Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

When Mast Cells Run Amok: A Comprehensive Review and Case Study on Severe Neonatal Diffuse Cutaneous Mastocytosis.

Neonatal diffuse cutaneous mastocytosis (NDCM) is defined as the infiltration of the epidermis by a clonal proliferation of mast cells, observed at birth, without initial signs of systemic involvement. The typical driver mutation is in the KIT gene. We report a rare case of a boy, born at term, already presenting at birth with generalized subcutaneous nodules on the face, scalp, trunk, back, hands, and feet. The spleen, liver, and inflammatory markers were normal at birth. Tryptase was significantly elevated. A bone marrow biopsy showed no mast cell involvement at age 2 months. A punch biopsy at age 2 months revealed CD117-positive cells diffusely infiltrating the skin, with subsequent DNA NGS sequencing for the formalin-fixed paraffin embedded tissue (FFPE) identifying the pathogenic NM_000222.3:c.1504_1509dup; p.(Ala502_Tyr503dup) variant in the KIT gene previously associated with cutaneous mastocytosis. At 2 years follow-up, he had splenomegaly and multiple cervical and inguinal adenopathy, while the skin nodules persisted, especially on the scalp with accompanying pruritus. He received oral and local sodium cromoglycate, oral antihistamines, antibiotic cream for skin infection, and iron supplementation; however, compliance to treatment was relatively low. The prognosis is difficult to predict, as he developed systemic involvement, failure to thrive, and mild psychomotor delay. A case aggregation of NDCM reported in the literature was performed to provide a comprehensive overview of this rare pathology, to better understand the prognosis. NDCM is a life-threatening disease with severe complications. Almost half had severe complications, such as mast hepatosplenomegaly, adenopathy, bacterial infections, mast cell leukaemia, and systemic involvement.

Mast Cell Disorders of the Gastrointestinal Tract: Clarity out of Chaos.

Pathologists are increasingly asked to evaluate mast cell infiltrates in the gastrointestinal tract when there is clinical concern for systemic mastocytosis or a variety of functional disorders, including irritable bowel syndrome and mast cell activation syndrome. Neoplastic mast cells have established quantitative, morphologic, and immunohistochemical features that facilitate their identification in gastrointestinal mucosal biopsies. Specific qualitative and quantitative findings are lacking for inflammatory mast cell-mediated disorders. This review covers histopathologic features of mast cell disorders that affect the gastrointestinal tract and offers practical guidance for their assessment in mucosal biopsies.

Small bowel obstruction: a rare presentation of systemic mastocytosis.

Mastocytosis (MC) is a heterogeneous group of disorders characterised by abnormal growth, neoplastic proliferation and accumulation of mast cells. Approximately, 80% of patients with MC have evidence of skin involvement, while the rest may involve the gastrointestinal tract, liver, spleen or bone. Isolated gastrointestinal presentation of aggressive MC without bone marrow involvement and cutaneous symptoms is rare. Isolated MC with tumour cells infiltrating the ileum presenting with mechanical obstruction has not been reported in the literature to date. Here, we present a case of a patient in his late 50s who presented with malignant MC of the small bowel with obstruction in the emergency surgical outpatient department. The patient underwent surgical resection of the affected bowel. Histopathological examination along with immunohistochemistry revealed malignant MC. The further evaluation consisted of bone marrow biopsies, PET CT and other mutation analyses. However, the patient succumbed to death during the further course of treatment. The differential of MC must be kept in mind when there is the presence of abnormal hematopoietic cells in gastrointestinal biopsies even in the absence of cutaneous manifestations and bone marrow abnormalities.

Systemic Mastocytosis with Associated Hematological Neoplasms. Diagnostic features and unique response pattern to tyrosine kinase inhibitors and allo-bone marrow transplantation therapy.

