Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study

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Bone marrow mast cell quantification is proposed as a supplementary diagnostic and prognostic tool to differentiate AA from MDS-h. We aim to study the distribution of mast cells in hypoplastic marrow and determine its role in differential diagnosis of AA and MDS-h. Methods We analysed bone marrow biopsies of 65 cases of hypoplastic/aplastic marrow received during the year 2015-2021 for the distribution of mast cells using Toluidine Blue special staining. Hematopoietic stem cells were assessed with the help of CD34 immunohistochemistry. Results Increased mast cells were noted in 55.4% of all the cases, of which 48% were cases of AA and 21% were cases of MDS-h (P: 0.04). Overall, 76% of AA and 33% of MDS-h cases showed increased numbers of mast cells. Reduced hematopoietic stem cells were noted in 69.4% of the cases with elevated mast cells (P: 0.1). Conclusions Mast cell quantification in trephine biopsy of AA and MDS-h can act as a supplementary diagnostic tool and guide the management of the respective entities. " } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/12-823/v2", "name": "Diagnostic utility of mast cell analysis in hypoplastic bone marrows..." } } ] } Home Browse Diagnostic utility of mast cell analysis in hypoplastic bone marrows... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article G V C, Gupta S, Rao R et al. Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.12688/f1000research.130876.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] Chaithra G V https://orcid.org/0000-0002-5906-5197 1 , Soumya Gupta https://orcid.org/0000-0002-4067-6801 1 , Ranjitha Rao https://orcid.org/0000-0001-9786-0485 1 , Sharada Rai 1 , Nirupama Murali 1,2 , Sunita Hegde https://orcid.org/0000-0002-7944-5277 1 Chaithra G V https://orcid.org/0000-0002-5906-5197 1 , Soumya Gupta https://orcid.org/0000-0002-4067-6801 1 , [...] Ranjitha Rao https://orcid.org/0000-0001-9786-0485 1 , Sharada Rai 1 , Nirupama Murali 1,2 , Sunita Hegde https://orcid.org/0000-0002-7944-5277 1 PUBLISHED 14 Apr 2025 Author details Author details 1 Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India 2 Department of Pathology, Dr. Chandramma Dayanand Sagar Institute of Medical Education and Research., Bangalore, India Chaithra G V Roles: Conceptualization, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Review & Editing Soumya Gupta Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Resources, Software, Visualization, Writing – Original Draft Preparation Ranjitha Rao Roles: Formal Analysis, Investigation, Supervision, Visualization, Writing – Review & Editing Sharada Rai Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing Nirupama Murali Roles: Conceptualization, Methodology, Writing – Review & Editing Sunita Hegde Roles: Formal Analysis, Investigation, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Manipal Academy of Higher Education gateway. This article is included in the Oncology gateway. Abstract Background Haematological disorders characterized by hypocellular marrow like aplastic anaemia (AA) and hypocellular myelodysplastic neoplasm (MDS-h) are diagnostic challenges as the clinical and morphological features overlap, while the treatment and prognosis differ. Bone marrow mast cell quantification is proposed as a supplementary diagnostic and prognostic tool to differentiate AA from MDS-h. We aim to study the distribution of mast cells in hypoplastic marrow and determine its role in differential diagnosis of AA and MDS-h. Methods We analysed bone marrow biopsies of 65 cases of hypoplastic/aplastic marrow received during the year 2015-2021 for the distribution of mast cells using Toluidine Blue special staining. Hematopoietic stem cells were assessed with the help of CD34 immunohistochemistry. Results Increased mast cells were noted in 55.4% of all the cases, of which 48% were cases of AA and 21% were cases of MDS-h (P: 0.04). Overall, 76% of AA and 33% of MDS-h cases showed increased numbers of mast cells. Reduced hematopoietic stem cells were noted in 69.4% of the cases with elevated mast cells (P: 0.1). Conclusions Mast cell quantification in trephine biopsy of AA and MDS-h can act as a supplementary diagnostic tool and guide the management of the respective entities. READ ALL READ LESS Keywords Mast cell, Aplastic anaemia, MDS-h, Hypocellular marrow, Bone marrow niche, CD34, Hematopoietic stem cell. Corresponding Author(s) Soumya Gupta ( [email protected] ) Close Corresponding author: Soumya Gupta Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 G V C et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: G V C, Gupta S, Rao R et al. Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.12688/f1000research.130876.2 ) First published: 13 Jul 2023, 12 :823 ( https://doi.org/10.12688/f1000research.130876.1 ) Latest published: 14 Apr 2025, 12 :823 ( https://doi.org/10.12688/f1000research.130876.2 ) Revised Amendments from Version 1 The criteria used to categories AA and MDS-h was not mentioned in the previous version. The criteria used to categories AA and MDS-h was not mentioned in the previous version. See the authors' detailed response to the review by Valentina Giudice READ REVIEWER RESPONSES Introduction Haematological disorders characterised by hypocellular marrows like aplastic anaemia (AA) and hypocellular myelodysplastic neoplasm (MDS-h) are diagnostic challenges for haematologists as AA, MDS-h, other immune cytopenias, paroxysmal nocturnal haemoglobinuria (PNH), and inherited bone marrow (BM) failure disorders are all considered BM failure states with significant clinicopathological overlap. 1 – 3 However, the differentiation is critical as both AA and MDS-h have different management protocols with varying outcomes and prognoses. Compared to patients with AA, those with MDS-h have shorter median survival rates and exhibit a lower response to immunosuppressive therapy. 4 , 5 AA is defined as pancytopenia in the peripheral blood secondary to BM hypocellularity and is a diagnosis of exclusion. 