Mast Cells in the Microenvironment of Hepatocellular Carcinoma Confer Favorable Prognosis: A Retrospective Study using QuPath Image Analysis Software.

The insights provided by in-situ detection of immune cells within hepatocellular carcinoma (HCC) might present information on patient outcomes. Studies investigating the expression and localization of immune cells within tumor tissues are associated with several challenges, including a lack of precise annotation for tumor regions and random selection of microscopic fields of view. QuPath is an open-source, user-friendly software that could meet the growing need for digital pathology in whole-slide image (WSI) analysis. The infiltration of HCC and adjacent tissues by CD1a+ immature dendritic cells (iDCs), CD117+ mast cells, and NKp46+ natural killer cells (NKs) cells was assessed immunohistochemically in representative specimens of 67 patients with HCC who underwent curative resection. The area fraction (AF) of positively stained cells was assessed automatically in WSIs using QuPath in the tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells was evaluated for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS). The AF of mast cells was significantly greater than the AF of NKs, and the AF of iDCs was significantly lower compared to NKs in each region of interest. High AFs of mast cells in the IM and PT areas were associated with longer DFS. In addition, high AF of mast cells in IM was associated with longer OS. Computer-assisted analysis using this software is a suitable tool for obtaining prognostic information for tumor-infiltrating immune cells (iDCs, mast cells, and NKs) in different regions of HCC after resection. Mast cells displayed the greatest AF in all regions of interest (ROIs). Mast cells in the peritumor region and IM showed a positive prognostic significance.

High Intraepithelial Mast Cell Density in Warthin's Tumor.

BACKGROUND/AIM: Warthin's tumor, the second most frequent neoplasia of the parotid gland, is characterized by a proliferation of both epithelial and lymphoid components. In addition to epithelial and lymphoid cells, various other cell types are implicated to varying degrees in the immune response. Notably, mast cells have long been recognized as a consistent cell population within this tumor. Despite the historical acknowledgment of mast cell presence, their true distribution and significance within Warthin's tumor remain unclear. In this study, we aimed to elucidate the distribution and significance of mast cells in Warthin's tumor. MATERIALS AND METHODS: Histochemical and immunohistochemical methods were employed for the evaluation of mast cells within tumor specimens. RESULTS: Our study revealed a notable concentration of mast cells in the epithelial component of Warthin's tumor. Microscopic examination showed predominant lymphoid and epithelial elements with occasional cystic formations. Immunohistochemical analysis identified mast cells in both components, emphasizing their role in the tumor microenvironment. Double immunostaining (mast cell tryptase and CD34) revealed no significant correlation between mast cells and blood vessels. Intraepithelial mast cells (IEMCs) had a significantly higher density in the epithelial component, suggesting a potential association with the tumor's benign nature. The relationship between IEMCs and epithelial cells, especially in the presence of cystic structures, offers valuable insights into the unique features of Warthin's tumor. CONCLUSION: Our study contributes to the understanding of mast cells in Warthin's tumor, highlighting a substantial concentration within the epithelial component. This knowledge may pave the way for further investigations into the roles of mast cells in the pathogenesis and treatment of Warthin's tumor.

Immunohistochemical staining with CD117 and PGP9.5 of excised vestibular tissue from patients with neuroproliferative vestibulodynia.

