Unicentric Castleman disease concurrent with primary biliary cholangitis/autoimmune hepatitis overlap syndrome: A Case Report

Abstract

IntroductionCastleman disease (CD) is a rare lymphoproliferative disorder classified as unicentric (UCD) or multicentric, with distinct clinical behaviors. Concurrent primary biliary cholangitis (PBC)/autoimmune hepatitis (AIH) overlap syndrome has rarely been reported in CD.Case PresentationA 54-year-old man presented with abdominal pain and multiple paraaortic lymphadenopathies. Lymph node resection confirmed the hyaline-vascular subtype of UCD on histopathological and immunohistochemical examination. Persistent liver enzyme elevation during follow-up prompted gastroenterology referral. Serology demonstrated antinuclear antibody (ANA) and antimitochondrial antibody (AMA) positivity with elevated IgG and IgM. Liver biopsy showed features of PBC with prominent interface hepatitis, lobular activity, and rosette formation, fulfilling the Paris criteria for PBC/AIH overlap syndrome.ConclusionThis case illustrates a rare coexistence of histopathologically confirmed hyaline-vascular UCD with PBC/AIH overlap syndrome, underscoring the need for autoimmune liver screening in CD patients with unexplained hepatic enzyme abnormalities.

Keywords

Introduction

Castleman disease (CD) is a rare clinicopathological entity encompassing a heterogeneous group of lymphoproliferative disorders characterized by distinctive histopathological features of lymphadenopathy.¹ It includes a spectrum of uncommon conditions such as unicentric CD (UCD), idiopathic multicentric CD (iMCD), and human herpesvirus-8-associated MCD (HHV-8+ MCD).² The unicentric form, particularly the hyaline-vascular subtype, typically follows a benign clinical course and can be successfully managed with surgical resection. Although the coexistence of CD with autoimmune manifestations has been documented in the literature, concurrent hepatic autoimmune disease—specifically primary biliary cholangitis (PBC) with autoimmune hepatitis (AIH) overlap syndrome—has been rarely reported. Herein, we present a case of histopathologically confirmed hyaline-vascular UCD in a patient subsequently diagnosed with PBC/AIH overlap syndrome, reported in accordance with the CARE (CAse REport) guideline.

Case Presentation

Patient Information and Clinical FindingsA 54-year-old man with an unremarkable past medical history was found to have multiple paraaortic lymphadenopathies (LAP), the largest measuring 3 cm in diameter, on imaging performed for abdominal pain.Diagnostic AssessmentLymph node dissection was performed with a preliminary diagnosis of lymphoma. Histopathological examination of the resected lymph node specimen revealed well-circumscribed encapsulated lymph nodes with numerous histiocytes and vascular proliferation in the interfollicular areas and subcapsular sinuses, regressed germinal centers with prominent vascular proliferation and hyalinization, fibrosis, focal multinucleated giant cells, and noncaseating granuloma formations. Immunohistochemical analysis demonstrated a mixed pattern with CD3 and CD20, few Ki-67- and BCL2-positive germinal centers, negativity for HHV-8 and cyclin D1, and sinusoidal histiocytic reactivity with CD68 and CD163. Focal OCT2 reactivity was also noted in the absence of Reed-Sternberg-like cells. These findings were interpreted as consistent with the hyaline-vascular subtype of Castleman disease.
Upon persistent elevation of liver function tests during follow-up (aspartate aminotransferase [AST]: 171 U/L, alanine aminotransferase [ALT]: 217 U/L, γ-glutamyltransferase [GGT]: 366 U/L, alkaline phosphatase [ALP]: 301 U/L, total bilirubin: 2.4 mg/dL), the patient was referred to gastroenterology. Serological workup revealed elevated immunoglobulin G (IgG) (23.8 g/L) and immunoglobulin M (IgM) (6.6 g/L) levels, along with positivity for antinuclear antibody (ANA) and antimitochondrial antibody (AMA). Liver biopsy did not demonstrate a florid duct reaction; however, the overall histological findings were consistent with primary biliary cholangitis (PBC). Notably, the presence of prominent interface hepatitis, lobular activity, and rosette formation prompted the pathologist to recommend further evaluation for autoimmune hepatitis (AIH)/overlap syndrome. Integrating all histopathological findings, serological positivity, and the clinical presentation, the Paris criteria were used to establish a diagnosis of PBC/AIH overlap syndrome.⁸Therapeutic InterventionFollowing diagnosis, the patient was started on ursodeoxycholic acid combined with corticosteroid therapy. Azathioprine was added one week later.Follow-up and OutcomesAAt the 3-month follow-up, the patient's clinical and biochemical response was favorable, with normalization of liver function tests. Long-term follow-up data and treatment outcomes beyond this period were not available at the time of writing; this is stated explicitly as a limitation of the report.Ethical ApprovalEthical approval was not required.