6 MDS is a diverse collection of clonal disorders that affect the hematopoietic stem cells (HSCs) and are characterised by cytopenias of varying degrees in the peripheral blood and inefficient haematopoiesis with BM dysplasia. Myelodysplasias with hypocellular BM (MDS-h) comprises around 10–15% of all MDS cases and are characterized by BM hypocellularity. Both AA and MDS-h share a common pathophysiological pathway with CD34 positive progenitor cells being fundamental in the pathogenesis of both these entities. CD34 positive HSCs are the target of autoimmune attack in AA making its count significantly decreased in the BM of AA. Whereas CD34 progenitor cells are the cells from which MDS originates. This explains the elevated quantity of CD34 positive cells in the BM of patients with MDS as a result of neoplastic clonal expression. 3 Recent studies have proposed an additional mechanism exploring the possibility of the role of BM niche in the pathogenesis of AA. The BM microenvironments also known as the stem cell niche comprises endosteal cells, macrophages, fat cells, fibroblasts, mast cells and microvascular endothelial cells. 7 The stem cell microenvironment transmits signals to maintain the fundamental features of the HSCs such as the ability to self-regenerate and the capacity to reproduce all the lineages. Thus, alteration in the BM niche was considered as a potential cause of hematopoietic impairment; however, the ways in which these changes affect the development of the disease remains unclear. 8 Several researchers have studied the correlation between the BM microenvironment and dysregulated haematopoiesis. Alterations in the components of the microenvironment in the BM, including lymphocytes, mast cells, macrophages, and stromal cells, may be associated with the impaired haematopoiesis leading to AA and/or myeloproliferative neoplasms. The quantitative increase of mast cells in AA cases has been demonstrated in several studies and has resulted in the hypothesis that mast cells can cause cytotoxic effects on the hematopoietic cells in the marrow. 8 Mast cells originate from BM progenitor cells and migrate into various tissues to complete their maturation. BM mast cell quantification is proposed as a supplementary diagnostic and prognostic tool to differentiate AA from other BM failure conditions like MDS-h. 5 The percentage of mast cells in the BM is generally less than 1% of all the nucleated cells in the marrow and is distributed singly. 9 Mast cells stain metachromatically with Toluidine blue (TB), which stains the granules of mast cells purple to red. Histological staining with TB is a highly effective, rapid, direct and antibody-free technique to detect mast cells in tissue sections. 10 , 11 Mast cells have longer life spans and are not directly targeted by the autoimmune attack on the stem cell compartment, resulting in the relative increase in its number in the BM of patients with AA. The quantitative increase in mast cell is clonal in mastocytosis and benign in acquired AA. However, its nature is not completely understood in AA and MDS-h. 12 , 13 In AA, lower mast cell count is related to better prognosis, but no such relation exists in MDS. 5 Several researchers have shown increased numbers of mast cells in cases of AA and have proposed an association between the increased mast cells in the BM with the poor outcome of the patients. 14 , 15 Irrespective of the involved mechanism, a surge in the quantity of mast cells is assumed to be a factor responsible for the reduced cellularity observed in AA and MDS-h. 16 , 17 Therefore, the present study aimed to evaluate the diagnostic utility of mast cell quantification in hypoplastic marrow (HM) to distinguish AA from MDS-h. Furthermore, the association of increased mast cells with decreased HSC in the BM of such entities was analysed. Methods Ethical consideration All procedures performed in the current study were approved by Institutional Ethical Board, Kasturba Medical College, Mangalore (reference no.: IEC KMC MLR 12-2020/452 date: 24/12/2020). Formal written informed consent was not required since this study used retrospective biopsy samples and we received a waiver by the Institutional Ethical Board, Kasturba Medical College, Mangalore. Study design and setting A time bound retrospective study was conducted at the Department of Pathology, Kasturba Medical College, Mangalore, MAHE, from 25th December 2020 to September 2022, after ethical clearance. Inclusion and exclusion criteria Cases of hypoplastic/aplastic BM biopsies received from January 2015 to December 2021 were included in the study. We calculated a minimum sample size of 58, considering 80% power, 95% confidence level and a relative precision of 10%. Overall, 65 cases met the inclusion criteria of adequate marrow biopsy measuring at least 1 cm in length with minimum four marrow spaces. Cases with measurable disease positive leukaemia, those with poorly preserved paraffin blocks and inadequate biopsies were excluded. Clinical data like age, sex and any other significant details were obtained from the laboratory information system and the medical records department. Our study follows the Sager guidelines for reporting sex and gender information. Sex and gender differences were not taken into consideration for the design of the study. The information regarding the sex of the cases was collected from the lab information system and not determined by the investigators as it is a retrospective study done on archived slides and blocks. The slides and paraffin blocks of all the cases were retrieved and reviewed and the diagnosis of hypoplasia/aplasia was confirmed. Operating procedures and data analysis The H&E-stained tissue sections were studied to assess the cellularity and to identify the morphology of the marrow. All the cases were categorised into three categories namely, AA, MDS-h and HM due to any other cause according to their cytomorphological and haematological features. Cases of hypocellular marrow with persistent pancytopenia (>6 months), trilineage suppression in the BM and absence of abnormal cells and reticulin fibrosis along with at least 2 of the following hematological parameter: absolute neutrophil count <1.5 × 10 9 /L, platelet count <50 × 10 9 /L, hemoglobin <10 g/dl was put in the category of AA. Cases with hypocellular marrow with variable degree of cytopenia along with dysplasia in at least 10% of cells in one of the three lineages was put in the category of MDS-h. The remaining cases of hypoplastic marrow (BM cellularity less than 30% marrow cells in individuals who are younger than 60 years of age and less than 20% marrow cells in individuals above 60 years) which did not fulfill the criteria of the above two categories were categorised under HMs due to other causes. 