Case Report


Concomitant megaloblastic anemia and myelodysplastic syndrome

,  ,  

1 Graduate Student, Department of Community Health And Epidemiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

2 Physician, Clinical Associate Professor, Department of Internal Medicine, University of Saskatchewan/Saskatchewan Health Authority, Prince Albert, Saskatchewan, Canada

3 Professor, Department of Pathology, University of Saskatchewan/ Saskatchewan Health Authority, Saskatoon, Saskatchewan, Canada

Address correspondence to:

Anurag Saxena

MBBS, MD, M.Ed., MBA, FRCPC, FCAP, CHE, CCPE, Associate Dean, Postgraduate Medical Education, Room 402, St. Andrew’s College, 1121 College Drive, Saskatoon, SK, S7N 0W3,

Canada

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Article ID: 100026Z11AK2018

doi: 10.5348/100026Z11AK2018CR

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Khan A, Bensaleh A, Saxena A. Concomitant megaloblastic anemia and myelodysplastic syndrome. J Case Rep Images Pathol 2018;4:100026Z11AK2018.

ABSTRACT


Introduction: Megaloblastic Anemia (MBA) and Myelodysplastic Syndrome (MDS) are broadly regarded as mutually exclusive entities in the diagnostic workup of macrocytic anemia. MBA is a reversible form of ineffective hematopoiesis and MDS is an irreversible disorder of ineffective hematopoiesis manifested in part by karyotype anomalies due to DNA damage characterized by stem cell dysfunction. However, there is significant overlap in their clinical presentation and in investigatory parameters.

Case Report: A 67-year-old man initially presented with insidious onset fatigue and during diagnostic workup was found to have marked pancytopenia, macrocytic anemia, a megaloblastic peripheral blood picture and reduced serum Vitamin B12 establishing the diagnosis of MBA. Replacement therapy resulted in moderate improvement. Persistence of pancytopenia led to a bone marrow examination. The combination of a hypercellular marrow with significant erythroid dysplasia and a clonal abnormality-t (9;11)(p22;q23) led to a diagnosis of myelodysplastic syndrome–unclassified (MDS-U).

Conclusion: This case suggests that MBA & MDS can occur simultaneously and clinicians should take into account concomitant existence during the workup, when pancytopenia persists after treatment or there are other features suspicious for MDS.

Keywords: Megaloblastic Anemia, Myelodysplastic Syndrome, Pancytopenia

Introduction


Megaloblastic anemias (MBA) are a group of disorders characterized by peculiar morphological appearance due to dysfunctional maturation of hematopoietic precursors in the bone marrow. The cause is usually deficiency of either cobalamine (Vit B12) or folate that leads to defects in the synthesis and repair of DNA. MBA may also arise because of inherited or acquired abnormalities affecting the metabolism of these vitamins or because of defects in DNA synthesis not related to cobalamine or folate [1]. Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis due to an acquired and persistent clonal abnormality, often associated with karyotype anomalies resulting in cytopenia(s), dysplasia in one or more of the major hemopoietic cell lines and a propensity to progress into acute myeloid leukemia [2].

In the evaluation of patients with macrocytic anemia, although MBA and MDS are distinctly exclusive entities, there is, however, a significant overlap in clinical presentation, laboratory findings, pathological and cytogenetic features [3]. Often these two conditions are seen in the same age group i.e. elderly, median age MDS=70 Years [2], average age MBA≥70 Years [4] with vague symptoms of insidious onset fatigue and dyspnea. The diagnosis of MBA and MDS is relatively straight forward in most cases. However, morphological dysplasia as seen with MDS may be seen in Vit B12 deficiency or folate deficiency, alcohol excess, after cytotoxic chemotherapy, HIV infection and even in a minority of cells in the normal bone marrow [5]. For definitive diagnosis, assessment of disease severity and estimating prognosis, peripheral blood and bone marrow examination are most often performed [6]. The early morphological changes in MDS may be subtle - especially when only erythroid lineage is involved and many patients with normo- or macrocytic anemia in the elderly may be examples of MDS [7], as identified in one study where 15% of inpatients with unexplained cytopenias, macrocytosis or monocytosis ultimately proved to have MDS [8].