Systemic Mastocytosis is a clonal proliferation of mast cells; in a significant fraction of cases it is associated with another concurrent hematological neoplasm. Molecular analysis of KIT mutations and other associated genetic alterations suggest a common origin in the stem cell compartment. Mast cell infiltration patterns in bone marrow biopsy may be subtle in cases associated with t (8;21) AML. Here we report three cases of clonally related SM-AHN, two cases with SM-CMML and one case with SM- t (8;21) AML. We describe in detail the bone marrow infiltration pattern at diagnosis and during the course of treatment with allogeneic stem cell transplant and novel TK inhibitors, showing the unique dynamics of mast cell clearance after therapy.

Aggressive systemic mastocytosis of colon and lymph node: A case report.

RATIONALE: Mastocytosis is a group of rare neoplastic diseases characterized by monoclonal proliferation of mast cells in the skin or other tissues and organs, including cutaneous mastocytosis and systemic mastocytosis (SM). Mastocytosis can also occur in the gastrointestinal tract, mostly manifested as increased mast cells dispersed in various layers of the intestinal wall; a few may present as polypoid nodules, but rarely as soft tissue mass formation. Pulmonary fungal infections mostly occur in patients with low immune function and have not been reported in the literature as the initial manifestation in patients with mastocytosis. In this case report, we present the enhanced computed tomography (CT), fluorodeoxyglucose (FDG) positron emission tomography/CT, and colonoscopy findings of a pathologically confirmed patient with aggressive SM of the colon and lymph nodes and extensive fungal infection of both lungs. PATIENT CONCERNS: A 55-year-old female patient visited our hospital because of repeated cough for more than half a month. Laboratory tests revealed a significantly high CA125 serum level. Chest CT showed multiple plaques and patchy high-density shadows in both lungs, and a small amount of ascites was observed in the lower-level image. Abdominal CT revealed a soft tissue mass with an ill-defined boundary in the lower ascending colon. Whole-body positron emission tomography/CT images showed multiple nodular and patchy density-increasing lesions with significantly increased FDG uptake in both lungs. The wall of the ascending colon in the lower segment was significantly thickened with soft tissue mass formation, and retroperitoneal lymph node enlargement was accompanied by increased uptake of FDG. Colonoscopy revealed a soft tissue mass at the base of the cecum. DIAGNOSIS: Colonoscopic biopsy was performed and the specimen was diagnosed with mastocytosis. At the same time, a puncture biopsy was also performed on the patient's lung lesions, and pulmonary cryptococcosis was considered a pathological diagnosis. INTERVENTIONS: The patient was in remission after repeated treatment with imatinib and prednisone for 8 months. OUTCOMES: In the ninth month, the patient suddenly died of a cerebral hemorrhage. LESSONS: Gastrointestinal involvement due to aggressive SM presents with nonspecific symptoms and different endoscopic and radiologic findings. This is the first report of a single patient with colon SM, retroperitoneal lymph node SM, and extensive fungal infection in both lungs.

CRISPR/Cas9-engineering of HMC-1.2 cells renders a human mast cell line with a single D816V-KIT mutation: An improved preclinical model for research on mastocytosis.

The HMC-1.2 human mast cell (huMC) line is often employed in the study of attributes of neoplastic huMCs as found in patients with mastocytosis and their sensitivity to interventional drugs in vitro and in vivo. HMC-1.2 cells express constitutively active KIT, an essential growth factor receptor for huMC survival and function, due to the presence of two oncogenic mutations (D816V and V560G). However, systemic mastocytosis is commonly associated with a single D816V-KIT mutation. The functional consequences of the coexisting KIT mutations in HMC-1.2 cells are unknown. We used CRISPR/Cas9-engineering to reverse the V560G mutation in HMC-1.2 cells, resulting in a subline (HMC-1.3) with a single mono-allelic D816V-KIT variant. Transcriptome analyses predicted reduced activity in pathways involved in survival, cell-to-cell adhesion, and neoplasia in HMC-1.3 compared to HMC-1.2 cells, with differences in expression of molecular components and cell surface markers. Consistently, subcutaneous inoculation of HMC-1.3 into mice produced significantly smaller tumors than HMC-1.2 cells, and in colony assays, HMC-1.3 formed less numerous and smaller colonies than HMC-1.2 cells. However, in liquid culture conditions, the growth of HMC-1.2 and HMC-1.3 cells was comparable. Phosphorylation levels of ERK1/2, AKT and STAT5, representing pathways associated with constitutive oncogenic KIT signaling, were also similar between HMC-1.2 and HMC-1.3 cells. Despite these similarities in liquid culture, survival of HMC-1.3 cells was diminished in response to various pharmacological inhibitors, including tyrosine kinase inhibitors used clinically for treatment of advanced systemic mastocytosis, and JAK2 and BCL2 inhibitors, making HMC-1.3 more susceptible to these drugs than HMC-1.2 cells. Our study thus reveals that the additional V560G-KIT oncogenic variant in HMC-1.2 cells modifies transcriptional programs induced by D816V-KIT, confers a survival advantage, alters sensitivity to interventional drugs, and increases the tumorigenicity, suggesting that engineered huMCs with a single D816V-KIT variant may represent an improved preclinical model for mastocytosis.

