Disseminated histoplasmosis as pseudo <scp>R</scp>ichter's transformation in a patient with chronic lymphocytic leukemia
Authors: Preetesh Jain, Shimin Hu, Elias Jabbour, Koichi Takahashi, Naveen Pemmaraju, Susan O'Brien, Victor Eduardo Mulanovich, Zeev Estrov
Journal: American Journal of Hematology (2015)

A 75-year-old Caucasian male presented with a 4 months history of progressive fatigue, drenching night sweats, low grade fever, loss of appetite, abdominal discomfort, and weight loss, starting a few days after returning from a hiking trip in Oregon. Ten years prior to presentation he was diagnosed with chronic lymphocytic leukemia (CLL), treated with cyclophosphamide, fludarabine, rituximab, and alemtuzumab and attained complete remission. Physical examination revealed cervical lymphadenopathy and hepatosplenomegaly (Liver span 19 cm and spleen 8 cm below costal margins). Initial laboratory investigations showed: hemoglobin 9.8 g/dL, WBC 6.1 k/uL, absolute lymphocyte count 2.56 k/uL, and platelets 181 k/uL. He had elevated alkaline phosphatase 519 IU/L, beta-2 microglobulin 10.1 mg/L, serum calcium 11.4 mg/L, and normal LDH levels. A bone marrow (BM) aspiration and biopsy were compatible with relapsed CLL. Whole body positron emission tomography-computed tomography (PET-CT) scan using 18F-FDG (18-fludeoxyglucose) showed bulky paratracheal and subcarinal lymphadenopathy with high SUV (standardized uptake value) of 16 (Image 1A, arrow). Considering his clinical profile and high SUV, a provisional diagnosis of Richter's transformation (RT) of CLL was rendered and the patient was admitted in the hospital. With mediastinoscopy lymph node biopsy from the site of high SUV (Image 1A) was performed and it revealed lymphohistiocytic infiltrate composed of many small lymphoid cells admixed with increased histiocytes, many of which contained multiple intracellular microorganisms (Image 1B; H&E stain, ×1,000). Grocott's methenamine silver (not shown) and periodic acid-Schiff stains highlighted frequent clusters of microorganisms, compatible with a diagnosis of histoplasmosis (Image 1C; ×400; inset ×1000—arrow head showing encapsulated intracellular budding yeast cells in macrophages—little eyeballs in the cell appearance). However histoplasma antigens were not detected in the patient's serum or urine. Treatment with liposomal amphotericin B at the dose of 3 mg/kg every day for 2 weeks and oral itraconazole 200 mg twice a day was given and the patient significantly improved. He is currently under follow-up and is doing very well. RT refers to the transformation of CLL into an aggressive lymphoma, most commonly diffuse large B cell lymphoma and rarely Hodgkin's lymphoma or histiocytic sarcoma. Similar to our patient, patients with RT generally present with rapidly enlarging lymph nodes, worsening “B” symptoms, progressive organomegaly, and elevated serum LDH, sedimentation rate, serum calcium, and/or β2 microglobulin levels. The overall median survival of these patients is very poor (8–10 months). Current treatment options for these patients are limited and include intensive chemoimmunotherapy and/or stem cell transplantation (SCT) 1. It has been suggested that high SUV can reliably predict RT and that high SUV as assessed by a PET-CT scan is an independent predictor of inferior overall survival 2, 3. The clinical characteristics of this patient were secondary to histoplasmosis and mimicked the clinical features of RT. Clinical profile of this patient exemplifies that histopathology is of paramount importance and imaging with PET-scan alone is not sufficient to confirm the diagnosis of RT. Fungal infections such as histoplasmosis can also produce high SUV 4. Histoplasmosis should be suspected in patients with a travel history to endemic areas of histoplasmosis such as mid-west USA and/or a clinical presentation with mediastinal lymphadenopathy, organomegaly in patients with immunocompromised state, or pre-existing leukemia/lymphoma 5. The clinical picture of the present case emphasizes the importance of some of the fundamental principals in medicine—good history taking, thinking about differential diagnosis, and histopathological correlation with appropriate clinical, laboratory, and imaging studies. P.J., S.W., N.P., and Z.E., collected and analyzed pathology and wrote the paper. E.J., K.T, V.E.M. and Z.E. managed the patient. (A–C) shows PET-CT image and histopathological features of lymph node biopsy confirming the diagnosis of histoplasmosis. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]