Pediatric TAFRO syndrome: A multi-institution case series illustrating clinical challenges and excellent outcomes.

A rare lymphoproliferative disorder involving thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), renal dysfunction (R), and organomegaly (O), called TAFRO syndrome, was first reported in 2010. Considered a variant of idiopathic multicentric Castleman's disease, the recent discovery and rarity of this syndrome pose challenges to diagnosis and management. Herein, we review three pediatric cases, including an infant, that illustrate the heterogeneity of TAFRO syndrome. Despite differences in presentation and treatment responses, all patients experienced excellent outcomes. This multi-institutional case series highlights the need to work toward earlier diagnosis and improved long-term management recommendations for patients with TAFRO syndrome.

Artificial intelligence-based reticulin proportionate area - a novel histological outcome predictor in hepatocellular carcinoma.

AIMS: Reticulin stain is used routinely in the histological evaluation of hepatocellular carcinoma (HCC). The goal of this study was to assess whether the histological reticulin proportionate area (RPA) in HCCs predicts tumour-related outcomes. METHODS AND RESULTS: We developed and validated a supervised artificial intelligence (AI) model that utilises a cloud-based, deep-learning AI platform (Aiforia Technologies, Helsinki, Finland) to specifically recognise and quantify the reticulin framework in normal livers and HCCs using routine reticulin staining. We applied this reticulin AI model to a cohort of consecutive HCC cases from patients undergoing curative resection between 2005 and 2015. A total of 101 HCC resections were included (median age = 68 years, 64 males, median follow-up time = 49.9 months). AI model RPA reduction of > 50% (compared to normal liver tissue) was predictive of metastasis [hazard ratio (HR) = 3.76, P = 0.004, disease-free survival (DFS, HR = 2.48, P < 0.001) and overall survival (OS), HR = 2.80, P = 0.001]. In a Cox regression model, which included clinical and pathological variables, RPA decrease was an independent predictor of DFS and OS and the only independent predictor of metastasis. Similar results were found in the moderately differentiated HCC subgroup (WHO grade 2), in which reticulin quantitative analysis was an independent predictor of metastasis, DFS and OS. CONCLUSION: Our data indicate that decreased RPA is a strong predictor of various HCC-related outcomes, including within the moderately differentiated subgroup. Reticulin, therefore, may represent a novel and important prognostic HCC marker, to be further explored and validated.

Characteristics of thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly syndrome: a retrospective study from a large Western cohort.

Idiopathic multicentric Castleman disease (iMCD) is a non-clonal inflammatory lymphoproliferative disorder of unknown origin. Recently, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) emerged as a singular variant of iMCD in Asia and was associated with a severe course and a poor outcome. The present study describes the first large Western cohort of TAFRO syndrome patients (n = 25) meeting the All Japan TAFRO Syndrome Research Group diagnostic criteria. Characteristics of TAFRO patients were compared to iMCD-not otherwise specified (iMCD-NOS) patients used as a control group (n = 43). Our results show that despite baseline characteristics in accordance with previously reported series, Western TAFRO syndrome patients do not appear to present with a worse outcome than iMCD-NOS patients. There were no significant differences between the two groups regarding treatment choice, response to rituximab (71% vs. 67%) or tocilizumab (69% vs. 91%) in TAFRO and iMCD-NOS, respectively. The two-year overall survival was above 95% in both groups. Limits of inclusion and exclusion criteria for TAFRO definition are also discussed. Our findings raise the question of the singularity of the TAFRO entity in Western countries. The data should promote further research using unsupervised models to identify markers of disease severity in Western cohorts of iMCD patients.

Bone marrow findings of idiopathic Multicentric Castleman disease: A histopathologic analysis and systematic literature review.

Idiopathic multicentric Castleman disease (iMCD) is a polyclonal lymphoproliferative disorder characterized by constitutional symptoms, generalized lymphadenopathy, cytopenias, and multi-organ dysfunction due to excessive cytokines, notably Interleukin-6. Idiopathic multicentric Castleman disease is often sub-classified into iMCD-TAFRO, which is associated with thrombocytopenia (T), anasarca (A), fever/elevated C-reactive protein (F), renal dysfunction (R), and organomegaly (O), and iMCD not otherwise specified (iMCD-NOS), which is typically associated with thrombocytosis and hypergammaglobulinemia. The diagnosis of iMCD is challenging as consensus clinico-pathological diagnostic criteria were only recently established and include several non-specific lymph node histopathological features. Identification of further clinico-pathological features commonly found in iMCD could contribute to more accurate and timely diagnoses. We set out to characterize bone marrow (BM) histopathological features in iMCD, assess differences between iMCD-TAFRO and iMCD-NOS, and determine if these findings are specific to iMCD. Examination of BM specimens from 24 iMCD patients revealed a high proportion with hypercellularity, megakaryocytic atypia, reticulin fibrosis, and plasmacytosis across patients with both iMCD-NOS and iMCD-TAFRO with significantly more megakaryocytic hyperplasia (p = 0.001) in the iMCD-TAFRO cases. These findings were also consistent with BM findings from 185 published cases of iMCD-NOS and iMCD-TAFRO. However, these findings are relatively nonspecific as they can be seen in various other infectious, malignant, and autoimmune diseases.

