Category Archives: Bone Marrow

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, MPN, Hematopathology

MF3 – Reticulin Fibrosis

Diffuse increase of reticulin fibers with increased density and numerous intersections.  Increased thick bundles of fibers consistent with collagen fibrosis.  Osteosclerosis usually present.

Photomicrographs
Reticulin - MF3 fibrosis
Reticulin – MF3 fibrosis
Reticulin - MF3 fibrosis
Reticulin – MF3 fibrosis
Trichrome - MF3 fibrosis
Trichrome – MF3 fibrosis
Trichrome - MF3 fibrosis
Trichrome – MF3 fibrosis
References
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
 
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
Organ Systems, Bone Marrow, WHO Classification, MDS, Hematopathology

MDS Cytogenetics

The following are cytogenetic abnormalities that are considered as presumptive evidence of MDS in the setting of persistent cytopenias:
 
-7 or del (7q)
-5 or del(5q)
i(17q) or t(17p)
-13 or del(13q)
del(11q)
del(12p) or t(12p)
del(9q)
idic(X)(q13)
t(11;16)(q23;p13.3)
t(3;21)(q26.2;q22.1)
t(1;3)(p36.3;q21.2)
t(2;11)p21;q23)
inv(3)(q21q26.2)
t(6;9)(p23;q34)

Continue reading MDS Cytogenetics →

Organ Systems, Bone Marrow, WHO Classification, Hematopathology, Acute Leukemia

Acute Undifferentiated Leukemia

A vary rare acute leukemia that does not express markers considered specific for lineage determination. (e.g. MPO, esterase, cCD3, cCD22, strong CD19, etc.).  Typically there will be one or less lineage markers for any lineage.  CD34, HLA-DR, and TdT may be expressed, but are not specific for any lineage.
 

Care should be taken that immunophenotyping panels are extensive, and consideration is given to other entities such as plasmacytoid dendritic precursors, non-hematopoietic tumors, NK-cell precursors, etc.  Essentially, a diagnosis of exclusion.

Continue reading Acute Undifferentiated Leukemia →

Organ Systems, Bone Marrow, WHO Classification, Hematopathology, Acute Leukemia

Myeloid/Lymphoid Neoplasms Associated with Eosinophilia

  • PDGFA
    • Eosinophilia with increased tryptase and marrow mast cells
    • Cryptic deletion in chromosome 4q12
    • FIP1L1-PDGFA, many other partners
    • Responsive to tyrosine kinase inhibitors (e.g. imatimib/Gleevec®)
  • PDGFB
    • Eosinophilia combined with monocytosis that mimics CMML
    • t(5;12)(q31;33;p12) ETV6-PDGFB, many other partners
    • Responsive to TKIs 
  • FGFR1
    • Eosinophilia combined with AML or T-ALL
    • Associated with 8p11 translocations, FGFR1 with multiple partners
    • Not responsive to TKIs (poor prognosis)
  • PCM1-JAK2 (provisional entity)
    • Eosinophilia along with acute lymphoblastic leukemia (B-cell) or lymphoma (T-cell)
    • Bone marrow with lymphoid aggregates and increased/left shifted erythroid precursors (mimics PMF)
    • May respond to JAK2 inhibitors (e.g ruxolitinib/Jakafi®)
References

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