Hematology Quiz on Megakaryocytes and JAK2 Pathway

Platelet Count and Bone Marrow Findings

• Platelet count of ≥ 450 × 10^9/L can indicate a myeloproliferative neoplasm.
• Bone marrow biopsy shows proliferation of megakaryocytes, characterized by enlarged, mature forms with hyperlobulated nuclei.
• No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis; minimal increase in reticulin fibers is sometimes observed.
• WHO criteria for conditions like BCR-ABL1-positive CML, polycythemia vera (PV), primary myelofibrosis (PMF), and other myeloid neoplasms are not met.
• Presence of mutations in JAK2, CALR, or MPL is indicative of myeloproliferative neoplasms.

Minor Criteria for Diagnosis

• Clonal markers must be present to support a diagnosis.
• Reactive conditions must be excluded.

Primary Myelofibrosis (PMF)

• Unfavorable karyotype features include complex karyotype, inv(3), monosomy 5, del(5q), monosomy 7, del(7q), and others.
• Prefibrotic PMF requires three major criteria and at least one minor criterion from two consecutive biopsies.

Major and Minor Criteria for PMF

• Major criteria include megakaryocytic proliferation and atypia with reticulin/collagen fibrosis graded 2 or 3.
• Minor criteria may include leukoerythroblastosis.

Fibrosis Grades in PMF

• MF-0: Normal reticulin with no intersections; normal collagen.
• MF-1: Loose reticulin network with focal collagen deposition.
• MF-2: Dense reticulin with extensive intersections and occasional osteosclerosis.
• MF-3: Dense reticulin with coarse bundles of collagen, causing osteosclerosis and effacement of marrow spaces.

Juvenile Myelomonocytic Leukemia (JMML)

• Splenomegaly present in approximately 90% of cases at diagnosis.
• Commonly associated with thrombocytopenia.
• Aberrant blast populations display specific surface markers (CD7, reduced CD13/CD33).
• Poor prognosis linked to age over 2 years, low platelet counts, high hemoglobin F levels, or LIN28B overexpression.
• Around 25% of cases involve germline mutations, with PTPN11 or KRAS mutations leading to aggressive disease presentation.

Associated Syndromes

• Neurofibromatosis Type 1 (NF1): Characterized by xanthomas and café-au-lait spots.
• Noonan Syndrome: Features facial dysmorphia, congenital heart defects, and a possible link to JMML through PTPN11 mutations.
• CBL: Linked to autoimmune conditions and Noonan syndrome-like disorders.

Clinical and Genetic Criteria for JMML

• All clinical, hematological, and laboratory criteria must be met alongside at least one genetic marker from the RAS pathway (e.g., PTPN11, KRAS mutations).
• Absence of significant monocytosis and eosinophilia required for diagnosis.

Myeloproliferative Neoplasm NOS

• Diagnosis requires all three criteria suggesting MPN features, without significant monocytosis or eosinophilia.
• Bone marrow hypercellularity must occur without dysplastic features.

Mastocytosis

• Cutaneous Mastocytosis:

  • Adults primarily exhibit KIT p.D816V mutation, while children may have various KIT mutations or be wild-type.
  • Subtypes include maculopapular cutaneous mastocytosis and diffuse cutaneous mastocytosis, each with distinct clinical features.

• Systemic Mastocytosis:

  • Requires multifocal mast cell infiltrates and specific minor criteria for diagnosis, including aberrant expression of CD2, CD25, and CD30, along with elevated serum tryptase levels.

Diagnostic Considerations

• Essential criteria: specific cutaneous lesions and skin biopsies showing increased mast cells.
• Desirable criteria include aberrant mast cell immunophenotype and detection of KIT mutations in lesions.

Differential Diagnostic Features

• Subtype variants in systemic mastocytosis based on morphologic and diagnostic criteria differentiate between well-differentiated and aggressive presentations, including extensive mast cell involvement and elevated tryptase levels.### Rosai-Dorfman Disease
• Characterized by large histiocytes with round nuclei, prominent nucleoli, and abundant pale cytoplasm; often exhibits emperipolesis.
• Background contains abundant plasma cells; S100 immunostaining highlights emperipolesis.
• In cases that are difficult to diagnose, expression of OCT2 and cyclin D1 may be present without CD1a, CD207 (Langerin), or ALK.
• Associated with germline mutations in SLC29A3 (H syndrome/Faisalabad histiocytosis) and heterozygous mutations in FAS (TNFRSF6) leading to autoimmune lymphoproliferative syndrome.

Subtypes of Rosai-Dorfman Disease

• Classic (nodal) RDD: Most common; primarily involves cervical (>87%), inguinal (26%), axillary (24%), and mediastinal (15%) lymph nodes.
• Extranodal RDD: Affects 43% of patients, primarily in the nasal cavity, sinuses, salivary glands, skin, soft tissue, upper respiratory tract, bone, retro-orbital tissue, and CNS; rare splenic involvement.
• Familial RDD: Linked to germline mutations in SLC29A3 (20%) and FAS (41%).
• Neoplasia-related RDD: Associated with lymphoma, leukemia, and other histiocytoses like Langerhans cell histiocytosis.
• Immune-related RDD: Associated with systemic lupus erythematosus (SLE), juvenile arthritis, autoimmune hemolytic anemia, and HIV, often showing increased IgG4+ plasma cells.

ALK-Positive Histiocytosis

• Identified by tissue infiltration of histiocyte aggregates lacking high-grade atypia.
• Positive for multiple histiocytic markers (CD163, CD68, CD14, CD4, lysozyme).
• Histiocytes demonstrate ALK positivity (cytoplasmic pattern), rarely nuclear patterns.
• Associated chromosomal abnormalities include the Philadelphia chromosome and various monosomies and trisomies.

B-lymphoblastic Leukemia/Lymphoma Classes

• BCR::ABL1-like Features: 50% have rearrangements of CRLF2 linked with poor response to treatment.
• KMT2A Rearrangement: Linked to unfavorable prognosis; typically shows distinct immunophenotype.
• ETV6::RUNX1 Fusion: Most common and favorable; frequent expression of myeloid-associated antigens.
• TCF3 rearrangements: Several defined variants with diverse prognoses, including TCF3::PBX1 and TCF3::HLF fusions linked to aggressive clinical presentations.
• Other Genetic Alterations: Various subtypes with unique genetic features and differential prognoses, e.g., DUX4 with monocytic differentiation and potentially better outcomes.

Preneoplastic and Neoplastic Small Lymphocytic Proliferations

• Monoclonal B-cell Lymphocytosis: Defined by absolute monoclonal B cell count; identified by specific immunophenotypes and associated genetic alterations.
• Richter Transformation: Can lead to transformation into DLBCL or classic Hodgkin lymphoma; must differentiate from reversible transformation linked to ibrutinib treatment.
• Genetics at Transformation: Often involves complex karyotype, del(17p), or MYC rearrangement.

Marginal Zone Lymphoma

• Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT): Displays features resembling Peyer’s patch lymphoid tissue, highlighting its origin from mucosal-associated lymphoid tissue.

Prognostic Indicators in CLL

• Genetic factors play a significant role, with del(13q) indicating good prognosis, while del(17p) and certain mutations signal poor outcomes.
• Prognostic variables include CD38 and Zap 70 levels, reflecting underlying genetic profiles in chronic lymphocytic leukemia outcomes.

Test your knowledge on platelet counts and bone marrow findings related to megakaryocytes. This quiz covers the criteria for various myeloid neoplasms including CML, PV, and PMF, along with the significance of JAK2 mutations. Prepare to dive deep into hematological concepts and determine your understanding of these critical components.