Primary Myelofibrosis

Slide 1 · Primary Myelofibrosis

A clinicopathologic approach to marrow fibrosis and extramedullary hematopoiesis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how a clonal myeloproliferative neoplasm produces reactive marrow fibrosis.

Recognize the marrow, spleen and peripheral blood morphology of PMF.

Connect fibrosis to anemia, leukoerythroblastosis and splenomegaly.

Distinguish primary disease from other causes of marrow fibrosis.

Slide 3 · PMF within the spectrum of myeloid neoplasms

Myeloid neoplasms

Myeloproliferative neoplasms

Primary myelofibrosis

Myeloproliferation may ultimately coexist with marrow failure and extramedullary hematopoiesis.

Schematic

Slide 4 · Defining PMF

A clonal myeloproliferative neoplasm with atypical megakaryocytic proliferation.

Its defining late effect is progressive, obliterative marrow fibrosis.

Secondary hematopoietic sites become prominent as marrow function declines.

Slide 5 · Primary versus secondary myelofibrosis

Primary myelofibrosis

The neoplasm is classified as PMF at presentation.

Atypical megakaryocytes are part of the neoplastic process.

Progressive fibrosis disrupts the marrow.

Post-PV / post-ET myelofibrosis

Marrow fibrosis develops after established PV or ET.

The fibrotic stage can be morphologically indistinguishable from PMF.

Prior disease history is diagnostically decisive.

Slide 6 · A central paradox: Fibrosis is reactive

The neoplastic clone principally involves hematopoietic progenitors.

Fibroblasts depositing collagen are described as nonneoplastic.

Abnormal signals from neoplastic megakaryocytes promote stromal growth.

Slide 7 · Three principal driver genes

JAK2

Constitutive kinase signaling amplifies hematopoietic growth responses.

CALR

Mutant calreticulin contributes to MPL-pathway activation.

MPL

Altered thrombopoietin-receptor signaling promotes clonal expansion.

Slide 8 · The molecular signature is shared, not exclusive

JAK2, CALR or MPL mutations in approximately 90% of PMF cases.

These driver alterations are also seen in essential thrombocythemia.

Driver status supports clonality; It does not independently distinguish MPN subtypes.

Slide 9 · Convergent signaling toward proliferation

JAK2 / CALR / MPL alteration

Enhanced growth-factor signaling

Abnormal megakaryocyte expansion

Stromal stimulation

A shared molecular axis can generate different marrow phenotypes.

Schematic

Slide 10 · Why do abnormal megakaryocytes matter?

They show conspicuous nuclear atypia and abnormal clustering in marrow.

They are implicated as sources of fibrogenic growth factors.

Their effects extend beyond the neoplastic cells into the marrow stroma.

Slide 11 · Megakaryocyte–fibroblast interaction

Neoplastic megakaryocyte

Release of fibrogenic mediators

Nonneoplastic fibroblast activation

Marrow matrix accumulation

Fibrosis is an indirect consequence of the neoplastic megakaryocyte compartment.

Schematic

Slide 12 · Two mediators highlighted by Robbins

Platelet-derived growth factor

Acts as a fibroblast mitogen.

Promotes stromal cell proliferation.

Provides one candidate mechanism of fibroblast expansion.

Transforming growth factor-β

Has fibroblast-stimulatory activity.

Promotes collagen deposition.

Contributes to the angiogenic response.

Slide 13 · TGF-β links fibrosis and vascular change

The pathway favors increased collagen deposition by the stroma.

Angiogenesis is another recognized component of PMF marrow remodeling.

Vascular and stromal changes can amplify architectural distortion.

Slide 14 · Why the marrow becomes dysfunctional

Progressive stromal collagen

Reduced functional marrow space

Displacement of hematopoietic cells

Cytopenias and extramedullary hematopoiesis

The primary clinical effect is loss of effective marrow hematopoiesis.

Schematic

Slide 15 · Fibrosis changes the marrow niche

Normal spatial relationships between cells and sinusoids become distorted.

Hematopoietic elements are displaced as the fibrous matrix expands.

