Unexplained chronic cytopenia: is it idiopathic cytopenia of undetermined significance or myelodysplastic syndrome

Abstract

Idiopathic cytopenia is a condition where there is a decrease in peripheral blood counts causing either anaemia, leucopoenia and thrombocytopaenia. Most cases of cytopenia reveal a cause on further workup. But very rarely, in some cases, a definitive cause could not be identified. Unexplained cytopenia becomes challenging and poses difficulty in diagnosis and management. Discriminating these groups of bone marrow failure disorders from myelodysplastic syndrome (MDS) becomes an important clinical question. We describe a case of a middle-aged Hispanic woman who presented with pancytopenia and on extensive workup did not reveal any specific cause. Her bone marrow examination revealed severely reduced megakaryocytes but with normal haemopoiesis of other lineages. Cytogenetics, flow cytometry, comprehensive next-generation whole genomic analysis did not reveal any abnormalities. She fit the criteria for idiopathic cytopenia of undetermined significance rather than MDS. She remained asymptomatic and her counts never improved with immunosuppressives or thrombopoietin mimetics.

Background

Chronic unexplained cytopenia poses a challenge in both diagnosis and management. An extensive workup is usually needed to rule out the common and uncommon causes, before a definite diagnosis of idiopathic cytopenia of undetermined significance (ICUS) could be made. Bone marrow evaluation to rule out evolving myelodysplastic and clonal disorders becomes mandatory in these situations. ICUS is becoming increasingly recognised disorders in recent times and is clinically important to follow these patients over time, due to the risk of progression of ICUS into stem cell disorders.^{1 2} Those bone marrow failure disorders where clonality is identified are termed as clonal cytopenia of undetermined significance (CCUS). If any specific cytogenetic markers or dysplastic morphology is identified, they will be grouped under myelodysplastic syndrome (MDS).

Case presentation

A 67-year-old Hispanic woman with medical history of chronic thrombocytopaenia presented to us with fever, cough and sputum. She was not on any regular medications. She was a non-smoker and non-alcoholic. On presentation, she was haemodynamically stable. Physical examination did not reveal any abnormality other than pallor and slightly reduced breath sounds on the right lung base. Her laboratory investigations revealed severe macrocytic anaemia (haemoglobin (Hgb): 59 g/L), neutropaenia (ANC-1.1×10⁹/L) and thrombocytopaenia (platelet count: 10×10⁹/L). Renal and liver function tests were within normal limits. Her chest X-ray showed infiltrate on the lung base on right side. Based on the clinical and imaging findings, antibiotics were initiated to treat community-acquired pneumonia. Haematology was consulted for evaluation of pancytopenia.

On more probing into her history and from other medical records, we gathered that she had chronic cytopenia since last 5 years and had extensive workup including bone marrow biopsy. She was also treated with steroids, intravenous immunoglobulin and rituximab with no durable response so far.

Her further workup with us started with peripheral blood smear, which was unremarkable except for thrombocytopaenia (figure 1). Her nutritional workup including vitamin B₁₂, folate and ferritin did not reveal any abnormalities. Her viral screen including HIV, hepatitis A, B, C and parvovirus screen was negative. Haemolysis screen, paroxysmal nocturnal haemoglobinuria (PNH) screen and myeloma screen were negative. Her erythropoietin level was 74 IU/L. Her imaging studies did not reveal any hepatosplenomegaly or lymphadenopathy. Her autoimmune screen was tested to be weakly positive for antinuclear antibodies (1:160 and centromere pattern). Comprehensive connective tissue workup including antidouble-stranded DNA antibodies, anti-Smith antibodies, Sjogren antibodies, anti-Scl 70 antibodies, antiribonucleoprotein antibodies, rheumatoid factor, anti-Jo 1 antibodies, lupus anticoagulant, antineutrophil cytoplasmic antibodies (ANCA) antibodies, anticardiolipin antibodies were negative. Bone marrow biopsy showed slightly hypercellular marrow with markedly decreased megakaryocytes but preserved haematopoiesis of other lineages (figure 1). Cytogenetics (including chromosome 5, 7, 8, 20 analysis), myeloid mutation analysis, flow cytometry analysis did not reveal any abnormalities (figure 2). Florescent in situ hybridisation (FISH) analysis did not reveal any evidence of abnormality of chromosome 5,7, 8, 17 or 20. Hence no evidence for lymphoma or myeloma or leukaemia or myelodysplasia was identified from bone marrow analysis. She also did not show any over representation of HLA-DR16, a marker to assess response to immunosuppressive therapy. A comprehensive next-generation sequencing genomic analysis from bone marrow sample was performed but did not find any evolving abnormal mutations (figure 3). Her thrombopoietin (TPO) levels were measured to be high (1573 pg/mL), which was consistent with decreased megakaryocytes. Extensive workup carried out to rule out gastrointestinal bleed to assess the cause of anaemia did not reveal any abnormality. Repeat chest imaging after few weeks showed complete resolution of pneumonia thereby ruling out infection as the cause of cytopenia.

Figure 1.

(A): H&E stain, peripheral blood smear, original magnification X50 demonstrating thrombocytopaenia. Bone marrow biopsy (B, C); H&E stain, original magnification X 100(B), X4(C)) shows slightly hypercellular marrow with markedly decreased megakaryocytes but preserved haematopoiesis of other lineages. Immunohistochemistry for CD61 (D, E), original magnification X4(D], X100(E)) confirmed severely reduced megakaryocytes.