Pancytopenia encompasses a broad spectrum of differential diagnosis due to complex and multifactorial etiologies. The underlying diagnosis may be difficult, especially if there is no evidence of a neoplasm and often extensive studies are required to arrive at the precise diagnosis [9]. New onset pancytopenia can sometimes result from nutritional deficiencies of cobalamin or folate [10]. Hence, in all patients with pancytopenia and peripheral blood film showing megaloblastic processes, serum cobalamin and folate measurements are suggested [11]. Thus, in a patient with pancytopenia with no clinical or pathological features of multilineage dysplasia Vit B12 deficiency alone may be sufficient to explain pancytopenia reaching a definitive diagnosis of MBA. Our case report suggests otherwise, leaning more towards being wary of a seemingly innocent superficial clinicopathological picture.

Case Report


A 67-year-old man who was found to have both Vit B12 deficiency and MDS. His initial presentation in the Emergency Room included features of general weakness, fatigue, malaise, a pre-syncopal episode and weight loss. He had no regular medical follow up prior to this presentation and denied occupational exposure to radiation, industrial chemicals, chemotherapy (alkylating agents) or radiotherapy. The vital signs at this presentation were: blood pressure 89/31 mmHg, a heart rate of 99/min, respiratory rate 24/min and a temperature 37.4 ? and oxygen saturation of 99% at room air. Physical examination identified a pale, well appearing elderly man without clinically appreciable lymphadenopathy or hepato-splenomegaly. There was no evidence of autoimmune diseases i.e. rash or areas of vitiligo, swollen or inflamed joints. There was atrial fibrillation identified by electrocardiography. Chest radiograph was unremarkable. The CT scan detected mild splenomegaly.

There was pancytopenia at presentation. Relevant parameters are shown in (Table 1) prior to definitive diagnosis. At admission the reticulocyte count was 72 x 106/L. In the peripheral blood film blasts, significant dysplastic changes, leukoerythroblastic reaction or abnormal lymphoid cells were not seen.

The levels of analytes were as follows: Vit B12-52 pmol/L (reference range: >200 pmol/L), Methyl Malonic Acid - 2.9 μmol/L (reference range: less than 0.4 μmol/L), Carcinoembryonic antigen - 3.7 ng/ml (reference range: less than 5 ng /ml), PSA - 2.8 ng (reference range: less than 4 ng/ml), total Serum Protein - 60 g/L (reference range 64-82 g/L) and Serum Albumin - 37 g/L (reference range 35–50 g/L). Iron studies were within reference range. Antibodies to intrinsic factor were absent and the Coomb›s test was negative. Investigations for other concurrent autoimmune endocrinopathies were negative. Serology for Hepatitis B and Hepatitis C was negative. There was no monoclonal band on serum protein electrophoresis (SPEP).

Blood cultures taken earlier showed no growth.

In view of vitamin B12 deficiency, the patient was treated with oral Vit B12 and parenteral replacement therapy along with oral iron and folic acid on the 6th day of the admission. After one week of replacement therapy, there was moderate improvement in the hemoglobin level reaching 127 g/L and 147 g/L on the 20th and 30th day of the commencement of Vit B12 therapy. The WBC, platelets and MCV recovered to within reference range.

The presence of pancytopenia, had prompted for a bone marrow examination. The marrow was hypercellular (approximately 98%). Focally aggregates of erythroid precursors (positive for glycophorin A and E-cadherin) were present and there was maturation arrest. Dyserythropiesis was identified by defective hemoglobinization of cytoplasm, nuclear budding, and binucleate erythroid precursors. Blasts were not increased (2.4%). Mild dysplastic changes were observed in less than 10% of megakaryocytes (Figure 1), (Figure 2).

Cytogenetic analysis of the cultured bone marrow cells identified a clone with an abnormal male karyotype characterized by a translocation between the short arm of chromosome 9 and the long arm of chromosome 11 with breakpoints estimated to be with bands 9p22 and 11q23 in 2 out of 20 metaphase cells examined. Fluorescence in-situ hybridization performed on the interphase nuclei with the KMT2A (MLL) dual color, break apart probe (Abbott Molecular, Des Plaines, IL) revealed that this translocation - t(9;11) (p22;q23) - did not involve the MLL gene. In the latter case, a very small insertion of chromosomal material that includes a MLL translocation partner gene into the MLL gene could result in increased spacing between the 5’ Spectrum Green and the 3’ Spectrum Red signals compared to the other locus by FISH and easily go undetected. This would appear as two fusion (unrearranged) signals by FISH. These MLL rearrangements could be delineated by further molecular studies but this was not performed on our patient.

At this point the patient was diagnosed to have combined vitamin B12 deficiency and a myelodysplastic syndrome. The diagnosis of myelodysplastic syndrome, unclassified (MDS-U) was made in view of pancytopenia associated with significant dysplasia in only one lineage (erythroid) and the cytogenetic abnormality. A recommendation for clinical follow-up was made. The patient was seen in the outpatient clinic at yearly intervals and blood counts were performed.