Comprehensive mastocytosis data analysis from a single center.

Mastocytosis is a very rare disorder and is divided into three prognostically distinct variants by World Health Organization: Cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma or localized mast cell (MC) tumors. The wide range of complaints may cause patients to consult various clinics, with resulting mis- or underdiagnosis. Therefore, cooperation between different subspecialties is of paramount importance. In this article, we have compiled 104 adult mastocytosis cases diagnosed and followed in our Hematology and other clinics. 86 (82.7%) of 104 patients had systemic mastocytosis. Osteoporosis, disease-related complications, and secondary malignancies are important topics in this group. We know that indolent form has great survival. But smoldering or aggressive mastocytosis has a poor prognosis. CM and indolent SM have a significantly better prognosis compared to aggressive SM (p < 0.001). We found that the presence of more than 25% of mast cells in the bone marrow, the presence of concomitant marrow dysplasia, and the presence of disease-related complications affect survival (p < 0.001). In addition to the WHO classification, the IPSM scoring system is indicative of the prognosis in this rare disease.

Systemic mastocytosis with myeloid sarcoma and B-CLL: molecular and clonal heterogeneity in a rare case of SM-AHN with review of literature.

BACKGROUND: Systemic mastocytosis (SM) is a rare myeloproliferative disease that results from a clonal proliferation of abnormal mast cells in one or more extra-cutaneous organs. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) is the second most common subgroup and is diagnosed when WHO criteria for both SM and a hematological neoplasm of non-mast cell lineage are met. The SM-AHN category as currently proposed is highly heterogeneous in terms of pathogenesis, clinical presentation, and prognosis. CASE PRESENTATION: We present the first reported case of SM-AHN associated with two hematological malignancies of different lineages, a monocytic myeloid sarcoma and a B-cell chronic lymphatic leukemia. Cytogenetic and molecular analyses revealed a distinct clonal origin of the two associated malignancies. The SM-myeloid sarcoma clone demonstrated an abnormal karyotype, trisomy 8 and del(13)(q12.3q14.3), as well as mutations in KITD816V, DNMT3A and RUNX1. The DNMT3A mutation could be detected years before disease onset, supporting its potential role as early driver of leukemogenesis. No genetic aberrations could be identified in the CLL clone, which is assumed to present coincidentally. CONCLUSIONS: This report highlights the importance of full diagnostic work-up in SM patients in whom an associated hematological malignancy is suspected. Moreover, the importance of genetic analysis is highlighted, as it provides additional insights in the underlying clonal pathogenesis of different phenotypes, can aid in risk stratification, and may help identify potential therapy targets.

The international consensus classification of mastocytosis and related entities.

