Myelodysplastic Syndrome with Fibrosis

Differential Diagnosis

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 especially associated with marrow fibrosis include HIV, autoimmune and congenital

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

	Circulating Blasts	Marrow Blasts	Ring Sideroblasts	Dysplastic Lineages	Cytopenias
RCUD	<1%	<5%	<15%	Any 1 lineage	1 or 2
RARS	0	<5%	≥15%	Only erythroid	1 or 2
RCMD	<1%	<5%	Variable	2 or more lineages	1, 2 or 3
RAEB-1	<5%	5-9%	Variable	1 or more	1, 2 or 3
RAEB-2	5-19%	10-19% or Auer rods	Variable	1 or more	1, 2 or 3
del(5q)	<1%	<5%	Variable	Frequently hypolobated small megakaryocytes	Usually 1 (anemia)

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