MDS/MPN associated with SP3B1 mutation, thrombocytosis (circular siderocytes (10%) (SF3B1 40.5%, ASXL 19.8%, JAE2 R683G 17.5%, CBL 16.2%)).
MDS/MPN associated with SP3B1 mutation, thrombocytosis (circular siderocytes (10%) (SF3B1 40.5%, ASXL 19.8%, JAE2 R683G 17.5%, CBL 16.2%)).
JAK2, ASXL1, SF3B1, and CBL four mutations in bone marrow ringed siderocytes <15% of myelodysplastic/myeloproliferative neoplasm
summary
Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) is a clonal hematopoietic stem cell disease. It has dual characteristics of myelodysplastic (MDS) and chronic myeloproliferative neoplasm (MPN), that is, it has the pathologic hematopoiesis (dysplasia) and ineffective hematopoiesis of MDS, as well as the proliferation of a series or multiple series of cells in MPN causing an increase in blood cells. We report a case of MDS/MPN-SF3B1-T with four mutations in JAK2, ASXL1, SF3B1, and CBL to understand the new diagnostic criteria and improve the understanding of this type of disease.
case presentation
Patient, female, 72 years old, feeling increasingly weak, visited our hospital on 2024-07-23. Physical examination: body temperature 36.2°C, pulse 72 beats/min, respiration 18 times/min, blood pressure 115/63mmHg, no pallor of the skin and mucous membranes, no jaundice of the sclera, no rash or subcutaneous hemorrhagic spots on the skin and mucous membranes, superficial lymph nodes not palpable for enlargement, sternum without tenderness, bilateral lung breath sounds clear, no dry or wet rales heard, abdomen flat and soft, bowel sounds normal, no tenderness or rebound tenderness, liver and spleen not palpable, bilateral renal areas negative for percussion tenderness, no edema in the lower extremities.
investigations
Assistive Examination: Blood routine: White blood cells 7.54 x 10^12/L, Red blood cells 3.18 x 10^12/L, Hemoglobin 91g/L, Platelets 502 x 10^9/L. Anemia panel: Ferritin 317.40ng/mL, Erythropoietin 32.27mIU/mL;
Bone marrow smear staining: The proliferation of bone marrow nucleated cells is still active, with granulocytes accounting for 47.5%, erythrocytes for 37.5%, granulocytes to erythrocytes ratio of 1.27:1; granulocytes: intermediate and early myelocytes are visible, intermediate and late myelocytes and bacillary nuclear cells are underrepresented, segmented nucleated granulocytes are overrepresented, cell morphology in all stages is generally normal, eosinophils are visible; erythrocytes: early erythrocytes are visible, late erythrocytes are overrepresented, erythroblast morphology is generally normal, mature erythrocytes are of unequal size; lymphocytes are underrepresented, cell morphology is generally normal; 3 megakaryocytes are visible throughout the slide, platelets are clumped and in excess; iron staining: external iron, only one bone marrow nodule is (+), internal iron positivity rate is 74%, with 10% of the ringed sideroblasts. Bone marrow biopsy: collagen fiber proliferation is visible in the bone marrow stroma. Immunohistochemistry: (Bone marrow biopsy) erythrocytes are slightly more visible, primitive cell proliferation is not obvious, abnormal megakaryocytic hematopoiesis is not obvious, MF2 grade fibrosis is visible. Flow cytometry: Flow cytometry results show that CD34+ and CD117+ cells account for approximately 0.12% of the nucleated cells, the proportion is not high, and no significant immunophenotypic abnormalities are seen. The relative proportion of granulocytes is normal, and the immunophenotypes CD13, CD16, CD15, CD11b show no significant expression disorder. Bone marrow karyotype analysis conclusion: 46,XX[20]. Gene mutation frequency test results: SF3B1 40.5%, ASXL 19.8%, JAK2 R683G 17.5%, CBL 16.2%.
treatment
Currently, the patient only has mild anemia, occasionally feels fatigue, but generally does not affect daily life, no special treatment has been given, and blood routine tests are reviewed regularly.
outcome and follow-up
(2024-08-26) Routine blood test: White blood cells 8.33×10^9/L, red blood cells 3.43×10^12/L, hemoglobin 97g/L, platelets 487×10^9/L.
