Transformation of Castleman Disease into Angioimmunoblastic T-Cell Lymphoma Complicated by Hemophagocytic Lymphohistiocytosis: A Case Report and Literature Review

Abstract

Introduction

Castleman disease (CD) is a disease characterized by chronic lymphoid reactive hyperplasia. CD transforming into angioimmunoblastic T-cell lymphoma (AITL) complicated by hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal disease with rapid progression, poor treatment, and poor prognosis.

Case Presentation

We present a case of idiopathic multicentric CD-transformed AITL complicated by HLH that achieved good therapeutic outcomes after treatment with ruxolitinib combined with CHOP regimen. The Epstein-Barr virus (EBV) in the peripheral blood of this patient remained positive throughout the course of the disease.

Conclusion

EBV could be involved in the mechanism of CD transforming into AITL complicated with HLH. Ruxolitinib combined with CHOP regimen may be a potentially effective treatment for this disease.

Introduction

Castleman disease (CD) is a type of lymphadenopathy characterized by chronic reactive hyperplasia of lymphoid tissue. The incidence of CD is low, and the specific clinical manifestations are lacking. The diagnosis of CD is mainly based on histopathological features and immunohistochemistry. CD can be divided into unicentric CD (UCD) and multicentric CD (MCD). MCD can be further classified by etiologic driver: human herpesvirus 8 (HHV8)-associated MCD (HHV8-MCD); idiopathic MCD (iMCD), also called HHV8-negative MCD, and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS)-associated MCD (POEMS-MCD) [1]. Unicentric CD tends to have a good prognosis. MCD has a poor prognosis, with a mean survival of 30 months [2]. Moreover, MCD is often followed by lymphoma, Kaposi’s sarcoma, plasma cell tumor and other malignant tumors [3]. At present, cases of iMCD transforming into angioimmunoblastic T-cell lymphoma (AITL) are relatively rare. We report a case of iMCD transforming into AITL complicated by hemophagocytic lymphohistiocytosis (HLH).

Case Presentation

A 69-year-old man of Han Chinese was firstly admitted to our hospital with the complaints of systemic lymphadenopathy, abdominal distension and poor tolerance for 2 months in April 2020. Blood routine test after admission: white blood cells 5.34 × 10⁹/L, hemoglobin 99g/L, platelets 108 × 10⁹/L; superficial lymph node ultrasonography indicated multiple enlarged lymph nodes in the neck, supraclavicular, and inguinal regions. And the largest lymph node in the neck was 24 × 12 mm. Abdominal CT examination revealed multiple enlarged para-aortic and retroperitoneal lymph nodes. Cervical and inguinal lymph node biopsies were performed. Pathological findings showed CD with more plasma cell infiltration. An immunohistochemical study revealed that the lymph node tissue cells were weakly positive for CD38, CD138, Kappa, Lambda, CD3, CD20, Ki-67, CD21 (follicular dendritic cells), CD31 (blood vessel). T-cell receptor (TCR) gene rearrangement was negative. The in situ hybridization study revealed that the lymph node tissue cells were negative for Epstein-Barr virus (EBV)-encoded small RNA. C-reactive protein was 81.4 mg/L. Erythrocyte sedimentation rate was 73 mm/h. The serum ferritin level was 312 ng/mL. The copy number of EBVDNA was 1.58 × 10⁴ IU/mL. The level of immunoglobulin G was 24.7g/L. And the level of immunoglobulin G4 was 0.917 g/L. Positive for antinuclear antibodies. EBVDNA was detected in peripheral blood with a high copy number of 1.58 × 10⁴ IU/mL by quantitative polymerase chain reaction. KSHV/HHV8, CMV, and HIV in peripheral blood were all negative. This patient was diagnosed with iMCD. After the treatment of methylprednisolone (1 mg/kg) and tocilizumab (8 mg/kg), the patient’s condition improved significantly, and the lymph nodes were smaller than before. The patient continued to be treated with tocilizumab once a month for a total of 6 cycles. And the methylprednisolone dose was gradually reduced. After the end of treatment, the lymph nodes were significantly reduced and the symptoms of fatigue were relieved. Then follow-up at the clinic regularly.

