Myelodysplastic Syndrome with Fibrosis

Definition

• Myelodysplastic syndrome with increased fibrosis

Diagnostic Criteria

• Not yet a separate WHO category, but:
  • Clinically distinct (worse prognosis)
  • Diagnostically distinct (special differential diagnostic problems)
• Diffuse coarse reticulin fibrosis with or without collagenization
  • MF-2 or MF-3 in European consensus grading system (Thiele 2005)
• Any type of MDS may occur with increased marrow fibrosis
  • Occurs in 15% of MDS patients
  • Most common type is refractory anemia with increased blasts
• Usually results in an inadequate bone marrow smear
• Diagnosis may have to be based on the core
• CD34 staining may be valuable for identifying blasts in sections
• Usually associated with:
  • Pancytopenia
  • Dysplasia in at least two lineages
  • Modest or absent splenomegaly
• Distinction between various MDS may be compromised by fibrosis but should be made, if possible, based on standard criteria:

Myelodysplastic Syndromes

• RCUD = refractory cytopenia (anemia, neutropenia or thrombocytopenia) with unilineage dysplasia; RARS = refractory anemia with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RAEB = refractory anemia with excess blasts; del(5q) = 5q- syndrome
• All MDS must not have absolute monocytosis
  • If present, consider chronic myelomonocytic leukemia
• If chemotherapy or radiation therapy related, should be reported as "therapy-related myeloid neoplasm"
• In children, consider provisional WHO entity "refractory cytopenia of childhood" for low blast count MDS
• Myelodysplastic syndrome unclassifiable (MDS-U)
  • Must not meet criteria of any specific WHO category
  • Persistent cytopenia(s) with any of the following:
    • Unilineage marrow dysplasia with pancytopenia OR
    • <1% blasts in blood, <5% blasts in marrow and cytogenetic abnormalities but no lineage with ≥10% dysplastic forms OR
    • Findings of RCUD or RCMD but with 1% blasts in peripheral blood
      • (2-4% blasts would be classified as RAEB-1)
  • Nonclonal causes must be excluded

Original posting: 10/23/11

Supplemental studies

Cytogenetic studies should be performed in all cases of myelodysplasia or suspected myelodysplasia

• FISH for MDS associated abnormalities is not indicated for screening but is helpful if <20 metaphases were examined on karyotyping
• In the setting of persistent cytopenia in the absence of definitive morphologic features of MDS:
  • The following abnormalities are considered presumptive evidence of MDS
    • Deletions
      • -5, del(5q)
      • -7, del(7q)
      • del(9q)
      • del(11q)
      • del(12p)
      • t(12p)
      • -13, del(13q)
      • i(17q), t(17p)
      • idic(X)(q13)
    • Translocations
      • t(1;3)(p36.3;q21.2)
      • t(2;11)(p21;q23)
      • t(3;21)(q26.2;q22.1)
      • inv(3)(q21q26.2) and t(6;9)(p23;q24)
        • Most frequently present as AML and need to be closely monitored for overt transformation
      • t(11;16)(q23;p13.3)
  • The following are commonly found in MDS but are not by themselves considered definitional for MDS
    • +8
    • -Y
    • del(20q)

Differential Diagnosis

• Other hematolymphoid disorders
• Non-neoplastic simulators

Hematolymphoid Disorders with Marrow Fibrosis (overview)

Disorder	Distinguishing Feature(s)
Polycythemia Vera, Fibrotic Phase	History of PV / JAK2+
Essential Thrombocythemia, Fibrotic Phase (rare)	History of ET / may be JAK2+
CML, Fibrotic Phase	History of CML / BCR-ABL1+
MDS with Fibrosis	Dysplastic features in marrow
Acute Megakaryoblastic Leukemia	Blasts, acute onset
Osteosclerotic Myeloma	Plasma cells. light chain restricted
Acute Pan-myelosis with Myelofibrosis	Bone pain, acute onset
Primary Myelofibrosis	Clustered atypical megakaryocytic hyperplasia
Hairy cell leukemia	Clonal B cells