discussion
In 2001, the WHO myeloid neoplasm classification formally proposed the MDS/MPN disease classification. In 2008, refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T) was set as one of the provisional subtypes, temporarily categorized under MDS/MPN-U, with diagnostic criteria consisting of only two clinical and hematological features. In 2016, following the cancellation of the name refractory anemia (RA) in the MDS classification, the disease was correspondingly changed to MDS/MPN tumor with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), to highlight the characteristics of the overlapping MDS/MPN syndrome, and confirmed the existence of this subtype as a disease entity. In recent years, with the in-depth study of the molecular characteristics of hematological tumors, the World Health Organization (WHO) has continuously revised and refined the relevant classification criteria, introducing the new name MDS/MPN-SF3B1-T in the 2022 WHO classification. According to the diagnostic criteria of MDS/MPN-RS-T in the new classification, it can be seen that MDS/MPN-RS-T commonly presents with SF3B1 mutations (85% to 90%) and JAK2 mutations (33% to 77%), which can occur alone or simultaneously. Approximately 50% of MDS/MPN-RS-T patients have both SF3B1 and JAK2 mutations, which provides an interesting genetic explanation for the hybrid nature of MDS/MPN-RS-T between MDS and MPN. MDS-RS with multilineage dysplastic hematopoiesis often shows SF3B1 mutations, and ringed sideroblasts are commonly associated with SF3B1 mutation genes. If the percentage of ringed sideroblasts in nucleated red blood cells is ≥5% and there is an SF3B1 mutation, the diagnosis of MDS-RS can still be established; conversely, if the SF3B1 mutation is negative, the ringed sideroblasts need to be ≥15% to make a diagnosis of MDS-RS. Unlike MDS-RS, in MDS/MPN-RS-T, even if there is an SF3B1 gene mutation, it still requires the proportion of ringed sideroblasts to reach above 15%. SF3B1 mutations may be related to mitochondrial iron overload in sideroblasts, ineffective hematopoiesis, anemia (characteristics of MDS), while JAK2 and MPL mutations are related to thrombocytosis (characteristics of MPN). MDS/MPN-SF3B1-T not only includes traditional MDS/MPN-RS-T patients but also expands the diagnostic criteria to include patients with bone marrow RS <15% but with SF3B1 mutations. This revision reflects the researchers' emphasis on molecular characteristics in disease classification, providing a more precise basis for clinical diagnosis and treatment.
MDS/MPN-RS-T clinical features are similar to MDS-RS and essential thrombocythemia, with patients potentially having liver and spleen enlargement. However, MDS/MPN-RS-T patients often have higher hemoglobin levels, white blood cell (WBC) counts, and platelet counts compared to MDS-RS patients. Conversely, the hemoglobin levels, white blood cell counts, and platelet counts of MDS/MPN-RS-T patients are often lower than those of essential thrombocythemia patients. Additionally, some MDS/MPN-RS-T patients have bone marrow fibrosis. The incidence of thrombosis in MDS/MPN-RS-T patients is higher, and studies have shown that low-dose aspirin can reduce the risk of arterial thrombosis when platelet counts are below 1000 × 109/L, benefiting the patients.
Currently, there is no specific treatment plan for MDS/MPN-RS-T patients. The treatment plans for MDS and MPN are also applicable to such patients, and the use can be selected based on clinical conditions.
Prognosis-wise, the prognosis of reported MDS/MPN-RS-T cases is better than that of other types of MDS/MPN. One study shows that the survival period ranges from 5 to 233 months. According to a large-scale study by Broseus et al., the median overall survival (OS) of MDS/MPN-RS-T patients is better than that of RARS patients (76 months vs. 63 months), but lower than that of ET patients (117 months). The leukemia transformation rates of MDS/MPN-RS-T (1.8/100 per year) and RARS (2.4/100 per year) are similar, and the leukemia transformation rate of MDS/MPN-RS-T is higher than that of ET (0.7/100 per year). The study shows that, compared with RARS, in the multivariate analysis of 82 patients, the SF3B1 mutation seems to have no prognostic impact on MDS/MPN-RS-T.
Studies abroad have shown that patients with MDS/MPN-SF3B1-T and bone marrow RS <15% have a significantly poorer prognosis
Molecular abnormalities (such as ASXL1, SF3B1, and JAK2 V617F mutations) are not independent prognostic factors for survival in MDS/MPN-RS-T patients. However, age ≥70 years (P=0.006), hemoglobin (Hb) ≤10 g/dL (P=0.03), and abnormal karyotype (P=0.008) are associated with shorter overall survival.
However, previous researchers have believed that SF3B1 mutations are causally associated with MDS and MDS/MPN with increased RS. Therefore, these contradictory results further emphasize the importance of further investigating the role of SF3B1 mutations and other gene mutations in the pathogenesis of MDS/MPN-SF3B1-T.
This patient exhibits pathological hematopoiesis in the granulocytic, erythroid, and megakaryocytic series of bone marrow cells, with 10% of ringed sideroblasts. The karyotype is normal, and there are gene mutations of SF3B1 40.5%, ASXL19.8%, JAE2 R683G 17.5%, and CBL16.2%. Platelet count is also significantly increased, and it has characteristics of both MDS and MPN, consistent with the diagnosis of MDS/MPN-SF3B1-T.
In summary, the WHO revised the classification of MPN, MDS/MPN in 2016, formally establishing MDS/MPN-RS-T as an independent new subtype, highlighting the characteristics of the MDS/MPN overlap syndrome. In 2022, the WHO classification introduced MDS/MPN-SF3B1-T, expanding its diagnostic criteria. MDS/MPN-SF3B1-T is clinically rare, with non-specific clinical manifestations. Bone marrow pathological examination, iron staining, and genetic testing are crucial for disease diagnosis, while the role of genetic mutations in the occurrence and development of the disease still needs further study. Clinicians need to enhance their understanding to reduce missed and misdiagnoses.