Hodgkin lymphoma masquerading as HLH: A case presentation

Dear Editor,

Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially fatal hyperinflammatory syndrome that may be triggered by infections, autoimmune disorders, or malignancies such as lymphomas.^[1]

While HLH is most often linked to viral infections in immunocompromised patients, its presentation as the initial manifestation of Hodgkin lymphoma is rare and poses significant diagnostic challenges.^[2]

A 68-year-old male presented to a tertiary care center with a history of recurrent hiccups for 4 months, intermittent fever for 2 weeks, and altered sensorium for 5 days. His medical history was notable for surgical excision of a nasal septal plasmacytoma 1 year prior; however, no records were available. On physical examination, the patient appeared severely pale and had an enlarged left scalene lymph node, significant splenomegaly, and bilateral pitting pedal edema.

Initial laboratory investigations revealed pancytopenia with a hemoglobin level of 4 g/dL, a total leukocyte count of 2,000/µL showing neutrophilic predominance (86%) and lymphopenia (1.5%), and a platelet count of 45,000/µL. Peripheral smear demonstrated microcytic hypochromic red cells, leukopenia with lymphopenia, and thrombocytopenia. Serum ferritin was markedly elevated at 34,000 ng/mL.

Given the triad of fever, pancytopenia, and splenomegaly in the context of hyperferritinemia, HLH was clinically suspected. Further, the workup revealed elevated procalcitonin (13.70 ng/mL), suggesting underlying septic shock. Blood cultures were negative. Triglycerides were modestly raised at 220 mg/dL, while fibrinogen levels remained within normal limits. Contrast-enhanced computed tomography showed massive splenomegaly and multiple mediastinal and retroperitoneal lymph nodes. GeneXpert and viral screening, including common infectious etiologies, were negative.

Bone marrow aspiration was hemodiluted and revealed hemophagocytosis and a few large atypical cells [Figure 1a]. Bone marrow biopsy demonstrated hypercellular marrow (70–80%) with infiltration by large atypical cells exhibiting classic Reed-Sternberg morphology [Figure 1b]. Numerous pleomorphic cells with atypical mitoses, focal epithelioid histiocytic aggregates, and areas of necrosis were noted [Figure 1c]. Background hematopoiesis showed trilineage representation in limited areas. Significant fibrosis and stromal degeneration were observed, with reticulin staining indicating grade II fibrosis per the World Health Organization grading [Figure 1d]. Ziehl–Neelsen staining for acid–fast bacilli was negative.

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Figure 1:

(a) Bone marrow aspirate showing hemophagocytosis, (b) ×100 magnification of bone marrow biopsy showing atypical cells (shown by the red arrows), Inset: ×400 magnification of the atypical cells, (c) x200 magnification: Area of bone marrow biopsy showing collections of histiocytes with necrosis, (d) x400 magnification: Reticulin stain highlighting the increase in fibrosis, (e) x400 magnification, CD30 IHC, (f) x400 magnification, CD15 IHC, and (g) x400 magnification, PAX5 IHC, (h) x400 magnification ALK1 IHC.

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Immunohistochemistry showed the atypical cells to be strongly positive for CD30 and CD15, weakly positive for PAX5 (compared to surrounding reactive B-cells), and negative for cytokeratin and ALK-1 [Figure 1e-h]. These findings were diagnostic of bone marrow infiltration by classic Hodgkin lymphoma.

Ultimately, although HLH is most commonly associated with infections, autoimmune conditions, and certain malignancies – particularly lymphomas – Hodgkin lymphoma remains a rare and often under-recognized manifestation. HLH patients require clinicians to suspect malignancy, especially if persistent fever, pancytopenia, and organomegaly exist. Prompt bone marrow examination may be important in establishing the diagnosis. Immunophenotyping supports this examination.