Category Archives: MDS/MPN

Bone Marrow, MDS, MDS/MPN, MPN

Myelofibrosis – Etiologies

Myelofibrosis is characterized by (typically) increased reticulin fibrosis or (less commonly) collagen fibrosis (trichrome stain). Hematologic malignancies are often leading culprits, but consideration of other etiologies should be considered.

The following categories and entities should be considered with the finding of myelofibrosis.

Infectious diseases
  • Tuberculosis
Autoimmune disorders
  • Systemic lupus erythematosus (SLE)
  • Sjogren’s syndrome (SS)
  • Systemic sclerosis
  • Primary autoimmune myelofibrosis
  • Connective tissue disease
Drug associated conditions
  • Thrombopoietin receptor agonist toxicity
Endocrine disorders
  • Hyperparathyroidism (primary or secondary)
  • Vitamin D deficiency (nutritional or rickets)
  • Osteomalacia
Hematologic malignancies
Other hematologic malignancies
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Gray platelets syndrome
Other
  • Primary hypertrophic osteoarthropathy
  • Paget disease
  • Metastatic solid tumor malignancies
Myelofibrosis Grading
Grade
Comment
Scattered linear fibers without intersections.  Normal bone marrow.
MF1
Loose network of reticulin fibers with intersections (particularly perivascular)
Diffuse increase of reticulin fibers with increased density and numerous intersections.  Focal bundles of thick fibers.
Diffuse increase of reticulin fibers with increased density and numerous intersections.  Increased thick bundles of fibers consistent with collagen fibrosis.  Osteosclerosis usually present.

In cases of MF2 or MF3, it is recommended to perform trichrome stain to evaluate for collagen fibrosis.

References

Marcellino B, Jamal El SM, Mascarenhas JO. Distinguishing autoimmune myelofibrosis from primary myelofibrosis. Clin Adv Hematol Oncol. 2018;16: 619–626.

Organ Systems, Bone Marrow, WHO Classification, MDS/MPN

MDS/MPN-RS-T

 
Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a hybrid myeloproliferative and myelodysplastic neoplasm that contains thrombocytosis and ring sideroblasts.  There are also generally characteristic clinical and molecular abnormalities.
Diagnostic Criteria
  • Anemia with erythroid dysplasia (+/- multilineage dysplasia)
    • <1% blasts in the peripheral blood
    • <5% blasts in the bone marrow
    • ≥15% ring sideroblasts
  • Platelet count >/= 450 K, which is persistent
  • Does not meet the criteria for another hematopoietic neoplasm, specifically:
    • BCR–ABL1 negative
    • No PDGFRA, PDGFRB, FGFR1 rearrangements
    • PCM1–JAK2 negative
    • No t(3;3)(q21.3;q26.2), inv(3)(q21.3q26.2), or del(5q)
  • No history of a myeloproliferative and/or myelodysplastic neoplasm.  There is an exception for a previous history of MDS with ring sideroblasts (MDS–RS).
Clinical Features
  • Anemia: Usually milder than that typically associated with myelodysplasia
  • Splenomegaly is present in approximately 40% of cases
Molecular Features
  • Cytogenetic abnormalities – 10% of cases
  • SF3B1 mutation – 60-90% of cases
    • >60% of cases have JAK2 mutation
    • <10% of cases have associated CALR or MPL mutations
References
Gurevich I, Luthra R, Konoplev SN, Yin CC, Medeiros LJ, Lin P. Refractory anemia with ring sideroblasts associated with marked thrombocytosis: a mixed group exhibiting a spectrum of morphologic findings. Am J Clin Pathol. 2011;135: 398–403. doi:10.1309/AJCPT0B6VEQPRCOA
 
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127: 2391–2405. doi:10.1182/blood-2016-03-643544
 
Swerdlow SH, Campo E, Harris, NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds); WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition). IARC: Lyon 2017
Organ Systems, Bone Marrow, WHO Classification, MDS, MDS/MPN

SB3F1 Mutation

  • SB3F1 is a RNA splicesome, mutated SB3F1 may result in an alternative function proteins instead of a loss of function mutation (Obeng, et al.)  
  • Point mutations associated with MDS are in the regions of exons 14 to 16
  • ~25% of all cases of MDS have a SB3F1 mutation
  • ~80% of MDS-RS SLD have SBF3F1 mutation
  • 30-70% of MDS-RS MLD have SB3F1 mutation
  • 20% of MDS/MPN cases have SB3F1 mutation
  • Heterozygous mutation of SB3F1 mutation is associated with disease
  • Obeng et al. demonstrated in mice that an isolated SB3F1 mutation is sufficient to cause MDS-type findings
  • The presence of a SB3F1 mutation has a positive predictive value (PPV) of finding ring sideroblasts of 97.7%.

Continue reading SB3F1 Mutation →

Organ Systems, Bone Marrow, WHO Classification, MDS/MPN, MPN

Chronic Neutrophilic Leukemia (CNL)

Diagnostic Criteria
  • Activating CSF3R mutation (usually T618I or T615A)
  • WBC ≥ 25,000 (at least 80% neutrophils + bands, <10% neutrophil precursors)
    • No dysgranulopoiesis or monocytosis (<1,000/μL)
  • Bone marrow hypercellularity
    • <5% blasts
    • Increased granulopoiesis
    • No evidence of dysgranulopoiesis
  • No molecular abnormalities or diagnostic characteristics of another MPN or MPN/MDS

If a CSF3R mutation is NOT identified, the diagnosis of CNL can still be made if other reactive causes are excluded or other evidence of clonality is identified (persistent for at least 3 months). Continue reading Chronic Neutrophilic Leukemia (CNL) →