Mastocytosis is a neoplasm characterized by a clonal proliferation of mast cells, which accumulate in one or multiple organs, associated with an extremely heterogeneous clinical presentation. The disease can be limited to the skin (cutaneous mastocytosis) that is mostly seen in childhood and usually behaves in a benign fashion. Adult patients most often present with systemic disease with or without skin lesions. This includes indolent forms such as indolent systemic mastocytosis and its subvariant bone marrow mastocytosis, and smoldering systemic mastocytosis as well as aggressive forms including aggressive systemic mastocytosis, systemic mastocytosis with an associated myeloid neoplasm (previously called systemic mastocytosis with an associated hematologic neoplasm), and mast cell leukemia. In addition, mast cell sarcoma is a rare aggressive form of mastocytosis that can present in the skin as well as at extracutaneous sites. This review article focuses on the updates in mastocytosis of the 2022 international consensus classification (ICC).

Histamine and Serotonin Levels in Bone Marrow Stem Cells Niche as Potential Biomarkers of Systemic Mastocytosis and Myeloproliferative Disorders.

Bone marrow studies currently provide a lot of valuable information in the diagnostics of hematological diseases including hematopoietic stem cells disorders. Our studies on low-molecular weight organic compounds in bone marrow stem cell niche in various pathogenic conditions, revealed relatively high variability of histamine levels in different groups of hematological diseases. It was also found that serotonin levels were significantly lower than those typically measured in peripheral blood as well as many have the influence on stem cells proliferative potential. This paper presents findings from quantitative and statistical analyses of histamine and serotonin levels. Bone marrow collected from patients undergoing routine diagnostic procedures for hematological diseases and receiving inpatient treatment were analyzed. Histamine and serotonin levels were measured using hydrophilic interaction liquid chromatography (HILIC) coupled with tandem mass spectrometry. Obtained data were analyzed statistically and correlated with the diagnosed groups of hematological diseases and the parameters of complete blood counts. Histamine was found in all tested samples, including those from patients without malignancy, and the reported levels were comparable to the reference values in blood. This observation allows us to assume that bone marrow cells can produce and accumulate histamine. Moreover, the statistical analysis revealed a significant relationship between histamine levels and diagnosed mastocytosis, and between histamine levels and myeloproliferative neoplasms. Different results were obtained for serotonin, and its concentrations in most cases were below the limit of quantification of the method used (< 0.2 ng/mL), which can only be compared to peripheral blood plasma. In a few cases, significantly higher serotonin levels were observed and it concerned diseases associated with an increased number of megakaryocytes in the bone marrow.

Histopathology and Molecular Genetics in Systemic Mastocytosis: Implications for Clinical Management.

The diagnosis of systemic mastocytosis (SM) is based on various clinical, dermatological, serological, and hematological findings but essentially relies on histological evidence of an abnormal increase in tissue-localized mast cells (MCs). The extra-cutaneous organ most frequently affected is the bone marrow (BM), and therefore, histological examination of trephine biopsy specimens of the iliac crest is mandatory on suspicion of SM. At microscopic examination, neoplastic MCs show aberrant morphology, usually with prominent spindling. Immunohistochemistry is a useful tool in the diagnosis of SM because mast cell (MC) infiltrates may be slight and scarce, in a mixed background of lymphohistiocytic cells, eosinophils, and plasma cells. Moreover, neoplastic MCs exhibit an aberrant phenotype. Recent evidence, largely derived from molecular genetics, has enhanced the diagnostic capability of SM, also providing the basis for adequate prognostic and therapeutic evaluation. The cases herein reported illustrate the variable clinical manifestations and disease course of SM, focusing on diagnostic and therapeutic challenges. In accordance with the World Health Organization (WHO) classification and the International Consensus Classification (ICC) systems, our findings emphasize the importance of an integrated diagnostic approach for SM, with proper application of diverse assessment methodologies in order to improve SM classification and treatment effectiveness.

Living with systemic mastocytosis: Balancing between vulnerability and resilience: A qualitative study.