Even viable stem and progenitor cells may function in abnormal sites.

Slide 16 · Migration into secondary hematopoietic organs

Marrow hematopoiesis displaced

Neoplastic stem/progenitor cells circulate

Colonization of splenic / hepatic niches

Extramedullary hematopoiesis

The spleen becomes a major site of blood cell production.

Schematic

Slide 17 · Why extramedullary hematopoiesis is insufficient

Extramedullary red-cell production is disordered.

It does not fully compensate for suppression of marrow erythropoiesis.

The combined effects cause moderate to severe anemia.

Slide 18 · Disease evolution: Functional consequences

Cellular, proliferative marrow

Increasing stromal fibrosis

Marrow failure + splenic EMH

Late osteosclerotic remodeling

The phenotype changes over time; Early blood counts may be elevated, later counts may fall.

Schematic

Slide 19 · Early PMF: A cellular marrow

Schematic marrow compartment

Overall marrow cellularity may be increased.

Maturing cells of multiple lineages are present.

Megakaryocytic atypia is already evident.

Slide 20 · Early erythroid and granulocytic precursors

Apparently normal maturation morphology in early PMF.

This contrasts with the striking atypia of the megakaryocytes.

The dominant abnormality is not a general dysplasia of every lineage.

Slide 21 · Atypical megakaryocytes: Morphology

Size

Large and sometimes conspicuous cells.

Nuclear features

Bulbous, hyperchromatic or cloud-like nuclei.

Distribution

Abnormally clustered within the marrow.

Slide 22 · Megakaryocyte clustering is diagnostic context

Tight groups of atypical megakaryocytes suggest abnormal growth architecture.

Nuclear configuration is as important as megakaryocyte number.

Assessment requires an adequately sampled marrow biopsy.

Slide 23 · Prefibrotic / early stage: Matrix changes

Schematic marrow compartment

Fibrosis may be minimal at this stage.

Leukocytosis or thrombocytosis can predominate.

Morphology, not fibrosis alone, guides classification.

Slide 24 · Why early PMF may resemble other MPNs

Early marrow cellularity can resemble polycythemia vera.

Platelets may be elevated, bringing essential thrombocythemia into the differential.

Characteristic megakaryocyte atypia and the whole clinical picture are crucial.

Slide 25 · Overt PMF: Progressive matrix deposition

Schematic marrow compartment

Stromal fibrosis occupies increasing marrow space.

Residual hematopoietic cells become disorganized.

Atypical megakaryocyte clusters persist.

Slide 26 · The late marrow is hypocellular and fibrotic

With progression, hematopoietic elements are progressively depleted.

Diffuse fibrosis replaces spaces previously occupied by blood-forming cells.

Marrow failure results from both architectural loss and ineffective output.

Slide 27 · Intrasinusoidal hematopoiesis signals distortion

Hematopoietic cells can be found inside dilated marrow sinusoids.

This is a manifestation of severely disrupted marrow architecture.

It should be interpreted with megakaryocyte atypia and fibrosis.

Slide 28 · Osteosclerosis in very late disease

Schematic marrow compartment

The fibrotic marrow compartment may be replaced by bone.

The change is termed osteosclerosis.

It represents extreme marrow remodeling, not an early prerequisite.

Slide 29 · Biopsy: Cellular features versus stromal features

Hematopoietic compartment

Atypical megakaryocytes with unusual nuclei.

Abnormal clustering and variable maturation patterns.

Residual hematopoietic cellularity changes over time.

Stromal compartment

Reticulin / collagen deposition.

Distortion of vascular and marrow architecture.

Potential late osteosclerosis.

Slide 30 · Fibrosis is not pathognomonic for PMF

Marrow fibrosis can accompany other myeloproliferative neoplasms.

Granulomatous disorders and metastatic tumors may distort marrow.

Diagnostic interpretation requires integration with history and clonality.

Slide 31 · Organ distribution of extramedullary hematopoiesis

Spleen

Major extramedullary site; Often markedly enlarged.

Liver

Often moderately enlarged with sinusoidal hematopoiesis.

