Gray Zone Lymphoma Masquerading as Autoimmune Hepatitis

Introduction/Background/Significance: Gray Zone Lymphoma (GZL), "B-cell lymphoma, unclassifiable, with features intermediate between Diffuse large B cell Lymphoma and classical Hodgkin lymphoma," represents a rare and diagnostically challenging entity comprising < 2% of all lymphomas. The treatment approach remains undefined, with historical outcomes of 60-70% five-year overall survival using conventional chemotherapy regimens. The advent of CD30-targeted therapy with brentuximab vedotin (BV) has revolutionized treatment of CD30+ lymphomas, yet its role in frontline GZL remains investigational. We present a case highlighting diagnostic complexity of CD30+ mediastinal lymphomas (ML) and therapeutic success of early BV-based treatment.

Materials and Methods/Case Presentation/Objective: 33-year-old woman with a history of presumed autoimmune hepatitis (diagnosed May 2025, treated with steroids and azathioprine) presented in July 2025 with rapidly progressive malaise, dyspnea, and lymphadenopathy. Examination revealed systemic inflammatory response syndrome with tachycardia (HR >150 bpm), anemia, thrombocytosis, and cholestatic hepatic dysfunction. Imaging demonstrated a rapidly enlarging anterior mediastinal mass (8.2 cm to 13.5 cm within 48 hours) with extensive lymphadenopathy and moderate pleural effusion. PET imaging showed hypermetabolic disease limited to supradiaphragmatic regions with SUVmax values consistent with aggressive lymphoma. Left clavicular lymph node biopsy revealed large pleomorphic cells with cherry red nucleoli and horseshoe-shaped multinucleated Reed-Sternberg-like cells. Immunohistochemistry demonstrated CD30 (strong, diffuse), CD15 (weak, subset), PAX5 (weak), and MUM1 positivity, with negative staining for CD20, CD23, ALK1, all T-cell markers, and EBER ISH. Flow cytometry was nondiagnostic due to extensive necrosis. Review of the original liver biopsy revealed absence of interface hepatitis, no plasma cell infiltration, and a cholestatic pattern inconsistent with autoimmune hepatitis, suggesting hepatic involvement by lymphoma or paraneoplastic phenomenon.

Results/Description/Main Outcome Measures: The immunophenotype in conjunction with morphology and clinical presentation established the diagnosis of GZL. Given the diagnostic ambiguity between GZL and ALK-negative anaplastic large cell lymphoma, the patient's rapidly deteriorating clinical status, treatment was initiated with CHEP (cyclophosphamide, hydroxydaunorubicin, etoposide, prednisone) plus BV. The patient demonstrated rapid clinical response within two treatment cycles, with resolution of B-symptoms, normalization of liver function tests, hemodynamic stabilization, and complete symptomatic improvement. Interval imaging showed significant tumor reduction. Treatment was well-tolerated with no toxicities observed. The patient continues on therapy with quality of life restoration.

Conclusions: This case exemplifies the diagnostic challenges inherent in CD30+ ML and demonstrates the therapeutic efficacy of frontline brentuximab-based treatment in GZL. Key learning points include: the importance of comprehensive immunohistochemical evaluation in CD30+ lymphomas, with PAX5 expression serving as the critical discriminator for B-cell lineage; the recognition that apparent autoimmune conditions may represent paraneoplastic phenomena or direct organ involvement by lymphoma; the therapeutic success of CD30-targeted therapy in treating diagnostically ambiguous CD30+ lymphomas; and the paradigm shift toward biomarker-driven treatment approaches over traditional morphologic classification. The excellent clinical response achieved with CHEP-BV supports its consideration as a preferred frontline approach for CD30+ ML, regardless of precise histologic subclassification. This case contributes to the growing evidence base supporting CD30-targeted therapy in GZL and highlights the evolution toward precision medicine approaches in lymphoma treatment. Further prospective studies are needed to establish optimal treatment algorithms for this rare but increasingly recognized entity.