1 – 4 The special staining was done on paraffin embedded, formalin fixed tissue that was assessed for morphology. A representative block was selected in every case and TB special staining was performed, where 1% TB stain (1 gm TB in 100 ml H 2 O) was poured over the slides and kept for 90 seconds. The slides were then washed, dried and mounted. Quantification of mast cells was done by identifying the metachromatic granules in mast cell cytoplasm. Total number of mast cells was counted per 200 nucleated cells in 5-10 randomly selected high power fields. Mast cell percentage amongst all nucleated cells was calculated. Mast cell percentage of more than one was quantified as increased. Immunohistochemistry (IHC) for CD34 was performed on paraffin embedded, formalin fixed tissue that was assessed for morphology. A representative block was selected in every case. IHC staining was performed with a mouse monoclonal antibody against CD34 (Diagnostic BioSystems Cat# PDM050, RRID:AB_2934004). SITVue/DAB Detection System (Diagnostic BioSystems Cat# SIT-100D) was used as an intensification system to enhance the chromogenic signals of the primary antibody. The detailed description of all the procedural steps is available in Figshare. 25 Evaluation for CD34 was done in the cytoplasm of the hematopoietic progenitor cells and the number of positive cells was counted and assessed as less than or more than 0.5% of the total hematopoietic cells. Statistical analysis Data were analysed using IBM SPSS Statistics (RRID:SCR_016479) 25.0 version. The statistical significance of all variables was calculated using the Chi-squared test and Fisher’s exact test. P<0.05 was taken to be significant. Results This study included a total of 65 cases of hypoplastic and aplastic marrows that met the inclusion and exclusion criteria, of which 21 (32.3%) cases were AA, 12 cases were MDS-h (18.5%) and 32 (49.2%) cases were diagnosed as HM. A bimodal peak was noticed in the age distribution pattern with the majority of the population being from the paediatric and adolescent age group (32.3%) and the second peak comprising of people above 60 years of age (28.7%). The rest of the cases belonged to the age group of 20-60 years old. Slight male predilection was noted with M: F ratio being 1.6:1. Overall, 38% (25) of the total population were female and 62% (40) of the population were male. The demographic data of the individual cases are available as Underlying data. 25 Mast cells in the BM were highlighted by staining them with TB. Mast cells were counted amongst 200 nucleated cells. More than 1% of mast cells were seen in 36 (55.4%) of the total cases. Seven (10.8%) cases showed more than 10% of mast cells. Mast cell count of more than 1% was considered as increased. Increased numbers of mast cells were observed in most of the cases of AA (31, 48%) followed by HM (20, 31%), and MDS-h (14, 21%), while the rest of the cases showed less than 1% of mast cells in their marrow. The Chi squared test was done with respect to the increased number of mast cells and the different entities of AA, MDS-h and other causes of HM was significant (P: 0.040). The distribution of the increased mast cells amongst the various differentials in the contingency table is depicted in Table 1 . Metachromatically stained mast cells in light microscopy in a case of AA and MDS-h are depicted in Figure 1 and Figure 2 , respectively. These microphotographs are annotated and minimally cropped. The original unprocessed microphotographs are available as Underlying data. 25 Table 1. Distribution of cases with increased mast cells in AA, HM and MDS-h. AA, aplastic anaemia; HM, hypoplastic marrow; MDS-h, hypocellular myelodysplastic neoplasm. Increased mast cells AA HM MDS-h Count, n Percentage, % Count, n Percentage, % Count, n Percentage, % Absent 5 23.8 16 50.0 8 66.7 Present 16 76.2 16 50.0 4 33.3 Total 21 100.0 32 100.0 12 100.0 P value 0.04 Figure 1. Aplastic anaemia in 37 year old female patient. A: In low power view aplastic marrow is seen with cellularity less than 10% in the marrow spaces (magnification, 20×, H&E). B: Toluidine blue special staining in low power view shows metachromatically stained mast cells (magnification, 20×, Toluidine blue staining). C: Toluidine blue special staining in high power view shows six metachromatically stained mast cells in around 20-22 nucleated cells (magnification, 40×, Toluidine blue staining). Figure 2. Hypocellular myelodysplastic neoplasm in 16 year old male patient. Toluidine blue special staining in high power view shows four metachromatically stained mast cells in around 200 nucleated cells (magnification, 40×, Toluidine blue staining). CD34 IHC expression was assessed to calculate HSCs and categorised as more than and less than 0.5% of positive cells (decreased) amongst all the hematopoietic cells of the marrow. Decreased expression was noted in 45 (69.2%) of the cases. An increased number of mast cells was seen in 36 (55.45%) cases of the total study population while significantly decreased/absent HSCs were seen in 45 (69.2%) cases. A total of 25 (69.4%) of the cases that showed an increased number of mast cells also showed significantly decreased HSCs. Whereas 26 (57.7%) of the cases that had decreased HSCs showed an increased number of mast cells. However, the association between decreased HSCs and increased mast cells was statistically insignificant (Chi squared test, P: 0.10). The contingency table of the same is depicted in Table 2 . Table 2. Distribution of increased mast cells in cases with decreased HSCs. HSC, hematopoietic stem cell. Increased mast cells Decreased HSC Count, n Percentage, % Absent 19 42.22% Present 26 57.7% Total 45 100.0% P value 0.1 Discussion BM failure conditions with marrow that is hypocellular for age embodies a broad spectrum of acquired and inherited conditions. Patients with MDS-h are known to have a worse prognosis than those with AA because they are more prone to neoplastic progression. 