Trilineage myelodysplasia and hemophagocytosis associated with systemic lupus erythematosus
Authors: Aleksandra Paliga, Nasim Shahbazi, Carol Gonsalves, Janis Bormanis, Ruth Padmore
Journal: American Journal of Hematology (2011)

Marked trilineage myelodysplasia and hemophagocytosis was noted in the marrow of a 28-year old male of Filipino decent. Six days prior he had been admitted to the hospital for work-up of renal failure, proteinuria, hematuria, and pancytopenia. Past medical history was noteworthy for a 2-year history of a psoriatic like skin rash. The patient also had an emergency room visit for chest pain 1 week prior. He was diagnosed with likely pericarditis and discharged with indomethacin. At admission the patient's initial laboratory investigation was significant for a creatinine of 270 μmol/L (normal 62–106), potassium of 5.9 mmol/L (normal 3.5–5.1), hemoglobin 104 g/L (normal 130–170), mean corpuscular volume (MCV) of 79.7 fL (normal 80–100), reticulocytopenia of 19.3 × 109/L (normal 25–100), neutrophil count of 2.0 × 109/L (normal 2–7.5), and a platelet count of 105 × 109/L (normal 125–400). The results of his initial anemic workup were as follows: ferritin 6576 ug/L (normal 24-336), iron 8 umol/L (normal 12–31), iron binding capacity 34 umol/L (normal 45–81), % saturation 24 (normal 20–50), vitamin B12 380 pmol/L (normal 133–675) and serum folate 23.6 nmol/L (normal > 15). Fibrinogen was in the normal range (2.9 g/L, range 1.9–4.5 is normal). Other investigations showed elevated triglycerides at 3.30 mmol/L (normal <1.7 mmol/L) and C-reactive protein of 19.9 mg/L (normal <10). alkaline phosphatase (ALP), alanine aminotransperase (ALT) and gamma-glutamyl transferase (GGT) were in normal range while aspartate aminotransferase (AST) was 137 U/L (normal range = 15–37). Urine microscopy was positive for red blood cell casts, and 24-hr urine collection showed nephrotic range proteinuria (5.5 g) with an albumin to creatinine ratio in a spot urine sample of 235 g/mol. A transthoracic echocardiogram revealed a trivial pericardial effusion with echogenic deposits along the epicardium consistent with fibrin. Mild hepatosplenomegaly was discovered by ultrasound (liver 20 cm; spleen 14); right and left kidneys appeared normal. The patient was treated conservatively with insulin and glucose for hyperkalemia and was not initiated on any other medications at this time. Over the course of the next 6 days, the patient's peripheral blood counts gradually fell to a neutrophil count of 0.8 × 109/L, platelet count of 44 × 109/L, and hemoglobin of 72 g/L. The patient became febrile. He was initiated on fluconazole and pipercillin tazobactam; a bone marrow biopsy was performed the following day. The Wright-Giemsa stained bone marrow aspirate revealed trilineage dysplasia with erythrocytes and megakaryocytes showing the most prominent dysplastic features. Erythropoiesis was markedly decreased with multinucleation, karyorrhexis, and cytoplasmic nuclear dysynchrony predominantly in the late normoblasts (Image 1), while megakaryocytes were increased in number, small and hypolobated (Image 2). Granulocytes were present in normal amount, left shifted, and hypogranular. The bone marrow biopsy was normocellular (50% of intertrabecular space occupied) with a few strikingly pyknotic megakaryocytes (Image 3). Abnormal localization of immature precursors was absent, but uncharacteristic grouping of megakaryocytes was present (Image 3). Mild gelatinous transformation occupied 10% of the core biopsy (Image 3). CD 34+ stain to showed <3% precursor cells. Histiocytes were mildly increased and represented 2% of the nucleated cells, with a minority displaying hemophagocytosis (Image 4). Cytogenetic studies showed normal male karyotype, 46 X,Y. Initial cytomegalovirus (CMV) serologies where positive for both IgG and IgM, however CMV immunohistochemistry on the core bone marrow biopsy was negative. Of note, serology was negative for HIV, EBV IgM, parvovirus B19 IgM, histoplasmosis, toxoplasma, and