To Be (MDS) or Not To Be? The Conundrum of Cytoplasmic Vacuolation in Hematopoietic Precursors

Every hematopathologist and pathology trainee knows to be wary of the myriad of causes that could mimic the dysplastic changes seen in marrows involved by MDS. Many times morphology alone, without genetic or cytogenetic evidence of clonality can be tricky. The list of things that can recapitulate changes seen in MDS seems to grow longer every day – and with it the length of our ‘canned comments’ on ruling out reactive causes of dysplasia. Within the recent past, two bone marrow biopsies crossed my microscope, both sent to ‘rule out’ MDS. Both had almost identical morphologic findings, but very different diagnoses. Here are some representative images from the marrow aspirates and iron stains:

mds
Figure 1. Representative Wright-Giemsa stained cells from Case 1 (A and B) with accompanying iron stain (C) showing numerous ring sideroblasts.  Representative Wright-Giemsa stained cells from Case 2 (D) with accompanying iron stain (E) showing some ring sideroblasts. 

Discussion

Images A through C come from case 1, a 67-year-old woman with a past medical history of non-alcoholic steatohepatitis (NASH) complicated by hepatic encephalopathy and recurrent ascites who underwent bone marrow biopsy for new onset pancytopenia with transfusion-dependent anemia. The marrow was slightly hypercellular for age and showed progressive trilineage maturation. Granulocytic and erythroid progenitors did not reveal quantitatively significant dysplasia. The one dysplastic megakaryocyte identified is pictured here (panel A). Interestingly many erythroid and granulocytic precursors showed cytoplasmic vacuolation (panel B showing granulocytic vacuolation). An iron stain (panel C) revealed 44% ring sideroblasts. Case 2 is represented in images D and E and was from a 64-year-old man with no significant past medical history who presented with lethargy and anemia. This marrow was also slightly hypercellular for his age and showed borderline-significant dysplasia in megakaryocytic maturation. Granulopoiesis and erythropoiesis were unremarkable except for cytoplasmic vacuolations in many cells (panel D). An iron stain showed 8% ring sideroblasts (panel E).

Both cases were signed out descriptively, urging the clinician that we needed to rule out reactive causes of dysplasia before a definitive diagnosis of MDS could be rendered. In both cases we suggested waiting for the cytogenetics results for a more comprehensive analysis. Additionally, we recommended testing for serum copper since copper deficiency can be the cause of dysplastic morphology, cytoplasmic vacuolation, and ring sideroblasts.

Case 1 revealed markedly diminished copper and normal cytogenetics. Copper replenishment was curative. Case 2 revealed normal copper levels and a complex karyotype that contained numerous MDS-associated abnormalities confirming the clonal, and therefore malignant nature of these changes. Despite being almost identical morphologically, these case were diagnostically and prognostically poles apart.

Copper is an element that serves as a micronutrient required for hematopoiesis. It’s presence in many readily available foods including meat, fish, nuts, and seeds renders diet-related copper deficiency a rare phenomenon. Zinc-supplementation is one of the causes of copper deficiency in published reports. Copper deficiency has been well documented to mimic dysplastic changes seen in MDS; but these morphologic findings and cytopenia are reversible. Characteristically, cytoplasmic vacuolation is an important morphologic clue that there could be an underlying paucity of serum copper.  Another aspect of copper deficiency is the presence of ring sideroblasts which also can mean MDS. It is very important to consider this differential diagnosis when dealing with marrow specimens sent to rule out MDS. This Lablogatory post highlights the significant overlap between presentation and morphologic findings between MDS and copper deficiency supporting the notion that a high index of suspicion, good communication, stat copper levels, and cytogenetics or MDS FISH studies are very helpful in delineating benign from malignant.

References

  1. Dalal N. et al. Copper deficiency mimicking myelodysplastic syndrome. Clin Case Rep. 2015 May; 3(5): 325–327.
  2. Willis M.S. Zinc-Induced Copper Deficiency: A Report of Three Cases Initially Recognized on Bone Marrow Examination. AJCP. 2005 Jan; 123(1): 125–131
  3. D’Angelo G. Copper deficiency mimicking myelodysplastic syndrome. Blood Res. 2016 Dec; 51(4): 217–219.
  4. Karris S and Doshi V. Hematological Abnormalities in Copper Deficiency. Blood 2007 110:2677

 

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-Kamran M. Mirza, MD PhD is an Assistant Professor of Pathology and Medical Director of Molecular Pathology at Loyola University Medical Center. He was a top 5 honoree in ASCP’s Forty Under 40 2017. Follow Dr. Mirza on twitter @kmirza.

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