What are the typical clinical presentations of myelodysplastic syndrome (MDS) with trisomy 8?

Clinical Presentation of MDS with Trisomy 8

MDS with trisomy 8 presents with a distinctive clinical phenotype characterized by cytopenias (particularly macrocytic anemia), bone marrow dysplasia, and a strong association with auto-inflammatory/autoimmune manifestations, most notably Behçet's-like disease. 1, 2

Hematologic Manifestations

Cytopenias and Blood Count Abnormalities

• Macrocytic anemia is the predominant hematologic finding, often accompanied by cytopenias in other lineages 3
• Thrombocytopenia occurs in approximately 30% of cases and may be severe enough to cause bleeding complications 4
• Neutropenia may be present, though less commonly than anemia 1
• Peripheral blood smear may show dysplastic features including neutrophil hypersegmentation and macroovalocytosis 5

Bone Marrow Findings

• Bone marrow demonstrates dysplasia in ≥10% of cells in one or more myeloid lineages 1, 5
• Blast percentage varies depending on MDS subtype classification (MDS-SLD, MDS-MLD, MDS-EB-1, or MDS-EB-2) 1
• Cytogenetic analysis reveals trisomy 8 either as an isolated abnormality or with additional chromosomal changes 1

Auto-Inflammatory and Autoimmune Manifestations

Behçet's-Like Disease (Most Common)

• Behçet's-like disease occurs in approximately 52% of trisomy 8-MDS patients with inflammatory disorders, presenting with orogenital aphthosis, skin manifestations, and severe ulcerative digestive disease with ileocaecal distribution 2, 6
• This represents the dominant clinical phenotype among inflammatory manifestations associated with trisomy 8-MDS 2, 6

Other Inflammatory Presentations

• Recurrent fever is a hallmark feature, often accompanied by constitutional symptoms 3, 7
• Arthralgia and inflammatory arthritis occur in approximately 19% of cases with inflammatory disorders 2
• Gastrointestinal involvement beyond Behçet's-like disease, including inflammatory bowel disease-like presentations 3
• Elevated inflammatory markers, particularly hyperferritinemia, are characteristic findings 3
• Neutrophilic dermatoses including Sweet's syndrome 2, 6
• Less common manifestations include Sjögren's syndrome, autoimmune hemolytic anemia, aseptic abscesses, periarteritis nodosa, and unclassified vasculitis 2
• Pulmonary involvement with severe inflammatory pneumonitis has been reported, though less frequently 7

Temporal Relationship

• Auto-inflammatory features can occur before, concurrent with, or after the diagnosis of MDS 3, 6
• In some cases, clonal cytopenia with trisomy 8 presents with auto-inflammatory features without meeting full criteria for MDS (no dysplasia), representing a pre-MDS state 3

Prognostic Classification

IPSS-R Risk Stratification

• Trisomy 8 as a sole abnormality is classified as intermediate cytogenetic risk in the IPSS-R scoring system 1
• When trisomy 8 occurs with one additional abnormality, it remains intermediate risk 1
• Two or more additional cytogenetic abnormalities beyond trisomy 8 confer poor prognosis and are associated with higher overall mortality 8

Clinical Course

• The presence of inflammatory/autoimmune disorders does not impact overall survival or risk of progression to acute myeloid leukemia compared to trisomy 8-MDS without these features 2, 6
• Patients with inflammatory manifestations are more often non-European and have poor karyotype features 2

Key Diagnostic Considerations

Essential Workup

• Bone marrow aspirate with iron stain to assess dysplasia severity, enumerate blasts, and evaluate for ring sideroblasts 5
• Bone marrow trephine biopsy to assess cellularity, exclude fibrosis, and evaluate megakaryocytic dysplasia 5
• Cytogenetic analysis is mandatory to demonstrate trisomy 8 and identify additional chromosomal abnormalities 1, 5
• Vitamin B12 and folate levels to exclude nutritional causes, though these have limited sensitivity/specificity 5
• LDH, haptoglobin, and reticulocyte count to assess for hemolysis and ineffective erythropoiesis 5

Critical Pitfalls

• Peripheral blood smear alone is insufficient for MDS diagnosis and must be combined with bone marrow examination and cytogenetic analysis 5
• When dysplasia is subtle or equivocal, a 6-month observation period with repeat bone marrow investigation is recommended before confirming MDS diagnosis 5
• In patients with alcohol exposure history, careful evaluation is needed as alcohol is a recognized risk factor for MDS and can cause similar morphologic changes 5

Response to Immunosuppression

Treatment Patterns

• Glucocorticoids are effective for controlling inflammatory manifestations in 81% of treated patients, with complete response in 35% and partial response in 47% 2
• However, glucocorticoid tapering is often difficult, necessitating steroid-sparing strategies 3, 2
• JAK inhibitors show promise as anti-inflammatory agents with glucocorticoid-sparing effects and good tolerance 3
• Traditional immunosuppressive therapies including TNF-α inhibitors are usually ineffective 6
• Azacitidine targeting the underlying clonal disease achieves remission in 71% (5/7) and partial response in 29% (2/7) of patients with inflammatory manifestations, representing the most effective strategy even in low-risk MDS 2, 6
• Anti-thymocyte globulin (ATG) may be considered in select younger patients (<65 years) with normal karyotype or trisomy 8, short transfusion history, and HLA-DR15 genotype 1