A rare cause of cold agglutinin hemolytic anemia- Histiocytic sarcoma.

A 44-year-old female, known case of carcinoma vulva, status post-radical vulvectomy one and half years prior to presentation, presented with complaints of fever, jaundice, and shortness of breath of 15 days duration. Patient also had asymptomatic hypopigmented skin lesions since 4 years. On examination, patient had pallor, icterus, hepatosplenomegaly with hypopigmented scaly flat lesions all over the body. On evaluation, patient had a reduced hemoglobin of 4.6 g%, with mean corpuscular volume (MCV) of 123 fl and peripheral smear showed macrocytes and nucleated red blood cells [Figure 1a]. Liver function tests showed an increased bilirubin of 12.2 mg/dl with predominant unconjugated fraction, and an elevated lactate dehydrogenase (LDH) of 1495IU/l. In view of severe anemia, unconjugated hyperbilirubinemia and raised LDH we suspected hemolytic anemia and Coomb's test was sent, which showed direct Coomb’ 4+ and indirect Coomb's 3+ with positive cold agglutinins (titres >100). Thermal amplitude test revealed the agglutination to occur at 4°C. Patient was started on intravenous methylprednisolone and was evaluated for secondary causes of hemolytic anemia. Work-up to rule out infectious causes was done, including mycoplasma, Ebstein-Barr virus (EBV), cytomegalovirus (CMV), hepatitis B, hepatitis C, human immunodeficiency virus (HIV) which were negative. Connective tissue disease profile including antinuclear antibodies (ANA), anti dsDNA, anti-Smith, complement levels, anti-cardiolipin antibodies, lupus anticoagulant were negative. Serum electrophoresis was done which was normal: there was no M spike or an increase in the beta 2 microglobulin or an albumin globulin reversal. There was no increase in immunoglobulin M. As patient had moderate hepatosplenomegaly and cold agglutinin hemolytic anemia, lymphoproliferative disorders were suspected and contrast enhanced computed tomography (CECT) chest and abdomen was done which showed moderate hepatosplenomegaly with multiple heterogeneously enhancing hypodense lesions and small sub-centimetre enlarged para-aortic and aortocaval lymph nodes (largest diameter measuring 5 mm), the impression being metastases from an unknown primary. CT guided lymph node biopsy to exclude any underlying lymphoma or myeloma was not feasible. Bone marrow aspiration with biopsy was done.

Figure 1

(a) Peripheral smear: Normocytic, normochromic RBCs with few macrocytes, spherocytes (red arrow), polychromatophils (arrow head) and nucleated RBCs (blue arrow); (b) Bone marrow aspiration is hypercellular with erythroid hyperplasia (M: E- 1:2); c) Bone marrow biopsy shows erythroid hyperplasia (arrow), diffuse infiltration by large cells (arrow head), with large vesicular nuclei, prominent nucleoli and moderate cytoplasm, (d) ×100 (e) ×400

Skin biopsy of a hypopigmented scaly flat lesion was done. The bone marrow aspiration revealed an erythroid hyperplasia [Figure 1b], consistent with hemolysis. As the patient continued to have rapid ongoing hemolysis, patient was concomitantly started on rituximab. Patient continued to have hemolysis and succumbed to illness despite being treated with intravenous steroids and rituximab. Bone marrow biopsy report was received after patient died, which revealed histiocytic sarcoma [Figures 1c-e and Figure 2a-d]. The skin biopsy report was suggestive of epidermodysplasia verruciformis [Figure 3a-c] with no abnormal cells. Thus, a final diagnosis of histiocytic sarcoma presenting with cold agglutinin hemolytic anemia (with a prior history of vulval carcinoma; status post-vulvectomy) with epidermodysplasia verruciformis was made.

Figure 2

(a) LCA: Intense membrane positivity in the large cells; (b) MPO negative in large cells and positive in myeloid precursors; (c) CD 68 positive; (d) S100 focal positive

Figure 3

Skin Biopsy - Epidermodysplasia verruciformis: Shows hyperkeratosis, focal acanthosis, intranuclear inclusions (arrow) in stratum spongiosum and prominent keratohyaline granules (arrow head), (a). a × 100; (b). ×400, H and E, (c). hypopigmented skin lesions

Histiocytic sarcoma is a rare, aggressive neoplasm of tissue histiocytes presenting mainly in extranodal sites. The tumor is comprised of noncohesive large cells which are polygonal, ovoid with spindling. The cell consist of pleomorphic nuclei which are slightly eccentric with chromatin dispersed and small, prominent nucleoli.[1] On immunohistochemistry, the cells express cd68, lysozyme, cd4 and cd163, but specific T and B cell markers, epithelial markers, myeloid cell markers (e.g., myeloperoxidase, cd33), cd1a, s100 protein are not expressed.[12] Our patient had cd 68, leucocyte common antigen (LCA) positivity, with myeloperoxidase (MPO) being negative. A similar patient having histiocytic sarcoma but presenting with Coomb's negative hemolytic anemia has been reported earlier.[3] Like in our case, that patient was initially treated with steroids, rituximab, and IvIg, but failure to respond led to further investigation and a diagnosis of histiocytic sarcoma.[3] Cold agglutinin disease is rare, accounting for 15% of autoimmune hemolytic anemia (AIHA) cases, with an incidence of 1 per million people per year.[45] There are many causes of cold agglutinin hemolytic anemia associated with infections like mycoplasma, EBV, CMV; malignancies like leukemias, multiple myeloma, Waldernstorm's macroglobulinemia; and connective tissue disorders. To our knowledge there been no report of a patient with histiocytic sarcoma presenting with Coomb's positive cold agglutinin hemolytic anemia. The present case highlights the importance of investigating for secondary causes of hemolytic anemia. Histiocytic sarcoma may also be considered as a secondary cause of cold agglutinin hemolytic anemia although the association has not been documented earlier.

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