In June 2024, the patient was admitted to the cardiology department of our hospital due to chest pain. The patient had reenlarged lymph nodes in the neck, supraclavicular, axillary, and groin. The largest lymph node in the neck was 16 × 10 mm. Blood count examination after admission showed white blood cells 2.45 × 10⁹/L, hemoglobin 119.0g/L, platelets 34 × 10⁹/L. C-reactive protein was 15.6 mg/L. The liver function test showed that alanine aminotransferase was 322.50U/L, aspartate aminotransferase was 294.30U/L, total bilirubin was 124.60umol/L. β2 microglobulin was 6.07 mg/L. Lactate dehydrogenase was 1185.00U/L. The copy number of EBVDNA was 2.17 × 10⁵ IU/mL. Abdominal CT showed multiple enlarged lymph nodes in the abdominal cavity and retroperitoneum, more and more than before, accompanied by splenomegaly. The serum ferritin level was 5112 ng/mL. Coagulation showed a fibrinogen level of 1.06g/L. The triglyceride in blood was 4.22umol/L. The patient had a progressive decrease in blood cells and a fever with a temperature of 38.5°C. Subsequently, the decrease of blood cells continued, and the examination revealed that white blood cell count was 0.81 × 10⁹/L, neutrophil count was 0.32 × 10⁹/L, hemoglobin count was 85.0g/L, and platelet count was 16 × 10⁹/L. Bone biopsy was completed, and 12.0% of the cells with unknown classification were found in bone marrow smear, and hemophagocytic cells were found in bone marrow. The patient had hypocytopenia, increased ferritin, decreased fibrinogen/increased triglyceride, splenomegasia, hemophagocytosis, and fever. The patient was diagnosed with HLH and was treated with ruxolitinib combined with dexamethasone. After 1 day of treatment, the body temperature was normal; blood cells were higher than before. Subsequent cervical lymph node biopsy pathology revealed AITL (Fig. 1). And the immunohistochemical study revealed that the lymphoma cells were positive for PD-1, CXCL-13, CD2, CD3, CD5, CD7, CD21, Ki-67 (about 70%), and weakly positive for CD4, CD8, CD56, CD20, Pax-5, CD30 (Fig. 2). The in situ hybridization study revealed that the lymphoma cells were negative for EBV-encoded small RNA. Bone marrow immunotyping suggested that T-cell lymphoma invaded the bone marrow. The immunohistochemical results of the bone marrow were consistent with those of lymph nodes. Considering that the patient had AITL with HLH, the treatment was adjusted to ruxolitinib combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen. After completing the first course of chemotherapy, the patient’s lymph nodes were significantly smaller than before. The relevant indicators of HLH have improved, and it is evaluated as partial response (Fig. 3). After 3 weeks, the patient was readmitted to hospital for treatment. After admission, the left limb hemiplegia suddenly occurred. The improved head nuclear magnetic test indicated multiple acute infarcts in the left cerebral hemisphere, accompanied by cerebral hemorrhage in the right parietal lobe. The patient developed acute cerebral infarction and cerebral hemorrhage, and died 1 week later.

Fig. 1.

Pathological morphology of AITL. The structure of the lymph nodes was disrupted. The tumor cells were polymorphic and of medium size. The cytoplasm was lightly stained, the cell nuclei were irregular, and the nucleoli were prominent.

Fig. 2.

Immunohistochemistry of AITL. The lymphoma cells expressed CD2 (+), CD3 (+), CD5 (+), CD7 (+), CXCL-13 (+), and PD-1 (+).

Fig. 3.

Changes in related indicators after HLH treatment with ruxolitinib combined with CHOP. a Values of peripheral blood neutrophils and ferritin before and after treatment. Initiation of ruxolitinib treatment occurred at day 0. b Levels of peripheral blood triglycerides and fibrinogen before and after treatment. c Levels of peripheral blood total bilirubin and alanine aminotransferase (ALT) before and after treatment.

Discussion

The incidence of NHL in MCD is as high as 18%, in which B-cell NHL is the main incidence, and T-cell NHL is low, and transforming into AITL complicated by HLH has not been reported [4]. Among them, the relationship between MCD and lymphoma can be divided into two cases: coexistence of MCD and lymphoma transforming into MCD. Our case of AITL was complicated by HLH and combined with the patient’s medical history; AITL should be transformed from MCD. At present, the mechanism of MCD transforming into lymphoma is not clear, and more studies have recognized that it is related to viruses such as HIV, EBV, HHV-8, HBV, and other infections. After the virus enters the body, the immune response is over-stimulated, and the abnormal proliferation of lymphocytes leads to the occurrence of lymphoma. For example, Oksenhendler et al. [5] analyzed 60 HIV-positive MCD patients, 14 of whom developed secondary NHL within a median time of 20 months. They believe that HIV is involved in the process of MCD transforming into lymphoma, but the exact mechanism is still unclear. In addition, EBV also participated in the lymphoma transformation process of MCD, which may be related to the immune disorder after EBV infection [6]. The EBVDNA in peripheral blood of this patient was positive when MCD was diagnosed, and MCD may progress to AITL under the continuous stimulation of EBV. In addition, the current study found that HHV-8 and HBV are involved in lymphoma transformation in MCD patients. However, the mechanism by which these viruses cause lymphoma in MCD patients is still unclear.

