A Case of Hodgkin Lymphoma in a Gaucher Disease Patient: Distinguishing Gaucher and Pseudo‐Gaucher Cells
Authors: Natalia Scaramellini, Marta Canzi, Elena Cassinerio, Margherita Migone De Amicis, Loredana Pettine, Bruno Fattizzo, Francesca Gaia Rossi, Giorgio Croci, Irene Motta
Journal: American Journal of Hematology (2025)

A 35-year-old man came to our attention for the suspicion of Gaucher disease (GD). The patient had undergone a bone marrow aspirate and biopsy because of massive splenomegaly (30 cm), severe thrombocytopenia (platelet count 30 000/mm3), and mild anemia [hemoglobin (Hb) 12.1 g/dL] observed in the emergency department, where he presented for acute abdominal pain. Bone marrow biopsy (BMB) revealed foci of fibrosis accompanied by aggregates of CD163+/CD1a− epithelioid histiocytes, featuring a fibrillary, dimly eosinophilic, PASD+ cytoplasm, accounting for 60% of the cellularity. These histological findings were consistent with lysosomal storage disease. GD was then confirmed by beta-glucocerebrosidase activity on dried blood spot (GBA activity 0.4 μmol/L/h, n.v. > 3.5 μmol/L/h) and molecular analysis of the GBA gene that showed compound heterozygosity c.475C>T/c.1226A>G [p.(Arg159Trp)/p.(Asn409Ser)] mutations. At the time of diagnosis, he also had hyperferritinemia (serum ferritin 1300 ng/mL) with normal transferrin saturation (25%). Substrate reduction therapy with eliglustat was started with hematologic improvement at 1 year: platelet counts 55 000/mm3, Hb 14.1 g/dL, and reduction in the spleen volume (22 cm). A year and a half later, he complained of night sweats, weight loss of 3 kg over 3 weeks, and fatigue. Blood tests showed slightly microcytic anemia (Hb 10.5 g/dL, mean corpuscular volume 78.7 fL), platelet count three times the previous value (176 000/mm3), even higher values of ferritin (2756 ng/mL), and serologies negative for active infections (HIV CMV, EBV, and Toxoplasma). A total body CT scan showed cervical and thoracic lymphadenopathies up to 4.5 cm and an increase in spleen volume (25 cm). Bone marrow aspirate was negative, while BMB showed foci of Gaucher-type histiocytes, with scattered iron-laden cells, alternated with foci of sclerosis (Figure 1a), with admixed histiocytes, small lymphocytes, eosinophilic granulocytes, and rare scattered, CD30-positive Hodgkin and Reed-Sternberg (HRS) cells (Figure 1b), confirming the clinical suspicion of classical Hodgkin lymphoma (cHL). Interestingly, the diffused and massive macrophage infiltration, which initially masked the rare HRS cells, displayed a double functional phenotype, highlighted through immunohistochemical PD-L1 expression. On the one hand, we observed Gaucher cells with extremely dim PDL-1 intensity [1]; on the other hand, the tumor microenvironment (TME) of cHL expressed abundant PD-L1 (Figure 1c) [2, 3]. Pseudo-Gaucher cells have been reported in association with a variety of hematological malignancies and are a hallmark of increased cell turnover. Conversely, in GD, the metabolic defect leads to the accumulation of bioactive glycosphingolipids, which have long been held to drive carcinogenesis. The overall risk for hematological malignancies, particularly B cell neoplasm, is more than four times higher in GD patients, especially for non-Hodgkin lymphoma (approximately three times higher) and multiple myeloma (approximately nine times higher) [3-5]. This case elicits important messages for clinicians/hematologists: (i) in the presence of a diagnosis of a rare systemic disorder, concomitant diseases or complications can appear thus a critical approach is crucial instead of attributing all the signs and symptoms to the underlying disorder; (ii) GD presents an increased risk of hematological malignancies and, vice-versa, GD should be suspected in presence in patients with onco-hematological malignancies and features suggestive of GD; (iii) a close interaction between the clinicians and the pathologists is pivotal [6, 7]. Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. I.M. has been or is a current consultant for Sanofi and has received honoraria for lectures, financial support, and grants from Sanofi. B.F. received consultancy and speaker honoraria from Alexion, Annexon, janssen, Sanofi, Sobi, Roche, Novartis, Zenas. The authors have nothing to report.