Pulmonary Arterial Hypertension as an Unusual Presentation of Angioimmunoblastic T-Cell Lymphoma: A Case Report

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of mature peripheral T-cell lymphoma originating from follicular T helper cells [1]. Diagnosing AITL presents a challenge due to its diverse symptomatic presentation, which may include lymphadenopathy, B-symptoms (fever, weight loss, night sweats), skin rash, pleural effusion, hepatosplenomegaly, and immune dysregulation.

A comprehensive diagnostic approach is required, involving excisional lymph node biopsy, imaging and laboratory tests, and morphologic, immunophenotypic, molecular, and cytogenetic analyses [2]. Histologically, AITL exhibits lymph node structural effacement, enhanced proliferation of follicular dendritic cells, and high endothelial venules [3‒5]. Recent advancements in next-generation sequencing have identified mutations in genes such as Tet methylcytosine dioxygenase 2, DNA-methyltransferase 3A, isocitrate dehydrogenase 2-R172, and Ras homolog family member A, significantly aiding AITL diagnosis [6‒12]. The prognosis of AITL depends on various factors, including age, Eastern Cooperative Oncology Group (ECOG) performance status, presence of B-symptoms, extranodal involvement, and platelet count [2, 13].

This case report documents an 84-year-old male patient with AITL, who presented with an atypical manifestation of pulmonary arterial hypertension (PAH) and transudative pleural effusion. This case underscores the diagnostic complexity of AITL with nonclassical presentations and highlights the necessity of including AITL in differential diagnoses for patients with PAH. Notably, this patient exhibited clinical improvement with targeted treatment, marking the first documented case of PAH resolution following AITL treatment [14].

An 84-year-old male with a history of early gastric cancer (treated with endoscopic resection in 2016, with no node metastasis and cured after 6 years of regular follow-up) presented to the Department of Respiratory Medicine in May 2022 with dyspnea. Initial chest radiography revealed cardiomegaly and bilateral moderate pleural effusion (Fig. 1). Pleural fluid analysis indicated a transudative effusion, with fluid protein at 3.16 g/dL, serum protein at 6.87 g/dL, fluid lactate dehydrogenase (LDH) at 259 IU/L, and serum LDH at 740 IU/L. Transthoracic echocardiography (TTE) showed markedly increased right ventricular systolic pressure at 114 mm Hg, indicative of pulmonary hypertension. Computed tomography (CT) of the chest identified multiple mediastinal lymph node enlargements (Fig. 2).

The patient was subsequently referred to the Department of Hematology and Oncology. Laboratory findings included an elevated LDH level of 824 U/L and NT-pro-BNP at 1,090 pg/mL. A torso positron emission tomography (PET) scan was performed to evaluate for hematologic malignancy, revealing hypermetabolic lymph nodes and moderate splenomegaly (Fig. 3). An excisional biopsy of a right axillary lymph node confirmed the diagnosis of AITL. Immunohistochemical analysis showed positive staining for CD4, CD10, CD21, BCL6, and CXCL13 in the follicular dendritic cells (Fig. 4; Table 1). In situ hybridization detected positive Epstein-Barr encoding region signals. Next-generation sequencing identified mutations in two tier 1 genes and four tier 3 genes (Table 2).

Treatment with a mini-CHOP chemotherapy regimen (comprising adriamycin, cyclophosphamide, mesna, vincristine, and prednisolone) was initiated, planned for 6 cycles. Post the second chemotherapy cycle, a significant reduction in right ventricular systolic pressure to 36 mm Hg was observed on TTE, a notable improvement from 114 mm Hg in May. A follow-up PET scan after the third cycle showed complete remission (Fig. 5). Laboratory tests reported an LDH level of 171 U/L 1 week after the final cycle. The patient was then transferred to a local medical center for rehabilitation following a traumatic spine fracture due to patient falls incurred between the fifth and sixth chemotherapy cycles.