Reporting GuidelinesThis case report was prepared in accordance with the CARE guideline.

Discussion

Castleman disease, particularly its multicentric form, is well recognized for its association with systemic inflammatory manifestations, predominantly through hypersecretion of interleukin-6 (IL-6).³ In contrast, hyaline-vascular UCD has historically been classified as a localized disease with limited systemic involvement. While hepatomegaly, portal hypertension, and occasional cases of autoimmune hepatitis have been reported in the context of CD, concurrent PBC/AIH overlap syndrome with histopathologically and immunohistochemically confirmed hyaline-vascular UCD represents an exceptionally rare clinical scenario.⁴
In the present case, the noncaseating granuloma formations and multinucleated giant cells observed in the lymph node pathology initially raised granulomatous conditions such as sarcoidosis in the differential diagnosis. However, negativity for HHV-8 and cyclin D1 was critical in excluding reactive or neoplastic lymphoproliferative processes and mantle cell lymphoma.⁵ The sinusoidal histiocytic positivity with CD68 and CD163 reflects more limited histiocytic activation than the strong S100-positive pattern typical of Rosai-Dorfman disease and is interpreted as a reactive process consistent with CD.⁶ Focal OCT2 reactivity, in conjunction with the absence of Reed-Sternberg-like cells, supports the exclusion of Hodgkin lymphoma. This immunohistochemical profile strongly corroborates the diagnosis of hyaline-vascular UCD.
The pathogenetic relationship between CD and autoimmune liver disease has yet to be fully elucidated. Dysregulated immune activation—encompassing aberrant T- and B-cell responses, polyclonal hypergammaglobulinemia, and cytokine dysregulation—is thought to predispose to organ-specific autoimmunity, including biliary and hepatocellular autoimmune processes.⁴ Although hyaline-vascular UCD has historically been considered a non-inflammatory entity, emerging reports highlight its co-occurrence with IgG4-related disease and other immune-mediated conditions, suggesting that the immunological impact of this form may be broader than previously recognized.⁷ The granulomatous inflammation observed in the present case may itself be viewed as part of this expanded immunological spectrum.
PBC/AIH overlap syndrome is a well-defined yet uncommon clinical entity, occurring in approximately 8–10% of patients with PBC. Diagnosis is based on the Paris criteria, which require simultaneous fulfillment of features characteristic of both conditions.^8,9 In the present case, the dual positivity of ANA and AMA, accompanied by interface hepatitis, lobular activity, and rosette formation superimposed on a histological background consistent with PBC, constitutes compelling clinicopathological evidence for this overlap syndrome. Clinicians should be aware that features of PBC/AIH overlap may be identifiable even without pathognomonic findings such as florid duct lesions, and that histopathological assessment alone is insufficient—comprehensive multidisciplinary evaluation remains indispensable.
The co-occurrence of UCD and PBC/AIH overlap syndrome carries significant clinical implications. Monitor liver function tests and autoimmune serology during follow-up of patients with CD, including the hyaline-vascular UCD subtype, whenever the clinical picture warrants it. In particular, cholestatic presentations in the setting of CD should not be attributed solely to mechanical bile duct compression by adjacent lymphadenopathies; as illustrated by the present case, such findings may represent a clinically meaningful marker of coexisting systemic or organ-specific autoimmune disease.⁴ Conversely, in patients with cholestasis and autoimmune seropositivity, a prior history of LAP or CD should be actively sought, as it may inform the assessment of a potential immunopathological link.

Limitations

This report is limited by its single-case nature, precluding causal inference regarding the association between hyaline-vascular UCD and PBC/AIH overlap syndrome. Long-term follow-up data and treatment outcomes were not available at the time of writing. Additionally, we did not perform molecular investigations that might further elucidate the immunopathological link between the two conditions.

Conclusion

To the best of our knowledge, this case represents one of the few reported instances in which hyaline-vascular UCD, documented in histopathological and immunohistochemical detail, has been found to coexist with PBC/AIH overlap syndrome confirmed by dual ANA/AMA seropositivity and liver biopsy. This case underscores the importance of a comprehensive autoimmune workup in CD patients presenting with unexplained elevations in hepatic enzymes, irrespective of subtype. It highlights the potential for broad immune dysregulation even in the unicentric, hyaline-vascular form of the disease.

Declarations

Abbreviations

References

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