AITL is a type of peripheral T-cell lymphoma, accounting for 1%–2% of non-Hodgkin’s lymphomas and 15%–20% of peripheral T-cell lymphomas [7]. The incidence of AITL is low, while reports of AITL-associated HLH are rarer. The specific pathogenesis of AITL-related HLH remains unclear. Current studies have found that the pathogenesis of T-cell lymphoma-related HLH may be mainly related to the activation of TCR signaling pathway. For example, An et al. [8] used the primary tumor cells of a relapsed peripheral T-cell lymphoma-related HLH patient to conduct in vitro experiments, and found that the stimulation of lymphoma cells expressing TCR with plant hemagglutinin could induce the release of inflammatory factors, and monocytes showed phagocytosis of red blood cells and platelets. The lymphocytic phagocytosis did not occur after the TCR-silenced lymphoma cells were stimulated by phytohemagglutinin. However, there are often monoclonal changes of TCR gene in AITL, and the TCR pathway may be more easily activated to induce HLH. In addition, AITL lymphoma is often associated with EBV infection, and EBV is a very important trigger for HLH. It has been found that EBV encodes latent membrane protein-1 after infecting T cells, which can then activate the NF-κB pathway, leading to excessive secretion of inflammatory factors, and ultimately induce HLH [9]. In this AITL patient, there was not only monoclonal rearrangement of TCR gene, but also high load of EBVDNA in peripheral blood, both of which promoted the occurrence of HLH.

At present, there are few reports on AITL-related HLH, all of which are case reports, and the treatment effect is poor [10]. For example, Vella et al. [11] reported that a case of AITL-related HLH was treated with the HLH-2004 regimen, but the treatment effect was not good, and the patient soon developed a rapid deterioration of renal function and eventually died due to multiple organ failure. Zhang et al. [12] also reported that a case of AITL-related HLH was first treated with etoposide and dexamethasone. After 1 day of treatment, the body temperature was controlled and the level of platelet was also increased. After the treatment was adjusted to CHOP regimen, the patient finally achieved a good therapeutic effect. In addition, as a JAK1/JAK2 inhibitor, ruxolitinib has been applied in the treatment of HLH [13, 14]. Ruxolitinib mainly reduces the production of inflammatory factors by blocking JAK-STAT pathway to achieve the purpose of treating HLH, and it has achieved good curative effect [15, 16]. Our patient was initially treated with ruxolitinib combined with dexamethasone. After 1 day of treatment, the body temperature was normal and the blood cells increased. Then the treatment was adjusted to ruxolitinib combined with CHOP regimen. The treatment was adjusted to ruxolitinib combined with CHOP regimen, and good therapeutic effects were achieved in lymphoma and HLH after 1-month evaluation.

Conclusion

MCD with EBV or other viral infections are at risk for transformed AITL. AITL-related HLH has rapid onset, rapid progression, high mortality and poor prognosis. Once AITL-associated HLH is diagnosed, active treatment should be given as soon as possible, and ruxolitinib combined with CHOP regimen may be an effective treatment option. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000550691).

Statement of Ethics

Written informed consent was obtained from the patient’s son for publication of this case report and any accompanying images. This study protocol was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Approval No. 2024S992.

Conflict of Interest Statement

All authors state that they have no conflict of interest.

Funding Sources

This work was supported by Natural Science Foundation of Shandong Province (ZR2025MS1378) and Scientific Research Nurturing Fund of the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital (QYPY2025NSFC0801).

Author Contributions

Guangqiang Meng, MD, is the primary author of this report and is involved with data collection. Yan Wang, MD, and Saran Feng, MD, analyzed, and interpreted the patient data regarding. Min Yang, MD, and Qian Liu, MD, assembled figure(s). Saran Feng, MD, is principal investigator. All coauthors agreed with the contents of the manuscript.

Funding Statement

This work was supported by Natural Science Foundation of Shandong Province (ZR2025MS1378) and Scientific Research Nurturing Fund of the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital (QYPY2025NSFC0801).

Data Availability Statement

All data analyzed or generated for this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.