Hepatitis B and C. Top two rows, left and middle: Evidence of dysplastic erythropoiesis: karyorrhexis (A), cytoplasmic nuclear dysynchrony predominantly in the late normoblasts (B), multinucleation (A,C), and nuclear blebbing (D). ×1000 on oil. Top two rows, right: Micromegakaryocyte. ×1000 on oil (above). Hemophagocytosis. ×1000 on oil (below). Bottom two rows: Normocellular bone marrow with a few strikingly pyknotic megakaryocytes at ×200 and ×400, respectively (A,B), abnormal clustering of megakaryocytes at ×200 (C), mild gelatinous transformation occupying 10% of the core biopsy at ×200 (D). After bone marrow biopsy, the patient was initiated on filgrastim (300-μg SC for three doses) and prednisone (50 mg PO, daily). He also received one unit of platelets and three units of packed red blood cells. There was a very fast resolution of his neutropenia and thrombocytopenia 1 and 2 days later, respectively. Initial vasculitis investigations were positive for low complements (C3 and C4), positive antinuclear antibody (ANA) (titre 2560), positive anti-DNA double strand, and anti-smith antibodies. Skin lesions were interpreted as subacute cutaneous lupus. An eventual kidney biopsy on Day 9 of admission confirmed the diagnosis of class IV glomerulonephritis secondary to systemic lupus erythematosus (SLE). The patient was then started on darbepoetin (40 mcg SC, weekly), prednisone (70 mg PO, daily), and was also initiated mycophenolate mofetil (initially on 500 mg twice daily because of concern for myelodysplasia, but the dose eventually increased to 1,250 mg PO twice daily). Seven months later, his kidney function improved and his creatinine decreased to 150 μmol/L, albumin to creatinine ratio in random urine sample also decreased to 47 g/mol. He continued to have a normocytic normochromic anemia (Hgb 105 g/L, MCV 86), but his platelet and white blood cell counts remained in the normal range. Over the course of treatment, prednisone was tapered down, but the patient continued on mycophenolate mofetil. Darbepoetin was discontinued after 5 months of treatment. No follow-up bone marrow biopsy was done due to patient preference and lack of medical indication. However, the patient's rapid response to immunosuppressive medications, as demonstrated by improved peripheral blood counts, supports an immune mediated phenomenon as culprit. SLE is an autoimmune disease that attacks multiple organ systems, including the bone marrow microenvironment [1]. Literature on bone marrows in SLE patients is sparse and varied, describing mainly hypoplasia, hyperplasia, vasculitis, lympho/plasmacytosis, red cell aplasia, myelofibrosis, gelatinous transformation, and dyserythropoiesis [2-4]. Dysplastic bone marrow changes in SLE patients have also been described [1, 2, 4, 5]. In 2008, Oka et al. suggested that dysplastic bone marrow changes in SLE patients with unexplained cytopenias are reversible [5]. The presence of hemophagocytosis in our patient's bone marrow aspirate is suggestive of secondary hemophagocytic syndrome (HS). Indeed, our patient fulfills the diagnostic criteria for hemophagocytic lymphohistiocytosis having six of eight criteria including fever, splenomegaly, bicytopenia, hypertriglyceridemia, hemophagocytosis, and hyperferritinemia [6]. Secondary HS in SLE patients, otherwise referred to as "acute lupus HS" has been well described [7-10]. In the setting of autoimmune disease, HS may result from an infection, or more frequently, may represent a complication of the underlying illness. Overall, SLE-associated HS seems to define a severe SLE form and the need for prolonged immunosuppression [8, 9]. The mechanism leading to either myelodysplasia or hemophagocytosis is unknown, but both HS and myelo dysplastic syndrome (MDS) are implicated with a hypercytokinemia [5, 9]. As the diagnosis of both MDS and HS hinges primarily on morphology and may portend a poor prognosis and aggressive clinical management for the patient, it is important to keep the possibility of systemic lupus exacerbation in mind.