Fatal Hemophagocytic Lymphohistiocytosis Unmasking Epstein-Barr virus Negative Classical Hodgkin Lymphoma Misdiagnosed as Multisystem Sarcoidosis

Classical Hodgkin lymphoma (CHL) generates sarcoid-like granulomatous reactions in approximately 13.8% of cases, occasionally obscuring sparse Hodgkin/Reed-Sternberg (HRS) cells and causing misdiagnosis as sarcoidosis. CHL-associated hemophagocytic lymphohistiocytosis (HL-HLH) is a rare, life-threatening hyperinflammatory complication that carries significantly worse overall survival compared to non-HLH CHL. We report a case where CHL masked as multisystem sarcoidosis and ultimately unmasked as fulminant HLH upon corticosteroid taper, resulting in rapid clinical deterioration and death before treatment could be initiated.

A 71-year-old African American woman presented with progressive fatigue, weakness, and neuromuscular decline over several months, with recurrent hospitalizations for hypotension, neutropenia, and severe weakness. Workup revealed enlarging bilateral pulmonary nodules with atypical lymphohistiocytic infiltrates on EBUS biopsy, bone marrow showing 30% lymphohistiocytic infiltration with MF-2 fibrosis and hemophagocytosis, progressive sensorimotor polyneuropathy with left foot drop, extreme serum sIL-2R (56,250 U/mL), elevated ACE, hyperferritinemia, and pancytopenia. Flow cytometry, MAPK next-generation sequencing, and BRAF immunohistochemistry were negative for malignancy. EBV testing (EBER-ISH) was negative. Outside pathology identified rare scattered CD30-positive cells raising concern for CHL, but the absence of nodal disease and elevated ACE led to a working diagnosis of multisystem sarcoid-spectrum disease.

High-dose intravenous methylprednisolone followed by oral prednisone produced dramatic clinical recovery with normalization of blood counts, ACE, and inflammatory markers. Infliximab was initiated as a steroid-sparing agent. However, upon tapering prednisone to 30 mg daily, the patient developed fevers, worsening biomarkers, and a new 1.5 cm inguinal lymph node-her first excisable nodal disease-rapidly deteriorating into fulminant HLH physiology with severe ferritin-to-ESR dissociation (ferritin 2,800 ng/mL, ESR < 1) and an H-Score of 241. Excisional biopsy of the inguinal node confirmed classical Hodgkin lymphoma. The patient decompensated rapidly and died before CHL-directed therapy could be initiated.

In CHL with marked granulomatous reactions (≥50% cellularity), 75% of patients are over age 40, 69% present with advanced-stage disease, and most exhibit the mixed cellularity subtype. Cytokine secretion from HRS cells recruits diffuse lymphohistiocytic and granulomatous inflammation, concealing sparse diagnostic tumor cells on small tissue biopsies. This immunologic background creates two clinical pitfalls. First, empiric corticosteroid therapy produces false reassurance by temporarily suppressing immune activation and granulomatous burden, reinforcing an incorrect diagnosis. Second, tapering corticosteroids removes this suppression, potentially allowing rapid proliferation of malignant cells and driver cytokines, which can precipitate fulminant HLH. While HL-HLH is most strongly associated with EBV-positive mixed cellularity CHL, this case demonstrates that EBV-negative CHL can also trigger fatal HLH through HRS cell-driven cytokine dysregulation alone, underscoring that EBV negativity should not provide false reassurance against this complication. HL-HLH carries significantly worse overall survival compared to non-HLH CHL, and this case illustrates the narrow therapeutic window once fulminant HLH develops.

When granulomatous disease displays atypical features, profound immune activation, or sudden clinical worsening upon steroid tapering, clinicians must maintain a high index of suspicion for hidden CHL regardless of EBV status. This fatal outcome underscores the urgency of prompt repeat tissue biopsies and expert pathology review to identify the underlying malignancy before the window for treatment closes.