Figure 2.

Cytogenetic analysis showing normal karyotype.

Figure 3.

Next-generation sequencing analysis showing no evidence of evolving mutations.FDA, Food and Drug Administration.

Differential diagnosis

Differential diagnosis in this case was ICUS, MDS and autoimmune-related disorders.

Treatment

Patient remained asymptomatic with no bleeding issues even with chronic severe thrombocytopaenia. Her anaemia was initially managed with frequent blood transfusions. Her previous medical records showed that she was non-responsive to steroids, intravenous immunoglobulin and rituximab. Hence, alternate immunosuppressive including ciclosporin, azathioprine and mycophenolate mofetil (MMF) therapy was tried. She was intolerant to ciclosporin and could not continue further therapy. Azathioprine and MMF made her more myelosuppressive with the need for blood product support. Finally, she was also tried on TPO agonist (eltrombopag), which was also not successful in improving her counts.

Outcome and follow-up

She is currently followed up in the clinic every 6 weekly with routine monitoring of her blood counts. Since she remained asymptomatic and did not respond to any immunosuppressive therapies, she is not on any active treatment and is on active surveillance. Her red cell and platelet transfusion dependency has recently decreased with her Hgb maintaining between 70–80 g/L and platelet counts >10×10⁹/L.

Discussion

Cytopenia which does not have any specific attributable cause pose a difficult situation both with diagnosis and management. A thorough history including alcohol intake, toxin exposure and physical examination to assess organomegaly combined with an extensive workup including screening for nutritional deficiency states, viral infections, autoimmune disorders, haemolytic states, PNH should be extensively investigated. Imaging studies will help in assessment of lymphadenopathy and organomegaly as a cause of cytopenia. Bone marrow analysis including flow cytometry, karyotyping, FISH studies will be very helpful in these situations to assess for aplastic anaemia, fibrosis and bone marrow infiltration.²

Idiopathic cytopenias, which do not meet WHO criteria for any specific disease especially MDS, are classified as ICUS, CCUS and clonal haematopoiesis of indeterminate potential.³

The idiopathic cytopenia in our patient was subgrouped as ICUS, as she did not have any evidence of clonal disorders by karyotyping or FISH or next-generation sequencing.

The diagnostic criteria for ICUS include:

1. Cytopenia persistent for at least 6 months.

2. No dysplastic features on morphology.

3. Normal karyotypic analysis.

4. Absence of any haematological or non-haematological disorder as a cause of cytopenia.⁴

The threshold for blood counts for ICUS proposed in 2007 was Hb <11.0 g/dL, neutrophils <1.5×10⁹/L and platelets <100×10⁹/L. Cytopenia can be unilineage, bilineage or multilineage (ICUS -A, ICUS -N, ICUS -T and ICUS -BI/PAN).

If the cytopenia is associated with any morphological dysplasia in at least one myeloid lineage or cytogenetic abnormality of chromosome 5 or 7, then they are classified as MDS. A very sensitive parameter to distinguish between ICUS and MDS is the assessment of CFU progenitor cells. If a number of granulocyte-macrophage CFU cells and erythroid burst-forming units are normal, then MDS is very unlikely. But CFU assay is not a routinely performed assay and requires clinical expertise.^{1 5}

Little is known about the prevalence and the clinical course of ICUS. As per recent study, done in Mayo Clinic, a total of 2899 patients who were identified as idiopathic cytopenia underwent bone marrow analysis and finally 10 patients among them fulfilled criteria for ICUS. Follow-up of 6 months revealed that more than half of these patients developed overt MDS, the finding of which made them group ICUS as a potential pre-MDS disorders and also proposed routine follow-up of these patients.⁶

The natural clinical course of ICUS is variable.⁷ Some may develop into MDS or myeloid neoplasms over time. In others the cytopenia may either resolve or may remain stable without needing any specific cytopenia directed therapy. Hence there is a need to follow up these patients regularly although no guidelines exist regarding the exact frequency of follow-up. Our patient was followed every 6 weekly in outpatient clinic and till to date she remained asymptomatic. Her cytopenia never worsened and remained stable. Although our patient presented with pancytopenia on admission, her white cell counts improved, and now has only bicytopenia.

Trial of different immunosuppressive therapy in our patient did not make any difference to the course of the disease. One theory behind the development of ICUS is the negative regulation of haemopoiesis induced by transforming growth factor-beta or tumour necrosis factor-alpha, produced by the immune cells in occult disease. Theoretically, immunosuppressive should be beneficial if this theory holds good.

Learning points.

• Idiopathic cytopenia is a diagnosis of exclusion.

• All cases of unexplained cytopenia should have a bone marrow evaluation as part of workup.

• Next-generation testing and florescent in situ hybridisation may be helpful in diagnosing evolving clonal mutation.

• Idiopathic cytopenia without clonal evolution is termed as idiopathic cytopenia of undetermined significance (ICUS) whereas cytopenia with clonal evolution is termed as clonal cytopenia of undetermined significance.

• All ICUS patients should be routinely monitored due to the slight risk of progression into myelodysplasia or myeloid neoplasm.