Therapeutic Intervention with Dietary Chitosan Nanoparticles Alleviates Fish Pathological and Molecular Systemic Inflammatory Responses against Infections.

Marine bio-sourced chitosan nanoparticles (CSNP) are antimicrobial and immunomodulatory agents beneficial for fish medicine. Herein, dietary CSNP was investigated for the amelioration of the systemic inflammatory responses of an induced fish model. One hundred and forty-four rainbow trout were assigned to one pathogen-free and non-supplemented group (negative control), and three challenged groups: non-supplemented (positive control), CSNP-preventive, and CSNP-therapeutic. After a feeding experiment extended for 21 days, the organosomatic indices (OSI) and molecular aspects were assessed. After a challenge experiment extended for further 28 days, CSNP-therapeutic intervention was assessed on fish survival and systemic inflammatory responses on pathology, histo-morphology, and molecular aspects. With CSNP administration, OSI nonsignificantly decreased and the relative expression of targeted inflammatory-mediator genes was significantly increased. The CSNP-therapeutic fish showed an RPS of 80% as compared to the positive control group, and CSNP-therapeutic administration retained the highest gene expression augmentation up to 28 days after the challenge. Notably, the splenic reticulin fibers framework of the CSNP-therapeutic group retained the highest integrity among the groups during the infection. After recovery, reticulin fibers density in the CSNP-therapeutic samples was significantly higher than in the negative control group, which indicates high innate immunity. Thus, CSNP showed promising biotherapeutic features enhancing fish resistance against infections.

Advanced extramedullary hematopoiesis with a marked increase in reticulin fibers and hemorrhage on various organs: the first autopsy case report.

Myelofibrosis is characterized by stem cell-derived clonal proliferation potentially resulting in bone marrow fibrosis. As the disease progresses, extramedullary hematopoiesis is frequently detected in the spleen and the liver but rarely in other organs. We report a case of a 68-year-old woman with myelofibrosis with a JAK2 mutation, showing extramedullary hematopoiesis (EMH) in various organs with a marked increase in reticulin fibers, and myeloproliferative neoplasm (MPN)-related necrotizing crescent glomerulonephritis. She was admitted to our hospital owing to respiratory discomfort. Computed tomography revealed a mass in the anterior mediastinum. Ten days later, the patient died owing to respiratory distress. At autopsy, EMH were detected in the anterior mediastinum, heart, lung, spleen, and the kidney with a marked increase in reticulin fibers. We considered that respiratory distress was partially caused by EMH. In the kidney, necrotizing crescent glomerulonephritis was observed. Immunohistochemically, the glomerular basement and mesangial area were IgA- and C3d-positive. Ultrastructural examination revealed the presence of dense deposits in the subendothelial space and the mesangial and paramesangial areas. Thus, we suspected that MPN-related necrotizing crescentic glomerulonephritis harbored a pathogenesis similar to that of IgA-dominant post-infectious glomerulonephritis or IgA nephropathy. This case report could widen the spectrum of MPN- or EMH-related lesions.

Association of mast cells and bone marrow reticulin fibrosis in patients with bcr-abl negative chronic myeloproliferative neoplasms.

