Problems and pitfalls in grading of bone marrow fibrosis, collagen deposition and osteosclerosis – a consensus‐based study

Abstract

Aims In the era of potentially disease‐modifying agents such as Janus kinase inhibitors, accurate grading and differentiation of bone marrow (BM) fibrosis has become more relevant to assess staging of disease and therapeutic effects. However, different fibrosis grading models have been used in the past without uniformity, including the proposal by the World Health Organization. Current scoring systems are based only on reticulin fibrosis. Therefore, additional assessment of collagen and the grade of osteosclerosis appear to be essential to discriminate all components of the complex BM fibrous matrix. Methods and results We evaluated problems and pitfalls regarding staining techniques and the interpretation of reticulin fibrosis on a total of 352 samples. Furthermore, we propose a minor modification of the current grading and separate scoring for collagen deposition and osteosclerosis. Reproducibility of gradings was tested among 11 haematopathologists in a blinded assessment. Overall, the inter‐rater reliability of all three grading systems ranged between 0.898 and 0.926. Conclusions A standardized assessment of BM fibrosis with differentiation between reticulin, collagen and osteosclerosis is recommended to evaluate the various components of the fibrous matrix which may be delinked after therapy. In this regard, quality of staining and application of laboratory standards enable a highly reproducible scoring.

Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations

“…Uncontrolled BM stromal activation probably leads to the excessive release of IL-8 as a part of known cytokine-driven inflammatory state in MPNs, which contributes to the BM fibrosis [25]. Limitation of our study is that the grading of fibrosis was performed for reticular but not collagen fibrosis, due to the small number of patients with grades of fibrosis 2 and 3 [36]. Antiangiogenic effect of HU has been reported in sickle cell disease [37].…”

Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients

“…The grade of bone marrow stromal changes was assessed according to the new grading system. 25 We decided not to evaluate microvessel proliferation, another stromal alteration that occurs along with the increase of bone marrow fibrosis, 26 as it lacks a well-established grading system. Perivascular reticulin and collagen fibres were considered as internal quality controls, and fibre density was evaluated only in haematopoietic areas.…”

“…The histological analysis of bone marrow stromal changes, according to the grading system proposed by Kvasnicka et al, 25 Stromal changes evolved harmonically for the three morphological features, with few exceptions. Four of 60 cases with MF-1 reticulin fibrosis displayed Ost-2 osteosclerosis (7%) ( Figure 2).…”

Molecular profile of inflammatory and megakaryocytic factors in pediatric myelodysplastic syndrome with acute myelofibrosis

“…In general, MF secondary to myeloid neoplasms is thought to be a surrogate of a more advanced disease stage. MF is graded from 0 (no MF: scattered linear reticulin corresponding to normal bone marrow) to 3 (diffuse and dense increase of reticulin with extensive intersections with bundles of collagen and osteosclerosis) . In young patients, MF grade 3 is thought to be rare and usually MF grade 1 (loose network of reticulin) or grade 2 (dense network of reticulin with extensive intersections) are detectable .…”

“…MF is graded from 0 (no MF: scattered linear reticulin corresponding to normal bone marrow) to 3 (diffuse and dense increase of reticulin with extensive intersections with bundles of collagen and osteosclerosis). 4 In young patients, MF grade 3 is thought to be rare and usually MF grade 1 (loose network of reticulin) or grade 2 (dense network of reticulin with extensive intersections) Abbreviations: CCL5, C-C motif chemokine ligand 5; CXCL12, C-X-C motif chemokine ligand 12; ITGB3, integrin subunit beta 3; MF, myelofibrosis; MMP9, matrix metallopeptidase 9; PECAM1, platelet and endothelial cell adhesion molecule 1; ped-MDS-MF, pediatric fibrotic myelodysplastic syndromes; ped-PMF, pediatric primary myelofibrosis; TGFB1, transforming growth factor beta 1; THBS1, thrombospondin 1; TIMP1, TIMP metallopeptidase inhibitor 1; TUBB, tubulin beta class I are detectable. [1][2][3] The molecular mechanisms which induce MF are unknown, but it is likely that neoplastic cells stimulate fibroblasts via cytokines.…”