18 Haematologists still continue to struggle in making a precise diagnosis due to the blurred lines between AA, other mimicking conditions like MDS-h and the various inherited BM failure syndromes. Identifying the exact disorder leading to a HM is critical as the cause of the disease significantly affects the choice of therapy. 19 , 20 BM evaluation, comprising of both trephine biopsy and aspirate, is obligatory to ascertain the diagnosis. There is convincing evidence that these discrete haematological conditions share a conjoint pathophysiological pathway centred at the alteration and/or damage of the hematopoietic stem and progenitor cells (HSPCs) by the cytotoxic effect of T cells. Increased T cells produce excessive proinflammatory cytokines (interferon-γ and tumor necrosis factor-α), leading to the reduced proliferation and increased apoptosis of the HSPCs. 21 The distinction between AA and MDS-h is mostly dependent on the histomorphological and IHC features of the BM but in HMs it is challenging due to the scarcity of the hematopoietic cells present in the BM and the overlapping of the cytomorphological features of both the entities. 4 Erythroid dysplasia is not uncommon in AA and thus cannot be used as a sole distinguishing feature. Mast cell quantification in the BM was performed by several researchers and a common finding of increased number of mast cells in HMs was observed. 14 – 16 , 22 In our study we considered more than 1% of mast cells per 200 nucleated cells as the cut off for defining increase in the quantity of mast cells. The results in our study were similar to other studies with elevated mast cells seen in 55.4% of the total cases out of which the majority of the cases were AA (P<0.05). The quantity of mast cells ranged from 0-100 mast cells per 200 nucleated cells. The case with the highest number of mast cells belonged to the category of AA. However, the variation in the quantity of mast cells in both AA and MDS-h lies in the same range. This is consistent with the findings of Ingrid Fohlmeister 22 done on 48 cases of different forms of MDS and 59 cases of AA. They demonstrated that there was overlap in the number of mast cells found in the BM of individuals with AA and MDS-h. The number of mast cells varied from 0-205/mm 2 . Complex interactions between the hematopoietic cells and the BM niche occur during haematopoiesis, although the exact cause and mechanism involved in the deregulated haematopoiesis is unknown. HSCs reside in a specialized microenvironment (niche) in the BM. BM microenvironment is important in maintaining the function of HSC as it is thought to transmit signals sustaining key HSC properties like regenerating capability and multilineage reproducing capacity. Thus, alteration in the BM niche can be a potential factor associated with hematopoietic impairment. However, it is still unclear how these changes contribute to the development of the disease. In cases of idiopathic AA, the ineffective haematopoiesis can be considered as a result of some unknown changes in the BM microenvironment. Mast cells are considered by some researchers as a cause of the ineffective haematopoiesis in AA as it stimulates apoptosis and auto immune attack by cytotoxic killer cells. Studies have demonstrated that the BM of patients with AA shows increases in the quantity of mast cells and natural killer (NK) cells reflecting the cytotoxic or immune-mediated damage of the marrow. 8 , 11 Our study strengthens this hypothesis as 17 (48%) of the cases that showed an increased number of mast cells belonged to the patients with AA. Thus, increases in the numbers of mast cells can be considered as a causative factor for the insufficient haematopoiesis. However, in our study the association between increased mast cells and reduced HSCs was statistically insignificant. Patients with AA may have altered BM niches that contribute to the disease pathophysiology or cause ineffective haematopoiesis. Quantification of mast cell can help in identifying the prognosis of the cases of AA. Reduced numbers of mast cells are a good prognostic indicator in AA while no such relation is observed in cases of MDS. 16 Although hematopoietic stem cell transplantation plays a frontline role in the treatment of haemato-oncological conditions, there are still significant issues that need to be resolved, including the difficulty in finding matched donors and the ineffective engraftment of HSCs into the BM. An improved comprehension of the interactions amongst each component of the BM niche can help in identifying the potential therapeutic targets in cases of BM failure as well as myeloproliferative disorders. 23 Simulating the hematopoietic niche is a promising method for effectively increasing the number of HSPCs and fine-tuning their features ex vivo. The creation of a functioning hematopoietic microenvironment in vitro is still constrained by attempts to replicate it without a thorough grasp of the specific roles played by individual components involved in the hematopoietic setting. We believe that the detailed knowledge of the crucial cells in the BM microenvironment and the way they affect the regulation of HSCs can aid in establishing an ex vivo structural arrangement for the expansion of HSCs to provide a novel source of therapeutic blood cells for haematological disorders. 23 , 24 In conclusion, mast cell quantification in the BM biopsies with the help of TB special stain can act as a supplementary tool to distinguish the two entities as mast cells are increased in the majority of the cases of AA, while it is increased only in a few cases of MDS-h. Data availability Underlying data Figshare: mast cell quantification raw data.xlsx. https://doi.org/10.6084/m9.figshare.21966848 . 25 This project contains the following underlying data: 1. Excel sheet of complete data: rawdata.xlsx 2. STROBE_checklist. Mast cell quantification.docx 3. Unprocessed microphotographs: 1.jpeg, 2.jpeg, 3.jpeg, 4.jpeg, 5.jpeg, 6.jpeg 4. Procedure of CD34 IHC staining.docx Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). References 1. Tuzuner N, Cox C, Rowe JM, et al. : Hypocellular myelodysplastic syndromes (MDS): new proposals. Br. J. Haematol. 1995 Nov; 91 (3): 612–617. PubMed Abstract | Publisher Full Text 2. Tuzuner N, Bennett JM: Reference standards for bone marrow cellularity. Leuk. Res. 1994 Aug; 18 (8): 645–647. PubMed Abstract | Publisher Full Text 3. 