Fever: Harmless Heat or a Deadly Inferno? Unmasking Hemophagocytic Lymphohistiocytosis and Beyond: A Rare Case of Mast Cell Sarcoma and Overview of HLH

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal hyperinflammatory syndrome characterized by uncontrolled activation of the immune system, often secondary to infections, autoimmune diseases, or malignancies. While malignancy-associated HLH is increasingly recognized, its diagnosis remains challenging due to nonspecific clinical features that mimic other systemic illnesses. Mast cell sarcoma (MCS), an exceedingly rare and aggressive neoplasm of aberrant mast cells, is an exceptionally uncommon cause of HLH and is rarely reported in the literature. We described the case of a 70-year-old male who presented with persistent fever, weight loss, night sweats, and pancytopenia. Initial investigations for infectious, autoimmune, and neoplastic etiologies were inconclusive. The patient rapidly deteriorated despite empirical antimicrobial therapy and supportive care. Serial imaging revealed hepatosplenomegaly, and laboratory studies showed markedly elevated ferritin, lactate dehydrogenase (LDH), and soluble interleukin (IL)-2 receptor levels. Bone marrow biopsy demonstrated hemophagocytosis, and he fulfilled both HLH-2004 criteria and had a high HScore, confirming the diagnosis of HLH. Despite initiating HLH-directed therapy with high-dose corticosteroids and etoposide, the patient’s condition progressed rapidly, leading to multiorgan failure and death. Post-mortem examination revealed extensive infiltration of atypical mast cells in the bone marrow, spleen, liver, and lymph nodes. Immunohistochemistry confirmed the diagnosis of systemic MCS. This report highlights the diagnostic complexity of HLH, particularly when triggered by rare malignancies like MCS. The case emphasizes the need for high index of suspicion and early, aggressive diagnostic workup - including bone marrow evaluation and molecular studies - in patients presenting with fever of unknown origin, cytopenias, and systemic inflammation. Early identification of malignancy-associated HLH is critical, as targeted treatment of the underlying disease is often necessary for a favorable outcome. Awareness of atypical presentations and rare triggers is essential for timely diagnosis and management of this life-threatening syndrome.