One weak post-transfer, the patient was readmitted with dyspnea and fever. Chest radiography indicated increased right-sided pleural effusion. Intravenous antibiotic therapy was initiated for pneumonia. Pleural fluid analysis suggested exudative effusion, with fluid protein at 1.7 g/dL, serum protein at 4.66 g/dL, fluid LDH at 215 IU/L, and serum LDH at 207 IU/L. Chest CT revealed pulmonary artery embolization, and anticoagulation therapy was started. A repeat torso PET-CT scan and pleural biopsy performed to investigate potential recurrence confirmed maintenance of complete lymphoma remission. The patient was subsequently transferred back to the local medical center for continued rehabilitation.

In this case, an 84-year-old patient diagnosed with AITL exhibited lymphadenopathy and pleural effusion, commonly associated with AITL. However, the patient’s primary presenting symptom was dyspnea attributed to PAH, a notably rare manifestation in AITL, complicating the diagnostic process.

AITL lacks a universally accepted gold-standard treatment. Typically, therapeutic strategies range from single-agent oral therapies to intensive chemotherapy regimens, often incorporating the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) and may include autologous hematopoietic stem cell transplantation in certain cases, depending on prognostic risk classification [14‒18]. In this instance, the patient was treated with a mini-CHOP regimen, demonstrating a favorable response.

PAH is characterized by remodeling of the pulmonary vasculature, leading to increased pulmonary arterial pressure and vascular resistance, potentially progressing to right ventricular failure if left untreated [19]. Pathological hallmarks of PAH include the uncontrolled proliferation of endothelial cells, smooth muscle cells, fibroblasts, and inflammatory cell infiltration, resulting in luminal narrowing of pulmonary vessels [20]. Triggers for these changes may include factors such as shear stress, hypoxia, autoimmune phenomena, viral infections, drugs, toxins, or genetic alterations [21]. Inflammatory involvement in PAH pathogenesis is further supported by the presence of organized lymphoid follicles, T and B lymphocyte infiltration near lesions, and circulating inflammatory markers [22, 23].

In this patient, TTE performed before chemotherapy initiation confirmed PAH. Remarkably, during chemotherapy, symptoms of PAH, along with pleural effusion and dyspnea, showed significant improvement, particularly after the second cycle. Post the sixth chemotherapy cycle, complete remission was evidenced by PET-CT scans. This improvement trajectory suggests that PAH in this patient was secondary to AITL. The absence of other underlying diseases commonly associated with PAH reinforces this correlation.

However, the occurrence of AITL concomitant with PAH is exceedingly rare, and the pathophysiological mechanisms linking the two conditions remain unclear. The atypical presentation in cases of AITL with PAH can lead to diagnostic delays. Therefore, this case report not only contributes to the medical literature by documenting a rare instance of AITL with PAH but also underscores the need for further research to elucidate the potential interplay between these conditions.

This case report of an 84-year-old male patient diagnosed with AITL presenting with PAH and transudative pleural effusion highlights the diagnostic challenges and the potential for atypical manifestations of AITL. Despite the complexity of diagnosing AITL due to its diverse symptomatic presentation, the successful identification and treatment of this case underscore the importance of considering AITL in the differential diagnosis of patients with PAH. The patient’s clinical improvement following a mini-CHOP chemotherapy regimen, leading to the resolution of PAH and achieving complete remission, marks a notable instance in medical literature. This case reinforces the need for a comprehensive diagnostic approach to AITL, incorporating advanced molecular and cytogenetic analyses, and illustrates the effectiveness of targeted chemotherapy in managing both AITL and its rare complications such as PAH. Moreover, it calls attention to the necessity for further research to understand the pathophysiological links between AITL and PAH, aiming to improve diagnostic accuracy and treatment outcomes for patients with this rare lymphoma subtype.

We would like to express our sincere gratitude to the patient and their family for consenting to the preparation of this case report. Their cooperation and support have been invaluable in contributing to the advancement of medical knowledge and understanding.

Ethical approval was not required in accordance with the local guidelines for this retrospective, unplanned study. Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540784).

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

As the sole author of this study, Jiyoon Jung was responsible for all aspects of the research and also ensured the accuracy and integrity of all parts of the work, confirming adherence to professional standards for ethical and responsible research conduct. This includes the conceptualization and design of the study, data collection and analysis, interpretation of results, drafting and revising the manuscript, and final approval of the version to be published.

All the data generated or analyzed in this study are included in the published article. Further inquiries can be directed to the corresponding author.