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Giudice V, Selleri C: Aplastic anemia: pathophysiology. Semin. Hematol. 2022 Jan; 59 (1): 13–20. PubMed Abstract | Publisher Full Text 9. Orfao A, Escribano L, Villarrubia J, et al. : Flow cytometric analysis of mast cells from normal and pathological human bone marrow samples: identification and enumeration. Am. J. Pathol. 1996; 149 (5): 1493–1499. PubMed Abstract 10. Ribatti D: The staining of mast cells: A historical overview. Int. Arch. Allergy Immunol. 2018; 176 (1): 55–60. PubMed Abstract | Publisher Full Text 11. Puebla-Osorio N, Sarchio SNE, Ullrich SE, et al. : Detection of infiltrating mast cells using a modified toluidine blue staining. Methods Mol. Biol. 2017; 1627 : 213–222. PubMed Abstract | Publisher Full Text 12. Natkunam Y, Rouse RV, Zhu S, et al. : Immunoblot analysis of CD34 expression in histologically diverse neoplasms. Am. J. Pathol. 2000; 156 (1): 21–27. PubMed Abstract | Publisher Full Text | Free Full Text 13. Dasgupta S, Mandal PK, Chakrabarti S: Etiology of pancytopenia: an observation from a referral medical institution of eastern region of India. J. Lab. Phys. 2015; 7 (2): 090–095. Publisher Full Text 14. Orazi A, Albitar M, Heerema NA, et al. : Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anemia by CD34 and PCNA immunostaining of bone marrow biopsy specimens. Am. J. Clin. Pathol. 1997 Mar; 107 (3): 268–274. PubMed Abstract | Publisher Full Text 15. Özdemir Ö, Ravindranath Y, Savaşan S: Evaluation of long-term liquid culture grown human bone marrow mast cell cytotoxicity against human leukemia cells. Blood. 2002; 100 : 3690–3697. PubMed Abstract 16. Ozdemir O, Savaşan S: The role of mast cells in bone marrow diseases. J. Clin. Pathol. 2004 Jan; 57 (1): 108–109. PubMed Abstract | Publisher Full Text 17. Skibenes ST, Clausen I, Raaschou-Jensen K: Next-generation sequencing in hypoplastic bone marrow failure: what difference does it make? Eur. J. Haematol. 2021 Jan; 106 (1): 3–13. PubMed Abstract | Publisher Full Text 18. Khoury JD, Solary E, Abla O, et al. : The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022 Jul; 36 (7): 1703–1719. PubMed Abstract | Publisher Full Text | Free Full Text 19. Rohira N, Meenai FJ: A cross sectional study of clinical and aetiological profile of pancytopenia at a tertiary care hospital in Bhopal. Indian J. Pathol. Oncol. 2019; 6 (1): 67–74. Publisher Full Text 20. Drexler B, Tichelli A, Passweg JR: Bone marrow failure. Ther. Umsch. 2019; 76 (9): 523–529. PubMed Abstract | Publisher Full Text 21. Dhanjal TS, Pendaries C, Ross EA, et al. : A novel role for PECAM-1 in megakaryocytokinesis and recovery of platelet counts in thrombocytopenic mice. Blood. 2007 May 15; 109 (10): 4237–4244. PubMed Abstract | Publisher Full Text 22. Fohlmeister I, Reber T, Fischer R, et al. : Bone marrow mast cell reaction in preleukaemic myelodysplasia and in aplastic anaemia. Virchows Arch. A Pathol. Anat. Histopathol. 1985; 405 (4): 503–509. PubMed Abstract | Publisher Full Text 23. Costa MHG, de Soure AM , Cabral JMS, et al. : Hematopoietic niche - exploring biomimetic cues to improve the functionality of hematopoietic stem/progenitor cells. Biotechnol. J. 2018 Feb; 13 (2). PubMed Abstract | Publisher Full Text 24. Negendank W, Weissman D, Bey TM, et al. : Evidence for clonal disease by magnetic resonance imaging in patients with hypoplastic marrow disorders. Blood. 1991 Dec 1; 78 (11): 2872–2879. PubMed Abstract | Publisher Full Text 25. Gupta S: mast cell quantification raw data.xlsx. [Dataset]. figshare. 2023. Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 13 Jul 2023 ADD YOUR COMMENT Comment Author details Author details 1 Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India 2 Department of Pathology, Dr. Chandramma Dayanand Sagar Institute of Medical Education and Research., Bangalore, India Chaithra G V Roles: Conceptualization, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Review & Editing Soumya Gupta Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Resources, Software, Visualization, Writing – Original Draft Preparation Ranjitha Rao Roles: Formal Analysis, Investigation, Supervision, Visualization, Writing – Review & Editing Sharada Rai Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing Nirupama Murali Roles: Conceptualization, Methodology, Writing – Review & Editing Sunita Hegde Roles: Formal Analysis, Investigation, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 14 Apr 2025, 12:823 https://doi.org/10.12688/f1000research.130876.2 version 1 Published: 13 Jul 2023, 12:823 https://doi.org/10.12688/f1000research.130876.1 Copyright © 2025 G V C et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article G V C, Gupta S, Rao R et al. Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.12688/f1000research.130876.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 14 Apr 2025 Revised Views 0 Cite How to cite this report: Tashi T. Reviewer Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.180489.r381834 ) The direct URL for this report is: https://f1000research.com/articles/12-823/v2#referee-response-381834 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 May 2025 Tsewang Tashi , University of Utah and Salt Lake City Veterans Affairs Medical Center, Salt Lake City,, Utah, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.180489.r381834 This manuscript discusses the use of mast cells as an aide to differentiate aplastic anemia (AA) with hypoplastic MDS (h-MDS). The authors analyzed bone marrow samples of 65 cases, in a retrospective manner, and evaluated for mast cells using Toludine ... Continue reading READ ALL This manuscript discusses the use of mast cells as an aide to differentiate aplastic anemia (AA) with hypoplastic MDS (h-MDS). The authors analyzed bone marrow samples of 65 cases, in a retrospective manner, and evaluated for mast cells using Toludine blue stain and CD34 IHC. Although the hypothesis is sound and there are existing literature on this subject, I have few questions/concerns: 1) The criteria for classifying cases into either AA or MDS-h seem arbitrary, based on marrow morphology and clinical/lab information alone. There is no cytogenetics, FISH studies or molecular information available, which could actually be quite informative in aiding diagnosis. 