PURPOSE: Systemic mastocytosis is a rare group of haematological malignancies with heterogeneous symptoms from various organs, and an overall survival that ranges from normal for indolent SM (ISM) to 2-4 years for advanced SM subtypes (Adv SM). The purpose of this study was to describe the experiences of everyday life among persons diagnosed with ISM or Adv SM. METHODS: In this qualitative study, data were collected through purposive sampling and semi-structured interviews with 16 participants diagnosed with ISM (n = 9) or Adv SM (n = 7). Data were subsequently analysed with content analysis. RESULTS: Three main categories were identified. The persistent presence of the disease includes findings of how the symptoms affected the participants and how they handled its limitations and the adaptions and medication management required. Struggling against ignorance illustrates contacts with both healthcare professionals and strangers. The participants described being forced to be experts on SM due to a general lack of knowledge. An illness or wellness perspective encompasses the participants' feelings of vulnerability and alienation, but also how various strategies were used to gain emotional control. CONCLUSIONS: The disease has considerable impact on everyday life, with constant efforts required to manage symptoms and medication side effects. The complexity and rarity of the disease complicated relationships with healthcare professionals and contributed to feelings of marginalisation and alienation. The participants described feeling vulnerable, but used a multitude of strategies in their striving for resilience. Trusting relationships with healthcare professionals, family members and friends promoted a wellness perspective.

Immunohistochemical Staining to Identify Concomitant Systemic Mastocytosis in Acute Myeloid Leukemia with RUNX1::RUNX1T1.

Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P=0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P=0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.

Standards of Pathology in the Diagnosis of Systemic Mastocytosis: Recommendations of the EU-US Cooperative Group.

Pathology plays a central role in the diagnosis of systemic mastocytosis (SM), its delineation from other neoplasms and reactive conditions, and in monitoring of SM under therapy. The morphologic hallmark of SM is the accumulation of spindle-shaped, hypogranulated mast cells (MCs) in bone marrow (BM) and other extracutaneous tissues. Four of the 5 World Health Organization-defined diagnostic criteria (ie, compact MC aggregates [=major criterion]; atypical MC morphology; activating KIT point mutations; aberrant expression of CD25 and/or CD2 and/or CD30 in MCs [=minor criteria]) can be addressed by the pathologist. The final classification of SM variants as either BM mastocytosis, indolent SM, smoldering SM, aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), or MC leukemia (MCL) has important prognostic significance and requires the integration of certain morphological, clinical, radiological, and biochemical data, referred to as B- and C-findings. Substantial diagnostic challenges may be posed to the pathologist and clinician especially in the so-called advanced SM variants, that is, ASM, MCL, and SM-AHN. In this article, updated recommendations of the EU-US Cooperative Group regarding standards of pathology in the diagnosis of SM, presented during the year 2020 Working Conference held in September in Vienna, are reported.

Refined Treatment Response Criteria for Indolent Systemic Mastocytosis Proposed by the ECNM-AIM Consortium.

Indolent systemic mastocytosis (ISM) has a favorable prognosis and normal life expectancy. However, many patients suffer from mast cell (MC) mediator-related symptoms, which significantly affect quality of life (QoL). Cutaneous, gastrointestinal, and neurological complaints, musculoskeletal pain, and the presence of skin lesions, anaphylaxis, and osteoporosis are the main symptoms and signs in ISM and must be assessed in all patients before and during treatment. Validated mastocytosis-specific patient-reported outcome measures (PROMs) should be used for this purpose. Serum tryptase and KIT D816V allele burden are recommended as secondary outcome parameters, noting that they do not reflect the severity of signs, symptoms, and related QoL impairment, but indirectly express MC burden. Changes from baseline of 90%, 60%, and 30% indicate complete response >90%, major response 60% to 90%, partial response 30% to 60%, and no response <30% to treatment. To conclude, we recommend the use of PROMs as primary outcome parameters to define treatment response in patients with ISM in clinical trials and in everyday clinical practice.

Mast cell leukemia with novel BRAF variant and concomitant atypical KIT variant.

