Bone marrow morphology and disease progression in congenital thrombocytopenia: a detailed clinicopathologic and genetic study of eight cases

Abstract

Patients with congenital thrombocytopenia have an increased risk of developing myeloid neoplasms. In these cases, the morphologic distinction between disease at baseline and at progression is challenging. This report analyzes clinicopathologic features of congenital thrombocytopenia with long-term follow-up at one referral center. Records from the last 20 years were searched for cases of congenital thrombocytopenia with bone marrow biopsies and peripheral blood smears. The clinical, morphologic, immunophenotypic, and molecular features were analyzed. Six adult and two pediatric patients were identified (six male, two female). Age range at first biopsy was 1-47 (median, 31) years. Underlying diseases included thrombocytopenia-absent radius syndrome, congenital thrombocytopenia with radial-ulnar synostosis, MYH9-related disorder, shortened telomere syndrome, congenital thrombocytopenia with ANKRD26 mutation, and familial platelet disorder with predisposition to acute myeloid leukemia. Four patients had myelodysplastic/myeloproliferative neoplasm-like marrow changes such as hypercellularity, increased myeloid to erythroid ratio, numerous micromegakaryocytes (highlighted by CD42b), and marrow fibrosis. Two patients had marrow hypoplasia and two had unremarkable marrow morphology. Three patients-all in the myelodysplastic/myeloproliferative neoplasm-like group-developed disease progression characterized by erythroid and myeloid dysplasia, elevated bone marrow blasts, and new cytogenetic abnormalities. Unlike non-familial myeloid neoplasms, congenital thrombocytopenia patients in the myelodysplastic/myeloproliferative neoplasm-like group had a long and indolent clinical course (average age at disease progression, 47 years). In summary, three distinct morphologic types of congenital thrombocytopenia were identified: a hyperplastic myelodysplastic/myeloproliferative neoplasm-like group, a hypoplastic bone marrow failure-like group, and a group with relatively normal marrow morphology. Emergence of cytogenetic abnormalities and dysplasia in non-megakaryocyte lineages correlated with disease progression.

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…Bone marrow biopsies show increased reticulin fibrosis and increased numbers of dysplastic megakaryocytes, including micromegakaryocytes and/or hypolobated megakaryocytes. 37,38,40 The presence of megakaryocytic dysplasia may pose a diagnostic challenge to differentiation of thrombocytopenia in the setting of germline ANKRD26 mutation versus MDS.…”

“…60 Bone marrow biopsy may show moderately increased reticulin fibrosis, notable myeloid dysplasia, and megakaryocytic lineages characterized by predominantly small, hypolobated, dysplastic-appearing forms. 40 The affected families may have anticipation with progressive shortening of the telomeres in passing generations and show worsening phenotype. 58 In addition to predisposition to MDS/AML, the telomere disorders may be associated with a variety of solid tumors, including squamous cell carcinoma and stomach, lung, esophageal, and colon cancers.…”

Myeloid Neoplasms with Germline Predisposition

“…The BM is usually hypocellular for age and characterized by abnormal megakaryopoiesis (Fig. 1) [17,18]. Frequent eosinophilia has also been noted.…”

“…The myeloid neoplasms correspond predominantly to MDS/AML. Rare cases of CML, CMML, or chronic lymphocytic leukemia have also been described [18,[20][21][22], with BM morphology findings reported in 6 patients. All cases were characterized by prominent megakaryocytic atypia with an increased number of small hypolobated megakaryocytes (Fig.…”

“…A recent study undertaken at the Weill Cornell Medical College included detailed BM biopsy evaluations in a cohort of 8 patients with various entities within the group of congenital thrombocytopenia followed for up to 50 years [18]. The majority of patients had atypical, small, hypolobated megakaryocytes on the first BM biopsy (Fig.…”