BACKGROUND: Neuroproliferative vestibulodynia (NPV), a provoked genital pain characterized by severe allodynia and hyperalgesia, is confirmed in excised vestibular tissue by immunohistochemical staining (>8 CD117-positive immunostained cells/100× microscopic field) rather than by hematoxylin and eosin staining. AIM: In this study we sought to assess immunostaining of tissue samples obtained during vestibulectomy surgery and to correlate results with patient outcomes. METHODS: Patients (n = 65) meeting criteria for NPV who underwent vestibulectomy during the period from June 2019 through December 2022 formed the study cohort. We performed assessment of pathology of vestibular tissues by use of immunohistochemical staining, including quantitation of mast cells by CD117 (mast cell marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments. OUTCOMES: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement. RESULTS: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments. OUTCOMES: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement. RESULTS: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the median area of CD117 immunostaining was similar in both regions (0.69% and 0.73%). The median area of PGP9.5 immunostaining was 0.47% and 0.31% in these same regions. Pain scores determined with cotton-tipped swab testing were nominally higher in lifelong vs acquired NPV patients, reaching statistical significance in the 1:00-11:00 o'clock region (P < .001). The median score for the McGill Pain Questionnaire affective subscale dimension was also significantly higher in lifelong vs acquired NPV patients (P = .011). No correlations were observed between hematoxylin and eosin results and density of mast cells or neuronal markers. Of note, 63% of the patient cohort reported having additional conditions associated with aberrant mast cell activity. CLINICAL IMPLICATIONS: The pathology of NPV is primarily localized to the vestibular epithelial basement membrane and subepithelial stroma with no visible vulvoscopic findings, making clinical diagnosis challenging. STRENGTHS AND LIMITATIONS: Strengths of this study include the large number of tissues examined with what is to our knowledge the first-ever assessment of the 12:00 vestibule. Major limitations are specimens from a single timepoint within the disease state and lack of control tissues. CONCLUSIONS: Performing immunohistochemical staining of excised vestibular tissue with CD117 and PGP9.5 led to histometric confirmation of NPV, indications that NPV is a field disease involving all vestibular regions, validation for patients whose pain had been ignored and who had experienced negative psychosocial impact, and appreciation that such staining can advance knowledge.

Expression of CD25, mast cell markers and T-cell markers in eosinophilic esophagitis.

While eosinophilic esophagitis (EOE) is defined by histologic presence of eosinophils, a few studies have established the presence of mast cells in EOE and even shown their correlation with symptom persistence despite resolution of eosinophils. Expression of aberrant mast cell markers CD25 and CD2 have not been studied in EOE. This study quantifies the number of hotspot cells per high power field expressing CKIT/CD117, tryptase, CD25, CD2 and CD3 by immunohistochemical stains in endoscopic esophageal biopsies of the following three cohorts: (1) established and histologically confirmed EOE, (2) suspected EOE with biopsies negative for eosinophils, and (3) no history of or suspicion for EOE with histologically unremarkable biopsies. In this study, mast cells were highlighted by CKIT and tryptase in EOE, and not seen in other clinically mimicking cases. There were also significantly higher densities of CD25 and pan-T-cell marker staining in EOE cases. These findings suggest an inflammatory cellular milieu in EOE, beyond just eosinophils, that can be demonstrated by immunohistochemistry, and that invite further study into the role that these cells may play in EOE.

PGR-KITLG signaling drives a tumor-mast cell regulatory feedback to modulate apoptosis of breast cancer cells.

The immune microenvironment constructed by tumor-infiltrating immune cells and the molecular phenotype defined by hormone receptors (HRs) have been implicated as decisive factors in the regulation of breast cancer (BC) progression. Here, we found that the infiltration of mast cells (MCs) informed impaired prognoses in HR(+) BC but predicted improved prognoses in HR(-) BC. However, molecular features of MCs in different BC remain unclear. We next discovered that HR(-) BC cells were prone to apoptosis under the stimulation of MCs, whereas HR(+) BC cells exerted anti-apoptotic effects. Mechanistically, in HR(+) BC, the KIT ligand (KITLG), a major mast cell growth factor in recruiting and activating MCs, could be transcriptionally upregulated by the progesterone receptor (PGR), and elevate the production of MC-derived granulin (GRN). GRN attenuates TNFα-induced apoptosis in BC cells by competitively binding to TNFR1. Furthermore, disruption of PGR-KITLG signaling by knocking down PGR or using the specific KITLG-cKIT inhibitor iSCK03 potently enhanced the sensitivity of HR(+) BC cells to MC-induced apoptosis and exerted anti-tumor activity. Collectively, these results demonstrate that PGR-KITLG signaling in BC cells preferentially induces GRN expression in MCs to exert anti-apoptotic effects, with potential value in developing precision medicine approaches for diagnosis and treatment.