After six months periodic follow-up was done and initial diagnosis the blood counts were found to be normal. The patient was last seen two and half years after initial diagnosis and had blood counts within reference range.

Table 1: Relevant complete blood count values,in the first column the text with in brackets in reference range and units

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Figure 1: Trephine biopsy, H &E staining, 20x, hypercellular marrow with trilineage hematopoiesis.

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Figure 2: Trephine biopsy, H & E staining, 50x, aggregate of proerythroblasts and maturation arrest. (A) Bone marrow aspirate, Giemsa stain, 500x, Dysplastic erythroid precursors with Nuclear contour irregularities, defective hemoglobinization of cytoplasm and a mitotic figure (B).

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Discussion


To the best of our knowledge there is no case report of this combination of case of nutritional B12 deficiency and MDS, although one case with autoimmune pernicious anemia associated with trilineage dysplasia and genetic abnormalities has been reported [3]. The noninvolvement of MLL gen was interpreted to be either a clonal abnormality associated with a hematologic disorder or arare occurrence of cryptic MLL gene rearrangement [12]. Another similar yet distinct case of patient treated with chlorambucil for the treatment of renal amyloidosis secondary to rheumatoid arthritis presented at first with MBA with transient response to parenteral B12 therapy and then took a course of refractory anemia with excess blasts in transformation [13].

There is overlap in the clinical and pathologic features between MBA & MDS. As our patient had clinically proven low levels of serum cobalamine and in view of studies inferring that the bone marrow examination is rarely necessary or useful in the patients with macrocytosis and laboratory proven low cobalamin level [14] bone marrow examination was not performed at this stage Persistence of pancytopenia prompted a bone marrow examination. A hypercellular marrow with significant erythroid lineage dysplasia (coupled with dysplastic changes in less than 10% megakaryocytes) was detected along with a cytogenetic abnormality leading to a diagnosis of myelodysplastic syndrome –unclassified (MDS-U), according to the WHO 2008 classification [2].

Bi/pancytopenia can occasionally be seen with MBA while unilineage dysplasia is a well-known finding in MDS cases [2]. Moreover, in MDS some of the more common abnormalities include megaloblastoid erythroid precursors resembling those seen in megaloblastic anemias [15]. While a bone marrow examination of MBA may reveal erythroid islands composed of early megaloblasts these may sometimes be mistaken for ‘abnormal localization of immature precursors’ in MDS [16]. Further, some cytogenetic abnormalities, mostly reversible, have been observed in MBA cases [17],[18] and rarely may become established as soil for future development of MDS [19], especially in view of increased risk of myeloid leukemias in patients with pernicious anemia [20],[21]. Nonetheless careful and thorough clinicopathological examination combined with necessary cytogenetic and flow cytometric studies prove fairly efficient in diagnosing MDS, as in this case. The role of bone marrow examination is pivotal. Because of its invasive nature bone marrow needs to be obtained only if clinically indicated. Clinical pointers suggesting that bone marrow examination is required along with cobalamine levels include splenomegaly, unexplained lymphadenopathy, constitutional symptoms, a history of chemotherapy or exposure to ionizing radiation. Laboratory features suggesting a bone marrow examination include, oval macrocytosis in the absence of nutritional deficiencies, chronic alcoholism, or exposure to drugs, relative or absolute monocytosis, basophilia, appearance of atypical cells on the peripheral blood smear [7].

Conclusion


Our findings suggest that a high index of clinical suspicion must be maintained in the workup of patients who present with pancytopenia and who are found to have B12 deficiency, where after treatment either pancytopenia persists or there are features suggesting an additional pathologic process (e.g., splenomegaly).

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SUPPORTING INFORMATION


Author Contributions

Amal Khan - Substantial contributions to conception and design, Acquisition of data, Analysis of data, Interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published

Adel Bensaleh - Substantial contributions to conception and design, Acquisition of data, Analysis of data, Interpretation of data, Final approval of the version to be published

Anurag Saxena - Substantial contributions to conception and design, Acquisition of data, Analysis of data, Interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published

Guarantor of Submission

The corresponding author is the guarantor of submission.

Source of Support

None

Consent Statement

Written informed consent was obtained from the patient for publication of this case report.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Conflict of Interest

Authors declare no conflict of interest.

Copyright

© 2018 Amal Khan et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.


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