What are the causes of increased reticulin in bone marrow trephine biopsy?

Causes of Increased Reticulin in Bone Marrow Trephine Biopsy

Increased reticulin fibrosis in bone marrow can result from both clonal myeloid neoplasms and reactive conditions, with the most important distinction being between primary myelofibrosis and secondary reactive causes.

Primary Clonal Myeloid Neoplasms

Myeloproliferative Neoplasms (MPNs)

• Primary Myelofibrosis (PMF) is the prototypical cause, characterized by megakaryocyte proliferation and atypia with reticulin fibrosis grades 2-3 (diffuse and dense increase with extensive intersections) 1
• Pre-fibrotic PMF may show only grade 1 reticulin fibrosis (loose network with many intersections, especially perivascular), but requires accompanying megakaryocyte changes, increased marrow cellularity, and granulocytic proliferation 1
• Essential Thrombocythemia (ET) typically shows minimal or no reticulin increase, with only "very rarely minor (grade 1) increase in reticulin fibers" as part of diagnostic criteria 1
• Polycythemia Vera (PV) can develop reticulin fibrosis, with initial myelofibrosis present in up to 20% of patients at diagnosis, which may predict more rapid progression to post-PV myelofibrosis 1

Acute Leukemias

• Acute lymphoblastic and acute non-lymphoblastic leukemia commonly present with increased marrow reticulin at diagnosis, which resolves with effective anti-leukemic therapy and may reappear with relapse 2

Myelodysplastic Syndromes (MDS)

• MDS with fibrosis can show increased reticulin, though megakaryocyte morphology differs from PMF (lacking the characteristic small-to-large megakaryocytes with aberrant nuclear features and dense clustering) 3
• Hypocellular MDS variants may demonstrate reticulin fibrosis 4

Secondary Reactive Causes

Infectious and Inflammatory Conditions

• Infection can cause minor (grade 1) reticulin fibrosis secondary to chronic inflammatory response 1
• Autoimmune disorders produce reactive bone marrow fibrosis through chronic inflammatory mechanisms 1
• Other chronic inflammatory conditions result in secondary reticulin deposition 1

Lymphoproliferative Disorders

• Hairy cell leukemia characteristically causes increased bone marrow fibrosis ranging from focally increased reticulin to diffuse increase in both reticulin and collagen, which decreases during alpha-interferon therapy as the hairy cell population diminishes 1, 5
• Other lymphoid neoplasms can produce reactive marrow fibrosis 1

Metastatic and Toxic Causes

• Metastatic malignancy to bone marrow induces reactive fibrosis 1
• Toxic (chronic) myelopathies from various exogenous agents cause secondary reticulin deposition 1

Critical Diagnostic Algorithm

Step 1: Assess Reticulin Grade

• 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—may be reactive or early clonal disease 1
• Grade 2 (MF-2): Diffuse and dense increase with extensive intersections, occasionally with focal collagen bundles—suggests clonal process 1
• Grade 3 (MF-3): Diffuse and dense increase with coarse collagen bundles, usually with osteosclerosis—indicates advanced fibrosis 1

Step 2: Evaluate Megakaryocyte Morphology

• Small-to-large megakaryocytes with aberrant nuclear/cytoplasmic ratio, hyperchromatic, bulbous or irregularly folded nuclei, and dense clustering strongly suggest PMF 1, 3
• Giant, mature-appearing megakaryocytes with deeply lobulated nuclei suggest ET rather than PMF 3
• Normal megakaryocyte morphology points toward reactive fibrosis 1

Step 3: Test for Clonal Markers

• JAK2 V617F mutation (present in ~50% of PMF, >90% of PV) indicates clonal myeloproliferative neoplasm 1, 3
• CALR or MPL mutations (present in many JAK2-negative MPN cases) confirm clonal disease 1, 3
• Absence of all three major clonal mutations requires search for accompanying mutations (ASXL1, EZH2, TET2, SRSF2, SF3B1) or exclusion of reactive causes 1

Step 4: Exclude Reactive Causes

• Obtain detailed medication history, alcohol use, occupational exposures to exclude toxic myelopathies 4
• Evaluate for autoimmune disorders, chronic infections through appropriate serologic testing 1
• Perform flow cytometry to exclude hairy cell leukemia or other lymphoid neoplasms 5
• Consider imaging studies to exclude metastatic malignancy 1

Common Diagnostic Pitfalls

• Do not assume grade 1 reticulin fibrosis is always reactive—in the presence of characteristic megakaryocyte changes, increased marrow cellularity, and granulocytic proliferation, this represents pre-fibrotic PMF 1
• Do not diagnose PMF based on JAK2 mutation alone—this mutation occurs in multiple MPNs and requires meeting all three major WHO criteria plus minor criteria 3
• Do not overlook the possibility of concurrent conditions—patients with reactive causes of fibrosis (e.g., autoimmune disorders) are not immune to developing primary myelofibrosis if other criteria are met 1
• Do not fail to perform comprehensive bone marrow evaluation—assessment requires both aspirate with cytomorphology and trephine biopsy with reticulin staining, cytogenetics, and molecular testing 6, 4
• Consider trichrome staining for grades MF-2 or MF-3 to assess collagen deposition and osteosclerosis, as comprehensive evaluation of reticulin, collagen, and osteosclerosis has prognostic significance 1, 7