BACKGROUND: We aimed to investigate the association of bone marrow mast cell numbers (MCN) and the degree of reticulin fibrosis in patients with chronic myeloproliferative neoplasms (MPN). METHODS: This was a case-control study that recruited 47 patients who were diagnosed with bcr-abl negative MPN. Thirty patients with lymphoma served as controls. JAK2 mutation was studied and all subjects underwent bone marrow biopsy at the time of diagnosis. Mast and CD34+ cells were counted. Marrow reticulin fiber was graded. RESULTS: Thirty-four patients had essential thrombocythemia (ET), 8 patients had primary myelofibrosis (PMF) and 5 patients had polycythemia vera (PV). Fourteen MPN patients had JAK2, whereas the controls had not. MCN was higher in patients than controls (p = 0.001). There was no significant difference regarding CD34. Reticulin fibrosis was present in 57.4% of MPN patients, whereas there was any in controls. PMF patients had more CD34 + cells than PV and ET. PMF patients had more reticulin fibers compared with other subgroups (p < 0.001). MCN, but not CD34+ cell counts, was significantly higher in JAK2(+) patients than JAK2(-) patients. CONCLUSION: MCN and reticulin fibrosis were significantly increased in MPN patients. JAK2 positivity had significantly increased MCN compared to patients without JAK2. JAK2 was associated with increased reticulin fibrosis.

Reticulin staining pattern in the differential diagnosis of benign parathyroid lesions.

AIM: A reticulin staining pattern (RSP) can be used for the differential diagnosis of endocrine gland lesions, as in the adrenal and hypophysis glands. We aimed to use RSP for the differential diagnosis of parathyroid gland lesions. MATERIALS AND METHODS: In this study, we evaluated 97 parathyroid lesions in 85 patients, as well as 29 normal parathyroid glands. All sections were stained with a silver impregnation-based kit for the reticulin stain. The RSPs were classified as short thick fiber-, anastomosing- and nodular/alveolar-pattern. The dominant pattern was accepted as being greater than 50% in each section. RESULTS: Short thick fibers and anastomosing and nodular RSPs were seen in adenomas, but there was no alveolar pattern. Although nodular/alveolar patterns were seen in focal areas in hyperplasia, they never became the dominant pattern. Nodular dominant RSPs were seen in adenomas; however, nodular RSPs were not seen in hyperplasia in a dominant pattern (p = 0.049). While short thick fibers were not seen in normal glands, they could be seen in adenomas (p < 0.001) and in hyperplasia (p < 0.001). CONCLUSION: RSPs can be used in the differential diagnosis of parathyroid lesions. While short thick reticular fibers support adenomas and hyperplasia rather than normal tissue, a nodular dominant pattern supports adenomas rather than hyperplasia.

Histomorphometric approach to differentiate skin lesions of tuberculoid leprosy from sarcoidosis.

BACKGROUND: More than 200 000 new cases of leprosy are detected worldwide annually. Physicians commonly have difficulty in differentiating tuberculoid form of leprosy (TL) from sarcoidosis' cutaneous manifestation. METHODS: Skin biopsies of 33 patients with TL and 24 with sarcoidosis were reviewed on hematoxylin and eosin- and Gomori-stained sections, in order to find reliable criteria for distinguishing one disease from another. RESULTS: Nine of the 24 features analyzed presented significant predictive value for diagnosis (P < .05). Predominance of tuberculoid granulomas in adnexal and neural distribution, and granulomas replacing the nerves localized within sweat gland glomeruli were predictive to TL diagnosis. For sarcoidosis, dermal fibrosis, back-to-back distribution of the granulomas, presence of atypical giant cells and plasma cells, greater number of conventional giant cells, and spared nerves beside the granuloma were predictive criteria. The median surface density of reticulin fibers was significantly higher in sarcoidosis (3.44) than in TL (2.99). Nonetheless, using logistic regression, this variable did not discriminate between the diseases (P = .096). CONCLUSIONS: Isolated histological features are not fully predictive to differentiate the 2 diseases. However, those with statistical value can assist this distinction in diagnostic practice. Although the results of the analysis of the reticulin fibers density did not tell apart TL from sarcoidosis, they corroborate the idea of fiber fragmentation within tuberculoid leprosy granulomas, reiterating the importance of morphometry in the histological examination.

Diagnosing pituitary adenoma in unstained sections based on multiphoton microscopy.

PURPOSE: If we can find a new method that can achieve rapid diagnosis of adenoma during operation, it will help surgeon shorten the operation time and enhance the treatment efficacy. This study discusses the feasibility of multiphoton microscopy (MPM) in diagnosing pituitary adenoma. METHOD: MPM, based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) is performed for the diagnosis of pituitary adenoma in unstained sections. RESULTS: Our results show that MPM can reveal the variation of reticulin fiber by SHG signals of collagen, combined with the measurement of area of acinus, thickness of collagen fiber and collagen percentage. MPM can further reflect the change of meshwork in normal pituitary and hyperplasia quantitatively. And the characteristics of typical growth patterns of pituitary adenoma are demonstrated by the overlay of SHG and TPEF images. What's more, we can identify the boundary of normal pituitary, hyperplasia and adenoma from MPM images. And the experiment also results verify the feasibility of this method in frozen sections. CONCLUSION: These results indicated that MPM can make a diagnosis of pituitary adenoma by the morphological changes without routine pathological processing including hematoxylin-eosin (H&E) staining and other special staining. Therefore, this technique is expected to help diagnosis of pituitary adenoma during operation.