Lymph nodes

Foci may be present; Substantial adenopathy is uncommon.

Slide 32 · Spleen: Striking gross enlargement

The spleen is usually markedly enlarged in established PMF.

Very large spleens, sometimes approaching 4000 g.

Cut surfaces may appear firm and diffusely red to gray.

Slide 33 · Splenic microscopic evolution

Initial sinusoidal hematopoiesis

Expansion into splenic cords

Diffuse extramedullary production

Progression changes the organization of red-pulp hematopoiesis.

Schematic

Slide 34 · Splenic infarction is a complication

Subcapsular splenic infarcts are described in advanced disease.

A very enlarged spleen may have compromised regional perfusion.

A new focal pain syndrome warrants consideration of infarction.

Slide 35 · Liver involvement is often more modest

The liver may enlarge because of extramedullary hematopoietic foci.

Sinusoidal localization is emphasized in the Robbins description.

Hepatic enlargement is usually less prominent than splenomegaly.

Slide 36 · Lymph nodes can harbor hematopoiesis

Hematopoietic cells may seed lymph-node compartments.

Clinically important lymphadenopathy is uncommon in PMF.

Marked adenopathy should prompt evaluation for other explanations.

Slide 37 · Origin of the leukoerythroblastic blood picture

Distorted marrow / extramedullary sites

Premature release of precursors

Nucleated RBCs + immature granulocytes

Leukoerythroblastosis is a response to disordered hematopoietic architecture.

Schematic

Slide 38 · Nucleated erythroid cells in peripheral blood

Nucleated red-cell precursors normally mature within hematopoietic tissue.

In PMF, immature erythroid cells can appear in peripheral blood.

Their presence contributes to the leukoerythroblastic picture.

Slide 39 · Granulocytic left shift

Immature myeloid precursors escape into the circulation.

A left shift accompanies circulating nucleated erythroid cells.

This pairing suggests marrow disruption or extramedullary hematopoiesis.

Slide 40 · Dacryocytes: The teardrop-shaped erythrocytes

Dacryocytes are associated with mechanical distortion during transit from a fibrotic marrow.

Schematic — not a blood film

Slide 41 · Mechanistic interpretation of dacryocytes

Robbins suggests these cells may be damaged as they leave distorted marrow spaces.

The blood film reflects physical as well as biological marrow abnormalities.

The mechanism is plausible but not a disease-specific molecular signature.

Slide 42 · Characteristic does not mean specific

Supports PMF

Dacryocytes accompanied by leukoerythroblastosis.

Anemia and substantial splenomegaly.

Atypical megakaryocytes in fibrotic marrow.

Can occur elsewhere

Other infiltrative marrow disorders.

Granulomatous disease affecting the marrow.

Metastatic tumor with marrow distortion.

Slide 43 · Additional peripheral blood clues

Platelets may be unusually large.

Basophilia may be observed.

These findings are supportive but not specific for PMF.

Slide 44 · How counts change with disease stage

Hemoglobin

Progressive normocytic, normochromic anemia.

Leukocytes

May be elevated early, then normal or reduced.

Platelets

Often normal or increased at diagnosis; May decline later.

Slide 45 · Anemia: Predominant clinical laboratory problem

Moderate to severe normochromic, normocytic anemia is typical.

Loss of normal marrow erythropoiesis is a major mechanism.

Disordered extramedullary red-cell production further limits compensation.

Slide 46 · White cell counts are variable

The total leukocyte count is often normal or mildly reduced.

Marked leukocytosis may occur early in the course.

Absolute counts alone cannot establish or exclude PMF.

Slide 47 · Platelet counts change during progression

Early thrombocytosis is compatible with a proliferative phase.

At presentation, platelets may be normal or elevated.

Late thrombocytopenia can develop as marrow failure progresses.