2) Mast cells were stained with Toludine blue, which is OK. But it was not confirmed further with CD117 stain or tryptase stain to corroborate. Toludine blue can also stain basophils. 3) The authors note increased mast cells and describes them in percentages. Is the percentage of the whole marrow cellularity? 4) The authors did not look at mast cells morphologically under a microscope (except for a representative case). Are all the increased mast cells normal mast cells? Could there be mastocytosis? 5) If the hypothesis is that increased mast cells suppress hematopoiesis and deplete CD34 HSCs, then why don't we see that in systemic mastocytosis? 6) I think overall there are a lot of unanswered questions on the association and role of mast cells in AA and MDS-h, that it is quite premature at this stage to suggest is as a tool for diagnostic use, as the authors have claimed in their title. 7) Minor comment: Please use the term "hypoplastic MDS" consistently throughout. Authors have used different terms - "hypocellular MDS", "Myelodysplasia with hypocellular marrow" in the manuscript. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Myeloid malignancies and mastocytosis. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Tashi T. Reviewer Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.180489.r381834 ) The direct URL for this report is: https://f1000research.com/articles/12-823/v2#referee-response-381834 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 13 Jul 2023 Views 0 Cite How to cite this report: Giudice V. Reviewer Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.143665.r211585 ) The direct URL for this report is: https://f1000research.com/articles/12-823/v1#referee-response-211585 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 01 Nov 2023 Valentina Giudice , University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.143665.r211585 In this manuscript, Gupta et al. have investigated frequency of bone marrow mast cells in aplastic anemia (AA) and hypoplastic myelodysplastic syndromes (hMDS), as have proposed this cellular marker for differential diagnosis of these bone marrow failure syndromes. However, several ... Continue reading READ ALL In this manuscript, Gupta et al. have investigated frequency of bone marrow mast cells in aplastic anemia (AA) and hypoplastic myelodysplastic syndromes (hMDS), as have proposed this cellular marker for differential diagnosis of these bone marrow failure syndromes. However, several issues are present: This is a case series study and should be clearly stated also in the title. Indeed, to claim a "diagnostic utility" of a marker, more cases are required. In this case, the analysis is carried out on a total of 21 AA and just 12 hMDS, without a control cohort of non hypoplastic MDS. Diagnostic criteria used for AA and hMDS are not stated. Mastocytosis was ruled out? c-Kit mutations were excluded? No additional information on mast cell phenotype was reported, as mast cell related (tryptase, chymase, CD25, and CD117) antigens can be investigated also by IHC. Mast cells have been associated with neoangiogenesis also in MDS 1 , and could be increased in higher-risk MDS; therefore, some indications on clinical features of those patients should be clearly indicated at least in a table. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly References 1. Ribatti D, Polimeno G, Vacca A, Marzullo A, et al.: Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes. Leukemia . 2002; 16 (9): 1680-4 PubMed Abstract | Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Bone marrow failure syndromes; flow cytometry immunophenotyping I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Giudice V. Reviewer Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.143665.r211585 ) The direct URL for this report is: https://f1000research.com/articles/12-823/v1#referee-response-211585 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 14 Apr 2025 Soumya Gupta , Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India 14 Apr 2025 Author Response Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in ... Continue reading Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in sufficient detail and meeting all applicable standards of ethics of experimentation and research integrity. It is not just a collection and description of cases to be called as a case series. 2. In our study we included only the cases with hypoplastic marrows and none of the cases showed aggregates of mast cell to consider mastocytosis. However due to financial constraints additional IHC for mast cell phenotype and ckit mutation studies could not be performed. 3. We agree to your point that our sample size is less, which is a limitation of our study. 4. We would add the diagnostic criteria used to categories AA and MDS-h in the next version of the article. Thankyou. Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in sufficient detail and meeting all applicable standards of ethics of experimentation and research integrity. It is not just a collection and description of cases to be called as a case series. 2. In our study we included only the cases with hypoplastic marrows and none of the cases showed aggregates of mast cell to consider mastocytosis. However due to financial constraints additional IHC for mast cell phenotype and ckit mutation studies could not be performed. 3. We agree to your point that our sample size is less, which is a limitation of our study. 4. We would add the diagnostic criteria used to categories AA and MDS-h in the next version of the article. Thankyou. Competing Interests: No competing interests. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 14 Apr 2025 Soumya Gupta , Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India 14 Apr 2025 Author Response Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in ... Continue reading Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in sufficient detail and meeting all applicable standards of ethics of experimentation and research integrity. It is not just a collection and description of cases to be called as a case series. 2. In our study we included only the cases with hypoplastic marrows and none of the cases showed aggregates of mast cell to consider mastocytosis. However due to financial constraints additional IHC for mast cell phenotype and ckit mutation studies could not be performed. 