Myeloproliferative Neoplasms in Children

Abstract

Myeloproliferative neoplasms (MPN) are a group of clonal hematopoietic stem cell disorders characterized by aberrant proliferation of one or more myeloid lineages often with increased immature cells in the peripheral blood. The three classical BCR-ABL-negative MPNs are: 1) polycythemia vera (PV), 2) essential thrombocythemia (ET), and 3) primary myelofibrosis (PMF), which are typically disorders of older adults and are exceedingly rare in children. The diagnostic criteria for MPNs remain largely defined by clinical, laboratory and histopathology assessments in adults, but they have been applied to the pediatric population. The discovery of the JAK2 V617F mutation, and more recently, MPL and CALR mutations, are major landmarks in the understanding of MPNs. Nevertheless, they rarely occur in children, posing a significant diagnostic challenge given the lack of an objective, clonal marker. Therefore, in pediatric patients, the diagnosis must rely heavily on clinical and laboratory factors, and exclusion of secondary disorders to make an accurate diagnosis of MPN. This review focuses on the clinical presentation, diagnostic work up, differential diagnosis, treatment and prognosis of the classical BCR-ABL-negative MPNs (PV, ET and PMF) in children and highlights key differences to the adult diseases. Particular attention will be given to pediatric PMF, as it is the only disorder of this group that is observed in infants and young children, and in many ways appears to be a unique entity compared to adult PMF.

Keywords: Myeloproloferative neoplasms; essential thrombocythemia; pediatric myeloproliferative neoplasms; polycythemia vera; primary myelofibrosis.

Fig 1. Histopathology of Pediatric Essential Thrombocythemia (ET)

A–C) Representative images from the marrow of a 18-year-old female with marked thrombocytosis of 1,200 ×10⁹ cells/L. The hemoglobin was normal. No organomegaly was present. The BM karyotype was normal. Molecular studies confirmed a JAK2V617F mutation. Given the clinical and histopathologic features the patient was diagnosed with ET. (A) Bone marrow (BM) aspirate showing increased megakaryocytes (200x) and (B) frequent platelets (1000x). (C) BM biopsy showing a normocellular marrow for age with increased megakaryocytes occurring in small clusters and include large forms with “cloud-like” atypical nuclei (400x). (D–F) Representative images of a 9-year-old female with thrombocytosis and splenomegaly (WBC 9.9 ×10⁹ cells/L, Hgb 13.7 g/dL, MCV 80.4 fL, platelet count 847 ×10⁹ cells/L). Karyotype was normal. Molecular analysis was negative for BCR-ABL, but showed a JAK2 V617F mutation. The patient was initially diagnosed with MPN most consistent with ET based on the histologic findings, but over time developed increasing Hgb with concern for possible polycythemia vera. (D) BM aspirate with clusters of atypical megakaryocytes (400x). (E) BM biopsy shows a normocellular marrow for age with maturing myeloid and erythroid elements and increased eosinophils. Megakaryocytes are markedly increased and occurring in loose clusters. Large hyperlobated forms as well as condensed nuclear lobes are noted. Increased blasts (confirmed by CD34 and CD117 staining, not shown) were not noted (400x). (E) Reticulin stain shows only minimal to mild diffuse increase in reticulin (400x).

Figure 2. Myeloproliferative neoplasm (MPN) due to CALR mutation

Images of a 14-year-old female presenting with marked thrombocytosis and mild leukocytosis with increased myeloid precursors and nucleated red blood cells on her peripheral smear. Blood counts at presentation showed WBC 11 ×10⁹ cells/L (72% neutrophils, 25% lymphocytes, 2% metamyelocytes, 1% atypical lymphocytes), Hgb 11.3 g/dL, MCV 73, platelets 1,218 ×10⁹ cells/L. No splenomegaly present on exam. Karyotype was normal. Molecular analysis was negative for BCR-ABL, JAK2 V617F and MPL, but revealed a deletion type CALR mutation. The images show both features of essential thrombocythemia (ET) (large atypical often hyperlobated megakaryocytes) and primary myelofibrosis (PMF) (moderate increase in reticulin in increased vasculature) highlighting the fact that the histologic differential in these disorders is not always straightforward. (A) and (B) display representative images of the bone marrow (BM) biopsy showing a markedly hypercellular marrow for age with an increased myeloid to erythroid ratio and a marked increase in megakaryocytes, which occur in larger clusters with marked variation in size. Small forms with condensed chromatin as well as large forms with abnormal chromatin clumping and occasional markedly hyperlobated forms are see (200x and 400x). (C) and (D) Reticulin stain shows overall diffuse moderate increase in reticulin with marked perivascular fibrosis (200x and 400x). (E) CD61 highlights markedly increased atypical megakaryocytes occurring in clusters. CD61 is also positive in associated platelets that are increased (200x). (F) CD34 shows increased dilated vessels (200x).

Figure 3. Congenital Familial Myelofibrosis

Representative images from the bone marrow (BM) aspirate and biopsy of a 10-months-old male with the diagnosis of primary congenital familial myelofibrosis. The patient presented with easy bruising and petechiae on 2^nd day of life. He had an older brother with congenital myelofibrosis leading to high suspicion for a familial disorder. Blood counts showed mild leukocytosis of 12.56 ×10⁹ cells/L with 43% neutrophils, 41% lymphocytes, 12% monocytes, 2% eosinophils and 3% basophils. The Hgb was 8.4g/dL and the platelet count was 17×10⁹ cells/L. Cytogenetic and FISH studies showed a normal karyotype and were negative for monosomy 7, trisomy 8 and 5q-. Molecular studies were negative for JAK2 V617F, MPL and VPS45 mutations. A–E) The BM was aspicular and hypocellular secondary to difficult aspiration. Maturing myeloid and erythroid elements were noted with many hyperlobated neutrophils. Vitamin B12 and folate deficiency was ruled out. Background mature erythrocytes show anisiopoikilocytosis including microcytes, macrocytes, target cells, elliptocytes, pencil cells, acanthocytes and teardrop forms. Hypochromasia and Howell-Jolly body-like inclusions are also noted (1000x). F–L) Representative BM biopsy from the same patient. F and G) shows H&E images demonstrating a normo- to hypercellular marrow for age with moderate megakaryocytic hyperplasia occurring in loose clusters with dysmorphic features, including large forms, “cloud-like” nuclei and occasional small forms (400x). (H) Reticulin was moderately increased in particular in association with the megakaryocyte clusters (200x). (I) Immunohistochemistry (ICH) for CD34 shows no increase in blasts, but vascular proliferation, focal liminal distension and occasional intrasinusoidal hematopoietic elements (200x). (J) CD61 highlights clusters of atypical megakaryocytes with associated increase in platelets (200x). K) CD71 highlights erythroid precursors, minimally decreased (200x). L) CD68 is positive in scattered histiocytes but also highlights osteoclasts (200x).