Combined B12 and folate deficiency presenting as an aggressive hematologic malignancy

A 36-year-old male with history of alcohol and narcotic abuse presented to our outpatient hematology practice for evaluation of incidentally discovered anemia. He initially presented with abdominal pain several months prior and eventually underwent cholecystectomy. One month later he developed progressive diarrhea. Gastroenterologic evaluation at an outside hospital was unremarkable. A complete blood count (CBC) revealed a hemoglobin of 12.5mg/dL, with mean corpuscular volume (MCV) of 97 fL (Supporting Information Table 1). He was referred to a local hematologist for evaluation of anemia, at which time the hemoglobin was 11.6 mg/dL (MCV 102.3 fL). Additional testing at that time included metabolic panel, hepatic enzymes, and beta-2-microglobulin, all of which were within normal limits, and ferritin which was elevated at 1223 ng/mL. Bone marrow evaluation revealed normocellular, erythroid-dominant, megaloblastoid progressive, disordered trilineage hematopoiesis with ∼5–10% blasts, classified as myelodysplasia consistent with refractory anemia with excess blasts-1 (RAEB-1). Flow cytometry of bone marrow aspirate tissue demonstrated an increase in immature CD117+ myeloid cells (∼10%), and cytogenetic studies were negative for deletions at 5q and 7q or trisomy 8. He was given the diagnosis of myelodysplastic syndrome (MDS), most consistent with RAEB-1, and referred to our tertiary care center. He was seen in our clinic 10 days later, ∼3 weeks after initial bone marrow biopsy. The patient endorsed several months of chills, night sweats, lower extremity edema, and profound fatigue. At this time his hemoglobin was 7.9 mg/dL. Additional evaluation revealed thrombocytopenia and biochemical aberrations concerning for disseminated intravascular coagulopathy and tumor lysis syndrome. Given the concern for an aggressive hematologic malignancy, a repeat bone marrow biopsy was performed and the patient was admitted to our inpatient unit. Repeat laboratory studies performed on arrival to the inpatient unit revealed progressive anemia (hemoglobin 6.9 mg/dL, MCV 104 fL) with stable biochemical markers. He was given one unit of red blood cells, fluids, empiric antibiotics, and allopurinol. Twelve hours after admission, serum d-dimer and uric acid levels returned to normal, however lactate dehydrogenase, international normalized ratio, and partial thromboplastin time remained elevated. Peripheral blood smear revealed anisopoikilocytosis, nucleated RBCs, and hypersegmented neutrophils (Image 1A), with no circulating blasts. Bone marrow aspirate (Image 1B) and biopsy (Image 1C) performed the day previously revealed marked erythroid dysplasia and hyperplasia, and again demonstrated the presence of hypersegmented neutrophils with no blasts. Vitamin B12 and folate levels were both found to be low (186 pg/mL and 3.1 ng/mL, respectively), and high-dose supplementation was started (Day 65). As evidenced by rising hemoglobin and reticulocyte count, the patient demonstrated rapid bone marrow recovery within days of initiation of nutrient supplementation. He was discharged six days later, and was followed in our outpatient practice (Day 85). During this visit, laboratory testing revealed improvement in all cell counts, resolution of macrocytosis, and continued decline of serum LDH. The final diagnosis of combined B12 and folate deficiency resulting in anemia and thrombocytopenia with bone marrow morphology mimicking MDS was made. At last evaluation (>5 months later), the patient's hemoglobin had returned to normal (Day 161). During the patient's hospitalization, his primary symptom was persistent diarrhea. Our GI consultants recommended initiation of empiric cholestyramine to treat possible bile acid malabsorption. We speculate that both the patient's long history of alcohol abuse combined with chronic malabsorption resulted in his profound nutrient deficiency. Ineffective hematopoiesis may have resulted in rapid cellular turnover, which combined with volume depletion led to the biochemical abnormalities observed. It is possible that his megaloblastic anemia resulted in schistocytosis and thrombocytopenia, as has been reported 1. An estimated 10,300 cases of MDS are diagnosed annually in the US 2. Survival from this heterogeneous group of diseases is variable; a study examining SEER data from 2003 reported a 35% observed survival overall 2, highlighting the importance of early diagnosis. In the case presented, pathologic evaluation was key to diagnosis, as myelodysplasia resulting from MDS would reveal hyposegmented neutrophils, while both peripheral blood and marrow evaluation in our patient revealed hypersegmented neutrophils, typical of nutrient deficiency. Vitamin B12 and folate deficiencies are well-known causes of megaloblastic anemia, and a recognized cause of myelodysplastic marrow changes. While vitamin B12 deficiency severe enough to cause MDS-like morphology is unusual in the US, it is an important consideration when forming a differential diagnosis for this group of diseases. A recent case series from MD Anderson Cancer Center reported that 12% of MDS cases sent to their tertiary care center were re-classified after internal evaluation 3. Most of these cases were simply re-classified with regards to staging; however some patients (∼5%) were re-classified as not having MDS. Several diagnostic strategies have been suggested for patients with suspected MDS 4, 5, with a particular emphasis given to genetic and nutrient evaluation in patients < 50 years old. The patient presented here had begun consideration of allogeneic bone marrow transplantation prior his inpatient evaluation, highlighting the importance of thorough diagnostic assessment in the analysis of a dysplastic bone marrow. Pathologic evaluation of patient with suspected myelodysplastic syndrome. A: Peripheral blood smear demonstrating anisopoikilocytosis, nucleated RBCs (asterixes), and hypersegmented neutrophils (arrow) (Wright–Geimsa staining at 500×); (B) Bone mallow aspirate demonstrating dysplastic erythroid precursors, hypersegmented neutrophils (arrow) and a giant band cell (asterix) (Wright–Gelmsa staining at 500×); (C) Bone marrow biopsy demonstrating marked erythroid hyperplasia throughout and a normal megakaryocyte (asterix) (Periodic Acid-Schiff staining at 400×). Additional Supporting Information may be found in the online version of this article. 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