Slide 48 · Early versus advanced clinical phenotype

Finding

Earlier / proliferative

More advanced / fibrotic

Marrow

Increased cellularity

Obliterative fibrosis

Blood counts

Leukocytosis, thrombocytosis possible

Anemia ± thrombocytopenia

Spleen

Variable expansion

Often markedly enlarged

Architecture

Atypical megakaryocytes

Fibrosis ± osteosclerosis

Slide 49 · Typical presentation

PMF usually comes to attention in older adults, often after age 60.

Anemia develops gradually and may dominate the presenting symptoms.

Splenomegaly is another principal clinical trigger for investigation.

Slide 50 · Fatigue: A clinicopathologic correlation

Reduced effective red-cell production causes impaired oxygen delivery.

Patients may report exercise intolerance and decreased functional capacity.

Constitutional inflammation and increased metabolic activity may contribute.

Slide 51 · Splenomegaly and left upper quadrant fullness

Substantial extramedullary hematopoiesis expands splenic tissue.

Large splenic size produces fullness and abdominal discomfort.

Infarction may add a focal acute pain component.

Slide 52 · Constitutional symptoms

Weight loss and night sweats may develop.

The increasing hematopoietic cell mass is associated with altered metabolism.

Symptoms are clinically important but nonspecific.

Slide 53 · Hyperuricemia from cellular turnover

A high rate of cell turnover may increase uric acid production.

Secondary gout can complicate the clinical course.

Biochemical consequences reflect proliferative activity despite anemia.

Slide 54 · Initial investigation: An integrated pathway

CBC + blood film

Spleen and symptom assessment

Bone marrow biopsy

Molecular + exclusion studies

No isolated smear or mutation result is sufficient for classification.

Schematic

Slide 55 · Why bone marrow biopsy is essential

Peripheral blood abnormalities are not pathognomonic.

Megakaryocyte morphology, distribution and fibrosis require tissue evaluation.

A biopsy integrates cellular and stromal findings for diagnostic classification.

Slide 56 · Two morphologic stages in WHO-5 / ICC

Prefibrotic PMF

Megakaryocyte proliferation and atypia.

Increased marrow cellularity / granulopoiesis.

Fibrosis grade 0–1.

Overt fibrotic PMF

Megakaryocyte proliferation and atypia.

Reticulin and/or collagen fibrosis.

Fibrosis grade 2–3.

Slide 57 · WHO-5 / ICC: Diagnosis requires more than morphology

Demonstrate a driver mutation or other credible evidence of clonality.

Exclude other defined myeloid neoplasms and reactive fibrosis.

Integrate compatible clinical and laboratory features with the biopsy.

Slide 58 · Clinical–morphologic differential among classical MPNs

Feature

PMF

PV

ET

Defining feature

Atypical megakaryocytes; Fibrosis evolves

Increased red-cell mass

Platelet-predominant proliferation

Marrow

Megakaryocyte atypia; Variable fibrosis

Panmyelosis

Increased mature megakaryocytes

Blood pattern

Anemia / leukoerythroblastosis late

Erythrocytosis

Thrombocytosis

Later fibrosis

Intrinsic course

Possible spent phase

Possible spent phase

Slide 59 · The critical ET versus early PMF distinction

Both may carry JAK2, CALR or MPL driver mutations.

Both can present with thrombocytosis and increased megakaryocytes.

Megakaryocyte atypia, clustering and clinical context resolve the distinction.

Slide 60 · Separate PMF from post-PV / post-ET fibrosis

End-stage marrow appearances may be indistinguishable.

Documented antecedent PV or ET changes the disease classification.

Previous blood counts, treatment history and pathology are valuable.

Slide 61 · Rule out CML in the MPN workup

Chronic myeloid leukemia is a distinct myeloproliferative neoplasm.

Its defining BCR::ABL1 fusion differentiates it from PMF.

Molecular exclusion is integral to contemporary PMF classification.

Slide 62 · Consider reactive and infiltrative marrow fibrosis

Metastatic cancer and granulomatous disease can produce marrow distortion.

Other inflammatory or hematologic disorders may cause reactive reticulin deposition.

Biopsy morphology and appropriate clonality / exclusion testing matter.

Slide 63 · Major disease complications

Marrow failure

Progressive anemia and other cytopenias.