TAFRO syndrome successfully treated with tocilizumab: A case report and systematic review.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is considered as a unique clinicopathologic variant of multicentric Castleman's disease and is recently reported in Japan. This entity represents a severe inflammatory state leading to organ failures such as severe liver dysfunction seen in our case, and can be treated by immunosuppressive agents, steroids, and cyclosporine shown in several case reports. A systematic review and our case suggest the potential utility of tocilizumab as a treatment for TAFRO syndrome.

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

AIMS: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications. METHODS AND RESULTS: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients. CONCLUSION: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS.

Rethinking the usefulness of bone marrow biopsy on treatment decision in CLL patients at diagnosis.

We aimed to investigate the role of bone marrow infiltration pattern (BMIP) and bone marrow reticulin fibrosis (BMRF) in determining treatment demand in patients with diagnosis of chronic lymphocytic leukemia (CLL). We retrospectively evaluated the data of 65 patients, who were followed with the diagnosis of CLL at Istanbul Training and Research Hospital, Department of Hematology, between July 2007 and June 2016. The median age of the patients was 64 years (range, 32-83). Twenty-three (35.4%) patients were female, and 42 (64.6%) were male. Early/mild grade BMRF was observed in 46 (70.8%) patients and advanced grade BMRF in 19 (29.2%) patients. Eleven (23.9%) of 46 patients with early/mild grade BMRF and 10 (52.9%) of 19 patients with advanced grade BMRF required treatment during follow-up (p = 0.04). According to the BMIP, 14 (21.5%) patients had diffuse and 51 (78.5%) patients had non-diffuse BMIP. Eleven (78.6%) of 14 patients with diffuse BMIP and 10 (19.6%) of 51 patients with non-diffuse BMIP required treatment during follow-up (p < 0.001). In univariate analysis, both advanced grade BMRF and diffuse BMIP had an impact on occurrence of treatment demand (p = 0.028, HR = 3.535 vs. p < 0.01 HR = 15.033). Multivariate analysis also revealed diffuse BMIP to be effective (p < 0.001, HR 13.089), while advanced grade BMRF failed to significantly influence treatment demand (p = 0.140, HR 2.664). In conclusion, in the light of our findings, it is reasonable to consider that bone marrow biopsy at the time of diagnosis might provide a preliminary information about treatment demand in patients with CLL.

A stiff extracellular matrix is associated with malignancy in peripheral neuroblastic tumors.

PURPOSE AND OBJECTIVE: Improved prognosis for patients with peripheral neuroblastic tumors (PNB) depends on enhanced pretreatment risk stratification combined with research into new therapeutic targets. This study investigated the potential contribution of extracellular matrix (ECM) elements toward this endeavor. METHODS: We characterized certain elements such as reticulin fibers, collagen type I fibers, and elastic fibers by digital pathology in almost 400 untreated PNB. RESULTS: A reticular and poorly porous ECM was identified in neuroblastomas (NBs) from patients with clinical and biological features associated with poor prognosis compared with a loose and permeable matrix found in NBs of the favorable cohort. CONCLUSIONS: Aggressiveness patterns of ECM can be accurately determined by morphometric tools and could become candidate elements for novel therapies.

TAFRO syndrome: 2 cases and review of the literature.

Recently, more than ten cases of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome or Castleman-Kojima disease exhibiting such symptoms as thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly have been reported in Japan. We have found two cases of TAFRO syndrome and have reviewed another eighteen previously reported cases. Histological findings of the lymph nodes and levels of interleukin 6 (IL-6) and vascular endothelial growth factor in both serum/plasma and effusions are important characteristics for diagnosing this syndrome.

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

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.

Changes in bone marrow morphology in adults receiving romiplostim for the treatment of thrombocytopenia associated with primary immune thrombocytopenia.