The mast cell-T lymphocyte axis impacts cancer: Friend or foe?

Crosstalk between mast cells (MCs) and T lymphocytes (TLs) releases specific signals that create an environment conducive to tumor development. Conversely, they can protect against cancer by targeting tumor cells for destruction. Although their role in immunity and cancer is complex, their potential in anticancer strategies is often underestimated. When peripheral MCs are activated, they can affect cancer development. Tumor-infiltrating TLs may malfunction and contribute to aggressive cancer and poor prognoses. One promising approach for cancer patients is TL-based immunotherapies. Recent reports suggest that MCs modulate TL activity in solid tumors and may be a potential therapeutic layer in multitargeting anticancer strategies. Pharmacologically modulating MC activity can enhance the anticancer cytotoxic TL response in tumors. By identifying tumor-specific targets, it has been possible to genetically alter patients' cells into fully humanized anticancer cellular therapies for autologous transplantation, including the engineering of TLs and MCs to target and kill cancer cells. Hence, recent scientific evidence provides a broader understanding of MC-TL activity in cancer.

Mast Cell Activation Syndrome and Gut Dysfunction: Diagnosis and Management.

PURPOSE OF REVIEW: Mast cell activation syndrome (MCAS) is a clinical disorder that may explain irritable bowel syndrome (IBS) type symptoms as well as other allergic symptoms experienced by an individual. The diagnosis and treatment of MCAS with specific focus on gastrointestinal (GI) manifestations is reviewed. RECENT FINDINGS: Although biomarkers for MCAS remain elusive, testing for baseline serum tryptase will distinguish the type of mast cell disorder and urine tests for mast cell mediator metabolites may support the diagnosis. Endoscopy and Colonoscopy with biopsies is not used to diagnose MCAS but is important to rule out other conditions that may cause symptoms. There is increased awareness of the association between MCAS and autonomic dysfunction, small fiber neuropathy, and connective tissue disorders which all impact GI symptoms. MCAS is a disorder often of unknown etiology (idiopathic) and characterized by intermittent allergy type symptoms that affect multiple organ systems after exposure to a trigger. GI symptoms including abdominal cramping and loose stool are prominent and mimic those of IBS. Diagnostic testing is performed to assess for elevations in mast cell mediators during symptoms and to rule out other conditions. A comprehensive treatment plan includes medications that target mast cells, treatments for associated conditions including autonomic dysfunction, and management of comorbid psychiatric illness and nutritional deficits.

Vasoactive Intestinal Peptide Receptor, CRTH2, Antagonist Treatment Improves Eosinophil and Mast Cell-Mediated Esophageal Remodeling and Motility Dysfunction in Eosinophilic Esophagitis.

BACKGROUND AND AIMS: Ultrasonography has shown that eosinophils accumulate in each segment of the esophageal mucosa in human EoE, ultimately promoting esophageal motility dysfunction; however, no mechanistic evidence explains how or why this accumulation occurs. METHODS: Quantitative PCR, ELISA, flow cytometry, immunostaining, and immunofluorescence analyses were performed using antibodies specific to the related antigens and receptors. RESULTS: In deep esophageal biopsies of EoE patients, eosinophils and mast cells accumulate adjacent to nerve cell-derived VIP in each esophageal segment. qRT-PCR analysis revealed five- to sixfold increases in expression levels of VIP, CRTH2, and VAPC2 receptors and proteins in human blood- and tissue-accumulated eosinophils and mast cells. We also observed a significant correlation between mRNA CRTH2 levels and eosinophil- and nerve cell-derived VIPs in human EoE (p < 0.05). We provide evidence that eosinophil and mast cell deficiency following CRTH2 antagonist treatment improves motility dysfunction in a chronic DOX-inducible CC10-IL-13 murine model of experimental EoE. CONCLUSIONS: CRTH2 antagonist treatment is a novel therapeutic strategy for inflammatory cell-induced esophageal motility dysfunction in IL-13-induced chronic experimental EoE.

Primary preputial reconstruction following surgical excision of cutaneous mast cell tumours without penile amputation in eight dogs.