MDS with Fibrosis = descriptive term that includes primary MDS (often RAEB2) with fibrosis and therapy related myeloid neoplasms with fibrosis

Primary Myelofibrosis, Fibrotic Phase	MDS with Fibrosis	Post-Polycythemia Vera Myelofibrosis
JAK2V617F mutations in 50%	JAK2V617F mutations rare	JAK2V617F mutations in almost 100%
Tightly clustered hyperchromatic megakaryocytes	Increased but non-clustered dysplastic megakaryocytes	Variable size and increase in megakaryocytes
Prominent splenomegaly	Rare splenomegaly	Prominent splenomegaly
Does not meet criteria for MDS or PV	Commonly multilineage dysplasia and increased blasts	History of polycythemia vera

Myelofibrosis grade 2-3 and cytogenetic abnormalities are common in all three

Non-neoplastic disorders may simulate myelodysplasia

• Vitamin/micronutrient deficiencies
  • B12/folate
  • Copper
    • Ring sideroblasts present
    • Cytoplasmic vacuoles
    • May be due to
      • Zinc excess
      • Gastrectomy
      • Total parenteral nutrition
• Infections
  • HIV
  • Parvovirus
  • HHV-6 in children
• Toxins
  • Ethanol
  • Heavy metals
• Growth factors
  • Granulocyte-macrophage colony-stimulating factor (GMCSF)
  • Erythropoietin
• Drugs (numerous)
  • Chemotherapeutic agents
    • e.g. megaloblastoid change with folate antagonists
  • Valproic acid, MMF (mycophenolate mofetil), Ganciclovir
    • Pseudo-Pelger-Helger anomaly
• Autoimmune/rheumatologic
  • e.g. systemic lupus erythematosus
• Congenital
  • Congenital dyserythropoietic anemias
  • Inherited bone marrow failure syndromoes (Fanconi etc.)
  • Monocytopenia immunodeficiency syndrome

Myelodysplastic Syndromes

• RCUD = refractory cytopenia (anemia, neutropenia or thrombocytopenia) with unilineage dysplasia; RARS = refractory anemia with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RAEB = refractory anemia with excess blasts; del(5q) = 5q- syndrome
• All MDS must not have absolute monocytosis
  • If present, consider chronic myelomonocytic leukemia
• If chemotherapy or radiation therapy related, should be reported as "therapy-related myeloid neoplasm"
• In children, consider provisional WHO entity "refractory cytopenia of childhood" for low blast count MDS
• Myelodysplastic syndrome unclassifiable (MDS-U)
  • Must not meet criteria of any specific WHO category
  • Persistent cytopenia(s) with any of the following:
    • Unilineage marrow dysplasia with pancytopenia OR
    • <1% blasts in blood, <5% blasts in marrow and cytogenetic abnormalities but no lineage with ≥10% dysplastic forms OR
    • Findings of RCUD or RCMD but with 1% blasts in peripheral blood
      • (2-4% blasts would be classified as RAEB-1)
  • Nonclonal causes must be excluded

Clinical

• Poor survival (median 15 months)

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

• Chronic myeloid leukemia, BCR-ABL1 pos
• Chronic neutrophilic leukemia
• Chronic eosinophilic leukemia NOS
  • (see also Idiopathic hypereosinophilic syndrome)
• Polycythemia vera
• Essential thrombocythemia
• Primary myelofibrosis
• Mastocytosis
• Myeloproliferative neoplasm unclassifiable

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML)
• Atypical chronic myeloid leukemia, BCR-ABL1 negative
• Juvenile myelomonocytic leukemia
• Myelodysplastic / myeloproliferative neoplasm, unclassifiable
• Refractory anemia with ring sideroblasts associated with marked thrombocytosis
• Myelodysplastic / myeloproliferative neoplasm with isolated isochromosome 17q

