is surgical resection with a well-defined role for radiation and chemotherapy depending on stage at presentation, while management for T-LBL includes multiagent chemotherapy with limited role for surgical intervention making diagnostic distinction from thymoma critical. A multimodality diagnostic approach is necessary including a combination of clinical presentation, morphology, immunohistochemistry, flow cytometry, molecular and cytogenetic findings that can each provide valuable information toward arriving at an accurate diagnosis. Our evidence for T-LBL is supported by an aberrant immunophenotype by flow cytometry, molecular studies including T-cell clonality and whole exome sequencing demonstrating essentially identical, characteristic T-LBL mutations (NOTCH1, CDKN2A) in both the mediastinal/lung mass and bone marrow and the immunohistochemical positivity for LMO2, which provides distinction between neoplastic and non-neoplastic T-precursor cells (20). The evidence for the type B1-tymoma includes histologic findings of bland scattered thymic epithelial cells positive for cytokeratins, PAX8, and p40 as well as the indolent clinical course prior to diagnosis of T-LBL. It should be noted that LMO2 immunostain was performed postmortem and confirms the synchronicity these two malignancies.

Conclusions

Our case and this literature review highlight a need for meticulous evaluation as rarely both the presence of neoplastic epithelial cells of a thymoma along with atypical T-lymphoblasts have potential to co-exist. While the co-occurrence of these two malignancies is rare, the prognosis is poor and careful analysis is required as treatment are different. Here we demonstrate the utility of LMO2 as an immunohistochemical marker of LMO2 as a specific marker for T-LBL lymphoblasts as well as provide a framework for a multimodal diagnostic approach to distinguish these two disease entities.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-24-23/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-23/prf

Funding: This work received funding support from NYU Langone Department of Pathology Translational Research Program Grant.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-23/coif). A.L.M. serves as an unpaid editorial board member of Mediastinum from January 2024 to December 2025. All authors report that this work was supported by NYU Langone Translational Research Program Grant. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent for publication of this case report and accompanying images was not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/med-24-23
Cite this article as: Frazzette N, Ordner J, Narula N, Moreira AL, Park CY, Ward ND. Co-occurrence of thymoma and acute T-lymphoblastic leukemia/lymphoma: a case report and literature review. Mediastinum 2025;9:10.

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