CASE HISTORY: Medical records from a single referral hospital (Davies Veterinary Specialists, Hitchin, UK) were reviewed to identify dogs (n = 8) with preputial cutaneous mast cell tumours (CMCT) that underwent surgical excision and primary preputial reconstruction, preserving the penis and urethra, after clients declined alternatives such as penile amputation and urethrostomy, from June 2017-June 2022. CLINICAL FINDINGS: Tumours had a median diameter of 21.5 (min 15, max 30) mm, were located cranioventrally (3/8), caudoventrally (1/8), laterally (2/8) and dorsally (2/8) relative to the prepuce and were diagnosed as CMCT based on cytology. No dogs had hepatic or splenic metastasis on cytology but inguinal lymph node metastasis was identified in 3/4 dogs sampled. TREATMENT AND OUTCOME: The owners of all dogs had declined penile amputation and scrotal urethrostomy. The CMCT were excised and primary reconstruction of the prepuce performed. Surgical lateral margins of 10, 20 or 30 mm were used and the deep margin excised the inner preputial lamina or underlying muscular fascia. The deep margin for caudoventral CMCT involved excision of the underlying SC adipose tissue. Preputial advancement was performed in 3/8 dogs to achieve adequate penile coverage. Histopathology confirmed all CMCT were Kiupel low grade, Patnaik grade II with complete margins in 6/8 dogs but identified metastasis only in one inguinal lymph node from one dog. Two dogs encountered minor complications (infection and a minor dehiscence) and one dog had a major complication (infection with major dehiscence). Median follow-up duration was 125 weeks, excluding one dog with 4 weeks of follow-up. None of the dogs experienced local recurrence or died of mast cell disease during the available follow-up period. CLINICAL RELEVANCE:  This clinical study evaluated a surgical alternative to penile amputation and advanced reconstructive techniques for Kuipel low/Patnaik grade II preputial CMCT when these procedures were declined by owners. Surgical excision of preputial CMCT with lateral margins of 10, 20 or 30 mm with primary preputial reconstruction is achievable with low morbidity and a good outcome when penile amputation and scrotal urethrostomy is not an option.

[Unusual presentation of a mast cell tumor in the ear canal of a cat]. / Ungewöhnlicher Mastzelltumor im Gehörgang einer Katze.

A 12-year-old male neutered European Shorthair cat was presented for pruritus in the right ear region, bleeding from ear canal and a suspected polyp-like mass in its lumen.After the diagnostic imaging a biopsy of the mass was taken and submitted for histopathological evaluation. Histopathologic examination led to the diagnosis of low grade mast cell tumor. The subsequent staging examinations included ultrasonography of the liver and spleen as well as a complete blood count. Total ear canal ablation was performed on the same day, and the removed ear canal was again submitted for histopathologic evaluation of the surgical margins. The excision incision margins were free from infiltrating tumor cells. The cat was euthanised 14 months after the surgery. It is unknown whether the reasons for this were associated to metastatic spread of the initial mast cell tumor.A mast cell tumor in the ear canal is an unusual and rare finding, however it should be included in the list of differential diagnoses for ear canal tumors.

Clinical, pathologic, and molecular characterization of a non-metastatic multicentric cutaneous mast cell tumor in a cow.

Cutaneous mast cell tumors are rarely reported in cattle. Although mutations in the c-KIT gene have been shown to play a central role in the oncogenesis of canine mast cell tumors, few data are available in cattle. This report describes the clinical, histologic, immunohistochemical, and genetic features of a multicentric cutaneous mast cell tumor in an adult cow. An 11-year-old Prim'Holstein cow was presented for a 5-month history of multiple skin nodules. Cytologic and histologic analyses of the nodules led to a diagnosis of mast cell tumors. Immunohistochemical analysis for KIT expression showed a moderate to strong signal in neoplastic mast cells with a cytoplasmic and membranous pattern. Sequencing of the c-KIT gene coding sequence revealed no mutation. Despite partial response after corticosteroid treatment, euthanasia was elected. No metastases to the lymph nodes, spleen, and liver were identified at post-mortem and histologic examinations.