Myelodysplastic Syndromes (MDS)

• Refractory cytopenia with unilineage dysplasia (RCUD)
  • Refractory anemia
  • Refractory neutropenia
  • Refractory thrombocytopenia
• Refractory cytopenia with multilineage dysplasia (RCMD)
• Refractory anemia with ring sideroblasts (RARS)
• Refractory anemia with excess blasts (RAEB)
• MDS associated with isolated del(5q)
• Childhood myelodysplastic syndrome
  • Refractory cytopenia of childhood
• MDS unclassifiable
• Additional features that may be superimposed on above classification:
  • MDS with fibrosis
  • MDS, hypocellular

Therapy Related Myeloid Neoplasms

Bibliography

• Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
• Hofmann WK, Koeffler HP. Myelodysplastic syndrome. Annu Rev Med. 2005;56:1-16.
• Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood. 2000 Dec 1;96(12):3932-8.
• Oriani A, Annaloro C, Soligo D, Pozzoli E, Cortelezzi A, Lambertenghi Deliliers G. Bone marrow histology and CD34 immunostaining in the prognostic evaluation of primary myelodysplastic syndromes. Br J Haematol. 1996 Feb;92(2):360-4.
• Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88. Erratum in: Blood 1998 Feb 1;91(3):1100.
• Verburgh E, Achten R, Maes B, Hagemeijer A, Boogaerts M, De Wolf-Peeters C, Verhoef G. Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes. J Clin Oncol. 2003 Jan 15;21(2):273-82.
• Germing U, Gattermann N, Aivado M, Hildebrandt B, Aul C. Two types of acquired idiopathic sideroblastic anaemia (AISA): a time-tested distinction. Br J Haematol. 2000 Mar;108(4):724-8.
• Young NS. Paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes: clonal expansion of PIG-A-mutant hematopoietic cells in bone marrow failure. Haematologica. 2009 Jan;94(1):3-7.
  
• Konoplev S, Medeiros LJ, Lennon PA, Prajapati S, Kanungo A, Lin P. Therapy may unmask hypoplastic myelodysplastic syndrome that mimics aplastic anemia. Cancer. 2007 Oct 1;110(7):1520-6.
  
• Mufti GJ, Bennett JM, Goasguen J, Bain BJ, Baumann I, Brunning R, Cazzola M, Fenaux P, Germing U, Hellström-Lindberg E, Jinnai I, Manabe A, Matsuda A, Niemeyer CM, Sanz G, Tomonaga M, Vallespi T, Yoshimi A; International Working Group on Morphology of Myelodysplastic Syndrome. Diagnosis and classification of myelodysplastic syndrome: International Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Haematologica. 2008 Nov;93(11):1712-7.
  
• Maftoun-Banankhah S, Maleki A, Karandikar NJ, Arbini AA, Fuda FS, Wang HY, Chen W. Multiparameter flow cytometric analysis reveals low percentage of bone marrow hematogones in myelodysplastic syndromes. Am J Clin Pathol. 2008 Feb;129(2):300-8.
  
• Haase D, Germing U, Schanz J, Pfeilstöcker M, Nösslinger T, Hildebrandt B, Kundgen A, Lübbert M, Kunzmann R, Giagounidis AA, Aul C, Trümper L, Krieger O, Stauder R, Müller TH, Wimazal F, Valent P, Fonatsch C, Steidl C. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007 Dec 15;110(13):4385-95.
  
• Costa D, Valera S, Carrió A, Arias A, Muñoz C, Rozman M, Belkaid M, Coutinho R, Nomdedeu B, Campo E. Do we need to do fluorescence in situ hybridization analysis in myelodysplastic syndromes as often as we do? Leuk Res. 2010 Nov;34(11):1437-41.
• Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica. 2005 Aug;90(8):1128-32.