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Between a rock and a hard place

A 60 year old male consulted the outpatient clinic for progressively worsening right shoulder pain over the last few months, lightheadedness, and intermittent shortness of breath. He also complained of loss of balance with multiple falls in the past few weeks. He denied fever, chills, rigors, night-sweats, hematochezia, melena, or recent illness. Significant past medical history included localized diffuse large B cell lymphoma (DLBCL) of the forehead skin 4 years prior, for which he was treated with 5 of 6 cycles of rituximab, cyclophosphamide, adriamycin, vincristine and prednisone chemotherapy, bipolar disorder, a 50 pack-year smoking history, and alcohol consumption of 12 beers 4–5 times/week. The initial presentation does not raise concern for an acute illness, and is most consistent with a smoldering, progressive process with possible neurologic manifestations. The anamnesis raises the possibility of alcohol abuse related disease and/or malignancy potentially due to relapsed hematological disease or related to tobacco abuse. Physical examination showed overall good general conditions, the patient’s weight did not show change compared to previous records (BMI 27.1), there was hepatosplenomegaly, 3 and 2 cm below the respective costal margins, and limited range of motion of the right shoulder. The rest of the physical was normal. The initial neurological exam was normal. Complete blood count at presentation showed normal white cell and differential counts, severe anemia and moderate thrombocytopenia: Hg 5.9 g/dL, WBC 7.2 K/uL, PLT 70 K/uL. The presence of joint pain, severe bicytopenia, organomegaly and neurologic symptoms raises the differential of alcohol induced hepatitis and alcohol toxicity derived symptoms, malnutrition, Still’s disease, coagulopathy, and malignancy, especially hematolymphoid neoplasms. All these conditions warrant a hospital admission. The patient was admitted and received blood transfusions. Additional blood chemistry showed slightly abnormal liver function tests: aspartate aminotransferase 45 U/L, alanine aminotransferase 26 U/L, Gammaglutamyl transferase 169 U/L, total bilirubin: 1.2 mg/dL, direct bilirubin 0.4 mg/dL; nutritional studies showed a normal B12, folate and zinc; the iron panel showed severe hyperferritinemia: 1,388.7 ng/ mL, hemolysis panel showed a high LDH 746 U/L, undetectable haptoglobin< 7.8 mg/dL, normal plasma free hemoglobin and negative direct antibody test. Electrolytes, creatinine, coagulation studies, thyroid function tests were normal. Imaging studies showed superior subluxation of the humeral head as the cause for the shoulder pain, but also showed a significant increase in splenic size (16 x 7cm) compared to a previous study 4 years ago. There was no evidence of masses or lymphadenopathy. Acute alcoholic hepatitis and nutritional deficiencies can be excluded. The studies are suggestive of hemolysis, however the normal plasma hemoglobin and relatively low bilirubin are neither proportional to the degree of anemia nor consistent with significant hemolytic activity, and favor alcohol related chronic liver disease as an explanation for these results. A peripheral smear was requested to assess for hemolysis and/or coagulopathy; the smear showed a leukoerythroblastic reaction, hemophagocytic activity (Fig. 1A) and very rare atypical lymphoid cells. The findings prompted a flow cytometry study that showed decreased B-cells (1%) and no evidence of clonal populations. The presence of hemophagocytic activity in the peripheral blood is very unusual; the combination of hemophagocytosis, severe cytopenias, liver function abnormalities and hyperferritinemia are virtually diagnostic of hemophagocytic lymphohistiocytosis (HLH). The presence of HLH, a leukoerythroblastic reaction and rare atypical lymphoid cells are highly suggestive of bone marrow involvement by a lymphoma or a viral infection. A bone marrow biopsy performed the next day showed hemophagocytosis, histiocytic hyperplasia and very rare atypical B-cells apparent only on immunohistochemical stains, insufficient for diagnosis of lymphoma. Epstein Barr virus, cytomegalovirus and herpes virus immunostains were negative. Viral serologies were negative for Parvovirus B19, EBV, HSV, HIV. CMV IgG was positive with negative IgM. Blood, viral and fungal cultures were negative. Flow cytometry analysis was negative. Additional studies obtained in the course of a week included cerebrospinal fluid (CSF) tap, magnetic resonance imaging (MRI) of the brain, positron emission/computerized tomography scan (PET/CT), microbiology studies (bacterial, viral, fungal, mycobacterial), flow cytometry of CSF and autoimmune panel. Abnormal results included