The Significance of Unexplained Macrocytosis
Authors: Vega Jose , Younes Mohamad , Kuriakose Philip 
Published: October 2019

Abstract
Background: Macrocytosis is a relatively common finding in adult patients undergoing automated complete blood cell (CBC) counting with an incidence varying from 1.7 % to 3.6 %. Approximately 60% will not have associated anemia. Causes of macrocytosis include alcohol intake, vitamin B12 and folate deficiency, chemotherapy and other drugs, hemolysis or bleeding, liver dysfunction, myelodysplastic syndrome (MDS), and hypothyroidism. Approximately 10% of patients will have unexplained macrocytosis after laboratory evaluation. Data on the diagnostic approach and management of patients with unexplained macrocytosis are limited.
Methods: To investigate this topic, the records of 9,779 patients diagnosed with macrocytosis in our institution between 1995 and 2005 were reviewed. Macrocytosis was defined as a mean corpuscular volume (MCV) greater than 100 in two consecutive occasions. Patients with evidence of liver disease, alcohol abuse, hypothyroidism, folate or vitamin B12 deficiency, hemolysis, or use of any drugs known to cause macrocytosis were excluded. Patients found to have MDS or any other bone marrow disorder documented by bone marrow biopsy within 3 months of the diagnosis of macrocytosis were also excluded. Data collection included CBC and MCV at the time of diagnosis, time of first cytopenia, and last follow-up; bone marrow biopsies and monoclonal protein evaluation (MPEV) results were also collected. Patient outcomes were divided in 4 categories which included:
Resolved macrocytosis, defined as MCV less than 96 at the last follow-up. Worsening cytopenias, defined as development of new-onset anemia, thrombocytopenia, or leukopenia; or hemoglobin drop greater than 2 g/dl, or transfusion requirements. Bone marrow disorder, defined as morphologic, flow cytometric, and/or cytogenetic evidence of a primary bone marrow disorder. Stable disease, if none of the above conditions were met.
Results: Forty three patients were found to have unexplained macrocytosis. Twelve (28%) had associated anemia at the time of diagnosis. The median follow-up was 4 years. Five (11.6%) patients developed a primary bone marrow disorder (two B-cell lymphomas, two MDS, one plasma cell disorder), 7 (16.3%) developed worsening cytopenias, 30 (69.7%) had stable disease, and 1 (2.3%) resolved. The median time to first cytopenia was 18 months. Monoclonal paraproteinemia was found in 5 out of 22 patients tested (22.7%). The outcomes were not significantly different when comparing patients with or without anemia upon diagnosis of macrocytosis. The probability of a bone marrow biopsy establishing a diagnosis of a primary disorder was two out of six (33.3%) in patients with macrocytosis without anemia, compared to three out of four (75%) in patients with macrocytosis with anemia.
Conclusions: Unexplained macrocytosis may not be a benign condition and requires close follow-up as up to 27.9% of patients will develop worsening cytopenias (16.3%) or will be ultimately diagnosed with a primary bone marrow disorder (11.6%). We suggest a strategy of follow-up with CBCs every 6 months. Bone marrow biopsy should be performed at the time when cytopenias are present, since this approach might give a higher yield of diagnosis, and also provide information when the clinicians are more likely to take therapeutic decisions. Given the high incidence of monoclonal paraproteinemia in these patients, we propose that MPEV should be considered as part of the initial work-up for macrocytosis.