Mast cell leukemia (MCL) is a leukemic variant of systemic mastocytosis defined by mast cells ≥ 20% of marrow nucleated cells. Its incidence is < 1% of all systemic mastocytosis cases [1]. Clinical characteristics and treatment of the disease are not well established and overall prognosis is very poor. We report a case of de novo mast cell leukemia with novel BRAF variant, concomitant KIT exon 9 missense mutation and complex cytogenetic abnormalities. After careful review of the literature we have not found any prior reports of concomitant BRAF and KIT variants, and complex cytogenetic abnormalities in MCL. This case provides evidence that MCL can have wide spectrum of genetic abnormalities as well as accumulation of mutations in various genes including BRAF. This finding may have significant implications for the understanding of pathogenesis, diagnosis, as well as targeted therapy of MCL.

Mast cell neoplasm: a challenging pathological diagnosis.

Systemic mastocytosis (SM) is a myeloid neoplasm characterized by abnormal growth and accumulation of neoplastic mast cells in at least one extracutaneous site. Clinical presentation and course are variable, most patients are developing an indolent disease and some, an aggressive/leukemic form. Because of its rarity, most physicians are unfamiliar with this disease and do not readily diagnose it. In the present retrospective study, the authors describe 12 patients diagnosed with mast cell neoplasm. Cases were selected from three institutions from Campinas and São Paulo City, Brazil. Morphological features and diagnostic pitfalls are emphasized. Patients' age ranged from 15 to 81 years (mean 51.6 years). Male and female were affected similarly (1:1). Ten patients were classified as aggressive SM, one patient as SM with an associated acute promyelocytic leukemia with t(15;17), and one patient with mast cell sarcoma. The most common clinical findings included anemia (9 patients), thrombocytopenia (3 patients), and skin lesions (3 patients). Bone marrow was involved in 11 patients at diagnosis, followed by skin (5 patients). Five morphological patterns were present: mast cell aggregates (5), plasmacytoid (4), monocytoid (2), spindle cell (2), and epithelioid/pleomorphic (1); two patients showed two histological patterns. In all cases, neoplastic cells were positive for CD117/C-KIT. C-KIT D816V mutation was present in four patients, C-KIT K509I in two, and del(7q22) in one; in five cases no mutational status was available. Despite limited resources, basically morphology and a restricted immunohistochemical panel, it is possible to diagnose mast cell neoplasm. Of note, the pathologist should recognize the different morphological variants of the disease and include adequate markers when requesting immunohistochemical studies.

Histopathological characteristics are instrumental to distinguish monomorphic from polymorphic maculopapular cutaneous mastocytosis in children.

BACKGROUND: Mastocytosis is characterized by the accumulation of mast cells (MCs) in the skin or other organs, and can manifest at any age. A significant number of paediatric mastocytosis cases persist after puberty. In particular, monomorphic maculopapular cutaneous mastocytosis (mMPCM) is often persistent and associated with systemic mastocytosis. However, clinical differentiation of MPCM from polymorphic (p)MPCM can be difficult. AIM: To identify histopathological features that can help to distinguish mMPCM from other subtypes of paediatric mastocytosis. METHODS: This was a retrospective study using skin biopsies from patients with any subtype of mastocytosis. The localization and density of the MC infiltrate, MC morphology and expression of aberrant markers were evaluated and correlated with clinical characteristics. RESULTS: In total, 33 biopsies were available for evaluation from 26 children [(10 with mMPCM, 5 with mastocytoma, 3 with diffuse cutaneous mastocytosis (DCM), 8 with pMPCM)] and 7 adults with MPCM. The MC number was increased in all patients, but was higher in children than adults (P < 0.01). The presence of mMPCM was associated with sparing of the papillary dermis from MC infiltration, whereas MC density in the papillary dermis was highest in pMPCM and DCM (P < 0.01). The positive predictive value of the presence of a reticular MC infiltrate for mMPCM was 72.7% (95% CI 51.4-87.0), and the negative predictive value was 83.3% (95% CI 42.2-97.2). There were no relevant differences in the expression of CD2, CD25 or CD30 between the different subtypes. CONCLUSION: Skin histopathology might enhance the phenotypical differentiation of mMPCM from other subtypes in children, thereby increasing the accuracy of one's prognosis.