3. We agree to your point that our sample size is less, which is a limitation of our study. 4. We would add the diagnostic criteria used to categories AA and MDS-h in the next version of the article. Thankyou. Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in sufficient detail and meeting all applicable standards of ethics of experimentation and research integrity. It is not just a collection and description of cases to be called as a case series. 2. In our study we included only the cases with hypoplastic marrows and none of the cases showed aggregates of mast cell to consider mastocytosis. However due to financial constraints additional IHC for mast cell phenotype and ckit mutation studies could not be performed. 3. We agree to your point that our sample size is less, which is a limitation of our study. 4. We would add the diagnostic criteria used to categories AA and MDS-h in the next version of the article. Thankyou. Competing Interests: No competing interests. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Wu D. Reviewer Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.143665.r198788 ) The direct URL for this report is: https://f1000research.com/articles/12-823/v1#referee-response-198788 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 01 Nov 2023 Dijiong Wu , Department of Hematology, The First Affiliate Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, China Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.143665.r198788 The differentiation of AA and hypo-MDS remains a challenge in clinical. Chaithra, et a l. try to make a differentiation diagnosis based on the IHC count of CD34+ hematopoietic stem cell and TB+ mast cells. Totally 21 AA, 12 hypo-MDS and ... Continue reading READ ALL The differentiation of AA and hypo-MDS remains a challenge in clinical. Chaithra, et a l. try to make a differentiation diagnosis based on the IHC count of CD34+ hematopoietic stem cell and TB+ mast cells. Totally 21 AA, 12 hypo-MDS and 32 HM were included. Based on the report, there are many concern need to clarified and better explained: The differentiation of AA and hypo-MDS is quite difficulty in clinical, how the authors make the specific diagnosis of 21 AA and 12 MDS? Please explain in detail. Also, the accurate number of the AA and MDS are quite limited, which may contribute to the deviation. The distribution of hematopoietic cells in BM biopsy is not uniformly. The method of IHC may not practically represent the haematopoiesis, better adding the result of flow cytometry result, especially CD34+ cells. Result showed that there is a big different in the count of mast cell in AA, some case over 10%. Is there any difference in IST or HSCT response in AA with different range of mast cells? The conclusion in ABSTRACT showed that " Understanding its role in the bone marrow niche can enhance stem cell transplant treatment". Based on the data and analysis, its hard to get the conclusion, and the response of IST or HSCT were missing. Authors found that there are more mast cells in AA but not MDS, but there is still patient with gray expression. It would be better to have the probably rang to help the distinguish diagnosis. In the discussion part, authors clarified that "An improved comprehension of the interactions amongst each component of the BM niche can help in identifying the potential therapeutic targets", please name the potential therapies specially as example. Actually, with the development of HSCT, especially haploidentical HSCT, the donor of HSCT no longer a very big problem in the treatment of AA. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Hematologist I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Wu D. Reviewer Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.143665.r198788 ) The direct URL for this report is: https://f1000research.com/articles/12-823/v1#referee-response-198788 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 13 Jul 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 2 (revision) 14 Apr 25 read Version 1 13 Jul 23 read read Dijiong Wu , The First Affiliate Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China Valentina Giudice , University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy Tsewang Tashi , University of Utah and Salt Lake City Veterans Affairs Medical Center, Salt Lake City,, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Tashi T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 23 May 2025 | for Version 2 Tsewang Tashi , University of Utah and Salt Lake City Veterans Affairs Medical Center, Salt Lake City,, Utah, USA 0 Views copyright © 2025 Tashi T. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This manuscript discusses the use of mast cells as an aide to differentiate aplastic anemia (AA) with hypoplastic MDS (h-MDS). The authors analyzed bone marrow samples of 65 cases, in a retrospective manner, and evaluated for mast cells using Toludine blue stain and CD34 IHC. Although the hypothesis is sound and there are existing literature on this subject, I have few questions/concerns: 1) The criteria for classifying cases into either AA or MDS-h seem arbitrary, based on marrow morphology and clinical/lab information alone. There is no cytogenetics, FISH studies or molecular information available, which could actually be quite informative in aiding diagnosis. 2) Mast cells were stained with Toludine blue, which is OK. But it was not confirmed further with CD117 stain or tryptase stain to corroborate. Toludine blue can also stain basophils. 3) The authors note increased mast cells and describes them in percentages. Is the percentage of the whole marrow cellularity? 4) The authors did not look at mast cells morphologically under a microscope (except for a representative case). Are all the increased mast cells normal mast cells? Could there be mastocytosis? 5) If the hypothesis is that increased mast cells suppress hematopoiesis and deplete CD34 HSCs, then why don't we see that in systemic mastocytosis? 6) I think overall there are a lot of unanswered questions on the association and role of mast cells in AA and MDS-h, that it is quite premature at this stage to suggest is as a tool for diagnostic use, as the authors have claimed in their title. 