The effects of romiplostim on bone marrow morphology were evaluated in adults with immune thrombocytopenia (ITP). Patients with platelet counts <50 × 10(9)/L, ≥1 prior ITP therapies, and no collagen at baseline received weekly subcutaneous romiplostim starting at 1 µg/kg, adjusted to maintain platelet counts between 50 and 200 × 10(9)/L. Biopsies were scheduled after 1, 2, or 3 years of romiplostim (cohorts 1, 2, and 3, respectively). Irrespective of scheduled time, biopsies were performed earlier if patients discontinued or failed to achieve/maintain a response to romiplostim. Reticulin (silver stain) and collagen (trichrome stain) were graded by two hematopathologists using the modified Bauermeister scale (0-4). Of 169 patients, 131 had evaluable biopsies; 9/131 (6.9 %) had increases of ≥2 grades on the modified Bauermeister scale (cohort 1: 0/34; cohort 2: 2/39; cohort 3: 7/58), including two with collagen. Three of the nine patients had follow-up biopsies, including one patient with collagen; changes were reversible after romiplostim discontinuation. Of the nine patients, one had neutropenia detected by laboratory test and two had adverse events of anemia, both non-serious and not treatment-related. By actual exposure (as some biopsies did not occur as scheduled), the number of patients with grade increases ≥2 were year 1: 3/41, year 2: 1/38, year 3: 5/52. Twenty-four patients sustained platelet counts ≥50 × 10(9)/L for ≥6 months with no ITP medications after discontinuing romiplostim, i.e., they entered clinical remission of their ITP. In conclusion, in patients with ITP receiving romiplostim, bone marrow changes were observed in a small proportion of patients.ClinicalTrials.gov identifier: NCT#00907478.

Histopathology of the filum terminale in children with and without tethered cord syndrome with attention to the elastic tissue within the filum.

PURPOSE: To compare histologically transected fila from pediatric patients with tethered cord syndrome (TCS), with and without a low conus, with controls, focusing on collagenous and elastic tissue. METHODS: Thirty fila from patients with TCS, including 5 where minimal cautery was used prior to filum section, were compared with fila from 27 pediatric cadavers without TCS (controls). Sections of fila were stained with H&E, Masson trichrome and Verhoeff von Gieson elastic stains, and 7 with Gordon and Sweet's reticulin stain. RESULTS: Fila from controls showed loose fibrous connective tissue (FCT) with thin and evenly dispersed elastic fibers (EFs). Reticulin fibers (RFs) were seen in blood vessel walls and nerve twigs. Fat was identified microscopically in 2 fila. All fila from patients with TCS had dense FCT. The EFs were in normal numbers in 17, and focally or diffusely decreased in 13. All 25 patients where the fila were cauterized during resection had thick and coiled EFs. Coiling was not seen when minimal cautery was applied. RFs were seen in blood vessel walls and nerve twigs. Fat was identified in 19 patients. Findings were similar, whether the conus termination was normal or low. CONCLUSION: The fila of all patients with TCS, whether or not the conus was low, showed abnormal FCT. EFs were decreased in 48 % of patients; however, there were thick and coiled EFs in all patients. Coiling of EFs, initially thought to be an abnormality in patients, is considered most likely to be a result of cautery (i.e., artifactual/iatrogenic coiling).

United Kingdom immune thrombocytopenia registry: retrospective evaluation of bone marrow fibrosis in adult patients with primary immune thrombocytopenia and correlation with clinical findings.

Fibrosis has been reported in some patients with immune thrombocytopenia (ITP) treated with thrombopoietin receptor agonists (TPO-RA). However, fibrosis has also been reported in patients with various stages of ITP, who were TPO-RA treatment-naïve. In our study, we looked for fibrosis in bone marrow trephine biopsies taken at initial diagnosis from 32 adult patients with ITP. Ten of the 32 evaluated samples (31·25%) showed increased reticulin (Grade 1-2 on Bauermeister scale and Grade 0-1 on the European Consensus scale), which showed a positive correlation with ethnicity (0·3%) but did not correlate with disease severity, any clinical features or co-morbidities.

Fibrogenesis in Primary Myelofibrosis: Diagnostic, Clinical, and Therapeutic Implications.

Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis, osteosclerosis, and pathologic angiogenesis. Bone marrow fibrosis (BMF) plays a central role in the pathophysiology of the disease. This review describes current issues regarding BMF in primary myelofibrosis, including the pathophysiology and impact of abnormal deposition of excess collagen and reticulin fibers in bone marrow spaces, the modified Bauermeister and the European Consensus grading systems of BMF, and the prognostic impact of BMF on the overall outcome of patients with primary myelofibrosis. The impact of novel therapeutic strategies, including JAK-STAT inhibitors and allogeneic stem cell transplant, on BMF is discussed.