Pediatric bone marrow myelofibrosis (MF) is a rare and complex hematological disorder characterized by cytopenia, bone marrow fibrosis, and systemic symptoms such as bone pain and fever. Unlike its adult counterpart, pediatric MF exhibits diverse etiologies, variable clinical presentations, and different therapeutic responses. The rarity and heterogeneity of this condition pose significant challenges in diagnosis and treatment. In clinical practice, pediatric MF is classified into three main categories: primary myelofibrosis (PMF), myelofibrosis secondary to non-neoplastic or neoplastic disorders, and idiopathic myelofibrosis. Due to the lack of consensus on diagnostic criteria and management, refining classification systems and integrating clinical, pathological, and genetic findings are crucial for guiding therapy. This review summarizes existing literature and proposes a diagnostic algorithm to differentiate pediatric MF subtypes, ultimately improving patient outcomes.
Diagnostic Workup of Primary Myelofibrosis (PMF)
PMF is an extremely rare chronic myeloproliferative neoplasm in children, presenting with cytopenia, hepatosplenomegaly, bone marrow fibrosis, and systemic symptoms. Unlike essential thrombocythemia or polycythemia vera, which rarely progress to MF in children, PMF remains poorly characterized due to limited data. Reports indicate a male predominance and a median age of diagnosis around 3.4 years. Despite extensive studies on adult PMF, pediatric cases lack clear molecular and histopathological definitions. Studies have identified CALR and MPL mutations in some cases, but many remain triple-negative (JAK2, CALR, MPL). The revised World Health Organization (WHO) and International Consensus Classification do not distinguish pediatric PMF from adult PMF due to the overlapping features. However, given the limited number of cases, further research is needed to establish distinct diagnostic criteria for pediatric PMF.
Diagnostic Workup of Myelofibrosis Secondary to Non-Neoplastic or Neoplastic Disorders
Secondary myelofibrosis is more common in children than PMF and can result from non-neoplastic (e.g., autoimmune) or neoplastic disorders (e.g., leukemia, lymphoma). Among non-neoplastic causes, autoimmune myelofibrosis (AIMF) is a notable etiology, often associated with autoimmune syndromes or autoantibodies. Children with AIMF may show spontaneous resolution or respond to immunomodulatory therapy. AIMF typically presents with mild-to-moderate bone marrow fibrosis, a lack of somatic mutations in JAK2, MPL, or CALR, and an absence of malignant transformation. Histological features, such as polytypic plasmacytosis and lymphoid aggregates, help differentiate AIMF from PMF. However, refractory AIMF cases may require next-generation sequencing (NGS) to rule out rare genetic disorders.
Among neoplastic causes, myelofibrosis can be observed in hematopoietic malignancies such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and lymphomas. Bone marrow involvement in Hodgkin and non-Hodgkin lymphomas frequently presents with fibrosis and cytopenia. Differentiating MDS with fibrosis from PMF is particularly challenging, as both may exhibit atypical megakaryocytes. Chromosomal abnormalities and somatic mutations are key markers for distinguishing MDS from AIMF. Pediatric patients with MDS or PMF often require hematopoietic stem cell transplantation (HSCT) for definitive treatment.
Diagnostic Workup of Idiopathic Myelofibrosis
Idiopathic MF is a diagnosis of exclusion, applied when both PMF and secondary MF are ruled out. A retrospective review of 122 pediatric cases initially classified as idiopathic MF revealed that many had underlying hematologic malignancies or autoimmune disorders upon further examination. Infectious, thromboembolic, and hemorrhagic complications were commonly observed.
Given the potential for disease progression, careful follow-up with repeated bone marrow biopsies and molecular studies is recommended. Case studies illustrate the importance of serial assessments, as patients initially diagnosed with idiopathic MF may later develop acute leukemia. Advanced genetic panels, including germline and somatic mutation analyses, provide critical insights into the disease course.
Conclusion
Pediatric myelofibrosis encompasses a heterogeneous group of disorders with distinct clinical and pathological features. Given its rarity, diagnostic uncertainty remains a major challenge, necessitating a multidisciplinary approach integrating clinical, histological, and molecular findings. The proposed diagnostic algorithm offers a structured approach to classifying and managing pediatric MF. Future multi-institutional collaborations are essential to establish standardized guidelines for diagnosis and treatment, ultimately improving patient outcomes.
Full text
https://www.xiahepublishing.com/2771-165X/JCTP-2024-00035
The study was recently published in the Journal of Clinical and Translational Pathology .
Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.
