What is the management approach for a patient with reticulum (reticular) fibrosis, a condition characterized by fibrous tissue deposition in the bone marrow?

Management of Reticulin Fibrosis

The management of reticulin fibrosis depends entirely on identifying and treating the underlying cause—most critically distinguishing between primary myeloproliferative neoplasms (which require disease-specific therapy) and secondary reactive causes (which resolve with treatment of the underlying condition). 1

Initial Diagnostic Approach

The first priority is determining whether reticulin fibrosis represents a primary clonal myeloid disorder versus a secondary reactive process:

Grade the Reticulin Fibrosis

• Grade 0 (MF-0): Scattered linear reticulin with no intersections—normal bone marrow 1
• Grade 1 (MF-1): Loose network with many intersections, especially perivascular 1
• Grade 2 (MF-2): Diffuse and dense increase with extensive intersections, occasionally with focal collagen bundles 1
• Grade 3 (MF-3): Diffuse and dense increase with coarse collagen bundles, often with osteosclerosis 1

Evaluate Megakaryocyte Morphology

This is the critical distinguishing feature for primary myelofibrosis:

• Primary Myelofibrosis (PMF): Small-to-large megakaryocytes with aberrant nuclear/cytoplasmic ratio, hyperchromatic bulbous or irregularly folded nuclei, and dense clustering 1, 2
• Essential Thrombocythemia (ET): Large to giant mature megakaryocytes with extensively folded staghorn-like nuclei, randomly distributed without dense clustering 1
• Polycythemia Vera (PV): Smaller than normal megakaryocytes with hypolobulated nuclei ("dwarf megakaryocytes") 1

Test for Clonal Markers

• JAK2 V617F mutation: Present in ≥95% of PV, ~60% of ET, and ~50% of PMF 1, 3
• CALR mutations: Found in many JAK2-negative PMF and ET cases 1, 3
• MPL mutations: Present in 5-8% of PMF patients 1, 3

Management Based on Underlying Diagnosis

Primary Myelofibrosis (Grades 2-3 Fibrosis Required)

Diagnosis requires all 3 major WHO criteria plus 2 minor criteria 1, 3:

• Major: Megakaryocyte proliferation/atypia with reticulin/collagen fibrosis, exclusion of other myeloid neoplasms, presence of JAK2/CALR/MPL mutation 1, 3
• Minor: Leukoerythroblastosis, elevated LDH, anemia, palpable splenomegaly 1, 3

Treatment approach:

• JAK2 inhibitor (ruxolitinib) is the cornerstone therapy, with median overall survival of 84 months in treated patients 4
• Hematopoietic stem cell transplantation remains the only curative approach that reliably resolves bone marrow fibrosis 5
• Risk stratification using DIPSS or DIPSS-Plus scores guides treatment intensity 4, 6

Pre-fibrotic PMF (Grade 1 Fibrosis)

This is a critical diagnostic pitfall—grade 1 reticulin is NOT always reactive 2:

• Pre-fibrotic PMF shows grade 1 fibrosis but requires characteristic megakaryocyte changes, increased marrow cellularity, and granulocytic proliferation 1, 2
• Misdiagnosing this as ET has significant prognostic implications, as pre-fibrotic PMF has worse outcomes 3
• Treatment follows PMF protocols once diagnosis is confirmed 2

Post-PV or Post-ET Myelofibrosis

Diagnosis requires documentation of prior PV/ET plus grade 2-3 bone marrow fibrosis 1:

• Morphology shows overt reticulin and collagen fibrosis with clusters of atypical megakaryocytes 1
• Initial bone marrow reticulin fibrosis at PV diagnosis (present in ~14-20% of cases) predicts more rapid progression to post-PV myelofibrosis (2.2 vs 0.8 per 100 patient-years) 7
• Management follows PMF treatment algorithms 1

Polycythemia Vera with Fibrosis

• Moderate to marked reticulin fibrosis occurs in ~30% of CML cases and up to 20% of PV cases at diagnosis 1, 7
• Phlebotomy to maintain hematocrit <45% reduces thrombotic risk 8
• Low-dose aspirin for cardiovascular event prevention 8
• Cytoreductive therapy (hydroxyurea or interferon-alpha) for high-risk patients (age >60 or prior thrombosis) 8

Secondary Reactive Causes

These resolve with treatment of the underlying condition:

• Infection: Minor (grade 1) fibrosis from chronic inflammatory response—treat underlying infection 2
• Autoimmune disorders: Reactive fibrosis through chronic inflammation—treat autoimmune condition 2
• Metastatic malignancy: Reactive fibrosis from marrow infiltration—treat primary malignancy 2

Critical Pitfalls to Avoid

Do not assume grade 1 reticulin fibrosis is always reactive—it can represent pre-fibrotic PMF when accompanied by characteristic megakaryocyte changes, increased cellularity, and granulocytic proliferation 2

Do not diagnose PMF based on JAK2 mutation alone—this mutation occurs in multiple MPNs and requires meeting all 3 major WHO criteria plus 2 minor criteria 2, 3

Do not fail to perform bone marrow examination in patients with thrombocytosis—this can lead to misdiagnosis of ET when pre-fibrotic PMF is present, which has significant prognostic implications 3

Prognostic Implications

A comprehensive histological evaluation using the RCO score (reticulin, collagen, osteosclerosis, ranging 0-9) is more accurate than reticulin grading alone for identifying high-risk patients 6:

• Low-grade (RCO 0-4) versus high-grade (RCO 5-9) stromal changes correlate with overall mortality (P=0.013) 6
• High-grade RCO score associates with anemia, thrombocytopenia, peripheral blood blasts, and elevated LDH 6
• Combined RCO score with IPSS risk categories increases positive predictive value for mortality in high-risk patients 6

Survival in myelofibrosis has improved significantly in the last decade, from median 48 months (2000-2010) to 63 months (2011-2020), largely due to JAK inhibitor therapy and improved supportive care 4