7) Minor comment: Please use the term "hypoplastic MDS" consistently throughout. Authors have used different terms - "hypocellular MDS", "Myelodysplasia with hypocellular marrow" in the manuscript. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Myeloid malignancies and mastocytosis. I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Tashi T. Peer Review Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.180489.r381834) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-823/v2#referee-response-381834 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Giudice V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 01 Nov 2023 | for Version 1 Valentina Giudice , University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy 0 Views copyright © 2023 Giudice V. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In this manuscript, Gupta et al. have investigated frequency of bone marrow mast cells in aplastic anemia (AA) and hypoplastic myelodysplastic syndromes (hMDS), as have proposed this cellular marker for differential diagnosis of these bone marrow failure syndromes. However, several issues are present: This is a case series study and should be clearly stated also in the title. Indeed, to claim a "diagnostic utility" of a marker, more cases are required. In this case, the analysis is carried out on a total of 21 AA and just 12 hMDS, without a control cohort of non hypoplastic MDS. Diagnostic criteria used for AA and hMDS are not stated. Mastocytosis was ruled out? c-Kit mutations were excluded? No additional information on mast cell phenotype was reported, as mast cell related (tryptase, chymase, CD25, and CD117) antigens can be investigated also by IHC. Mast cells have been associated with neoangiogenesis also in MDS 1 , and could be increased in higher-risk MDS; therefore, some indications on clinical features of those patients should be clearly indicated at least in a table. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? Partly References 1. Ribatti D, Polimeno G, Vacca A, Marzullo A, et al.: Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes. Leukemia . 2002; 16 (9): 1680-4 PubMed Abstract | Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Bone marrow failure syndromes; flow cytometry immunophenotyping I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 14 Apr 2025 Soumya Gupta, Department of Pathology, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India Thankyou for reviewing our article. We would like to address your concerns about the article. 1.Our study presents the results of an original detailed study with proper methodology described in sufficient detail and meeting all applicable standards of ethics of experimentation and research integrity. It is not just a collection and description of cases to be called as a case series. 2. In our study we included only the cases with hypoplastic marrows and none of the cases showed aggregates of mast cell to consider mastocytosis. However due to financial constraints additional IHC for mast cell phenotype and ckit mutation studies could not be performed. 3. We agree to your point that our sample size is less, which is a limitation of our study. 4. We would add the diagnostic criteria used to categories AA and MDS-h in the next version of the article. Thankyou. View more View less Competing Interests No competing interests. reply Respond Report a concern Giudice V. Peer Review Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.143665.r211585) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-823/v1#referee-response-211585 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Wu D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 01 Nov 2023 | for Version 1 Dijiong Wu , Department of Hematology, The First Affiliate Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, China 0 Views copyright © 2023 Wu D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The differentiation of AA and hypo-MDS remains a challenge in clinical. Chaithra, et a l. try to make a differentiation diagnosis based on the IHC count of CD34+ hematopoietic stem cell and TB+ mast cells. Totally 21 AA, 12 hypo-MDS and 32 HM were included. Based on the report, there are many concern need to clarified and better explained: The differentiation of AA and hypo-MDS is quite difficulty in clinical, how the authors make the specific diagnosis of 21 AA and 12 MDS? Please explain in detail. Also, the accurate number of the AA and MDS are quite limited, which may contribute to the deviation. The distribution of hematopoietic cells in BM biopsy is not uniformly. The method of IHC may not practically represent the haematopoiesis, better adding the result of flow cytometry result, especially CD34+ cells. Result showed that there is a big different in the count of mast cell in AA, some case over 10%. Is there any difference in IST or HSCT response in AA with different range of mast cells? The conclusion in ABSTRACT showed that " Understanding its role in the bone marrow niche can enhance stem cell transplant treatment". Based on the data and analysis, its hard to get the conclusion, and the response of IST or HSCT were missing. Authors found that there are more mast cells in AA but not MDS, but there is still patient with gray expression. It would be better to have the probably rang to help the distinguish diagnosis. In the discussion part, authors clarified that "An improved comprehension of the interactions amongst each component of the BM niche can help in identifying the potential therapeutic targets", please name the potential therapies specially as example. Actually, with the development of HSCT, especially haploidentical HSCT, the donor of HSCT no longer a very big problem in the treatment of AA. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Hematologist I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Wu D. Peer Review Report For: Diagnostic utility of mast cell analysis in hypoplastic bone marrows for differentiation of aplastic anaemia from hypoplastic myelodysplastic neoplasm: A retrospective study [version 2; peer review: 3 not approved] . F1000Research 2025, 12 :823 ( https://doi.org/10.5256/f1000research.143665.r198788) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-823/v1#referee-response-198788 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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