Thrombosis / bleeding

Events can arise with qualitative platelet abnormalities.

Acute leukemia

A minority of cases transform to AML.

Slide 64 · Infection and bleeding risks

Cytopenias and marrow dysfunction increase vulnerability to infection.

Bleeding may be related to quantitative and qualitative platelet abnormalities.

Thrombotic events are another clinically important threat.

Slide 65 · Transformation to acute myeloid leukemia

PMF has an established risk of transformation to AML.

Robbins gives a broad transformation frequency of 5%–20%.

Leukemic evolution must be distinguished from fibrotic progression alone.

Slide 66 · Prognosis is variable

Robbins quotes a median survival range of 3–5 years discussion.

This broad historical estimate is not an individual prognosis.

Modern risk assessment must incorporate clinical, blood-count and molecular factors.

Slide 67 · Clinical logic: Connecting the main findings

Atypical megakaryocytes

Reactive matrix deposition

Marrow failure

Extramedullary hematopoiesis

Produces anemia, leukoerythroblastosis and often massive splenomegaly.

Schematic

Slide 68 · Case 1 — progressive anemia and splenomegaly

A 68-year-old develops fatigue and left upper quadrant fullness. Peripheral blood shows anemia, nucleated erythroid cells, granulocytic left shift and dacryocytes.

What marrow abnormality would best connect these findings?

Slide 69 · Case 1 — interpretation

A leukoerythroblastic film indicates disruption of normal marrow output.

Marrow fibrosis with atypical megakaryocytes would support PMF.

A biopsy and exclusion of alternative infiltrative disorders are essential.

Slide 70 · Case 2 — isolated thrombocytosis?

A patient with persistent thrombocytosis has a hypercellular marrow, dense atypical megakaryocyte clusters and minimal fibrosis. A JAK2 alteration is detected.

Why should essential thrombocythemia not be assumed?

Slide 71 · Case 2 — reasoning

JAK2 positivity does not discriminate ET from prefibrotic PMF.

Megakaryocyte atypia and clustering are more informative than platelet count alone.

Apply stage-specific WHO/ICC morphologic and exclusion criteria.

Slide 72 · Case 3 — fibrosis with previous PV

An individual with well-documented polycythemia vera develops falling hemoglobin, a very large spleen and marked marrow fibrosis.

What distinction must the diagnosis preserve?

Slide 73 · Case 3 — reasoning

This presentation raises post-PV myelofibrosis rather than de novo PMF.

Advanced fibrotic histology alone may not distinguish the two.

Prior diagnostic records are part of the pathologic evidence.

Slide 74 · Recognition summary: Connect finding to mechanism

Finding

Mechanistic explanation

Hypercellular early marrow

Increased production by the abnormal hematopoietic clone

Collagen-rich fibrosis

Fibroblastic response to abnormal megakaryocytic signals

Dacryocytes

Distortion during exit from affected marrow

Nucleated RBCs + myeloid precursors

Premature release / extramedullary contribution

Massive splenomegaly

Extensive extramedullary hematopoiesis

Slide 75 · Final synthesis

PMF is a clonal MPN whose fibrosis is largely a secondary stromal reaction.

Megakaryocyte atypia and clustering are central morphologic clues.

Marrow fibrosis produces anemia, leukoerythroblastosis and extramedullary hematopoiesis.

Diagnosis requires biopsy, molecular context and exclusion of mimics.

Slide 76 · References and classification context

Source

Use in lecture

Robbins, Cotran & Kumar, Pathologic Basis of Disease, 11th ed. (2026), Ch. 13, pp. 570–571

Core pathogenesis, morphology, presentation, course

Robbins, Ch. 13: PV, ET and Myeloid Neoplasms, pp. 560, 568–570

Differential and MPN parent context

Khoury et al. Leukemia. 2022;36:1703–1719. doi:10.1038/s41375-022-01613-1

WHO fifth-edition classification

Gianelli et al. Virchows Arch. 2023;482:53–68. doi:10.1007/s00428-022-03480-8

International Consensus Classification context