Machine learning-based identification and characterization of mast cells in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis. OBJECTIVES: Using machine learning, we localized and characterized esophageal mast cells (MCs) to decipher their potential role in disease pathology. METHODS: Esophageal biopsy samples (EoE, control) were stained for MCs by anti-tryptase and imaged using immunofluorescence; high-resolution whole tissue images were digitally assembled. Machine learning software was trained to identify, enumerate, and characterize MCs, designated Mast Cell-Artificial Intelligence (MC-AI). RESULTS: MC-AI enumerated cell counts with high accuracy. During active EoE, epithelial MCs increased and lamina propria (LP) MCs decreased. In controls and EoE remission patients, papillae had the highest MC density and negatively correlated with epithelial MC density. MC density in the epithelium and papillae correlated with the degree of epithelial eosinophilic inflammation, basal zone hyperplasia, and LP fibrosis. MC-AI detected greater MC degranulation in the epithelium, papillae, and LP in patients with EoE compared with control individuals. MCs were localized further from the basement membrane in active EoE than EoE remission and control individuals but were closer than eosinophils to the basement membrane in active EoE. CONCLUSIONS: Using MC-AI, we identified a distinct population of homeostatic esophageal papillae MCs; during active EoE, this population decreases, undergoes degranulation, negatively correlates with epithelial MC levels, and significantly correlates with distinct histologic features. Overall, MC-AI provides a means to understand the potential involvement of MCs in EoE and other disorders.

Diffuse Cutaneous Mastocytosis: A Current Understanding of a Rare Disease.

Mastocytosis is a heterogeneous disease characterized by the expansion and accumulation of neoplastic mast cells in various tissues. Diffuse cutaneous mastocytosis (DCM) is a rare and most severe form of cutaneous mastocytosis, which typically occurs in childhood. There have been reports of a familial DCM with specific gene mutations, indicating both sporadic and hereditary factors involved in its pathogenesis. DCM is associated with severe MC mediator-related symptoms and an increased risk of anaphylaxis. The diagnosis is based on the appearance of skin lesions, which typically show generalized thickening, erythroderma, blistering dermographism, and a positive Darier's sign. Recognition, particularly in infants, is challenging due to DCMs resemblance to other bullous skin disorders. Therefore, in unclear cases, a skin biopsy is crucial. Treatment focuses on symptom management, mainly including antihistamines and mast cell stabilizers. In extremely severe cases, systemic steroids, tyrosine kinase inhibitors, phototherapy, or omalizumab may be considered. Patients should be equipped with an adrenaline autoinjector. Herein, we conducted a comprehensive review of literature data on DCM since 1962, which could help to better understand both the management and prognosis of DCM, which depends on the severity of skin lesions, intensity of mediator-related symptoms, presence of anaphylaxis, and treatment response.

Sonographic and computed tomographic features of intestinal mast cell tumors mimicking alimentary lymphoma in 2 dogs.

Two shih tzu dogs were referred to our clinic because of hematochezia and vomiting. Abdominal ultrasonography revealed a focal, asymmetric, exophytic small intestinal mass with loss of wall layering and muscular layer thickening of the adjacent intestine. Computed tomography (CT) in both dogs revealed a focal, asymmetric, homogenously contrast-enhanced exophytic jejunal and duodenal mass with an intact mucosal layer and generalized lymphadenopathy. Metastasis and ulceration were not detected on CT. The initial imaging diagnosis was lymphoma in both dogs; however, histopathological examination revealed the presence of intestinal mast cell tumors (iMCTs). Despite its similarity to alimentary lymphoma, iMCT should be considered a possible diagnosis, based on imaging characteristics, to ensure that proper treatments are selected. This is the first veterinary report describing detailed ultrasonographic and CT characteristics of iMCTs. Key clinical message: This is the first veterinary case report demonstrating sonographic and computed tomographic features of canine iMCT, which can be misdiagnosed as alimentary lymphoma. This report provides another differential diagnosis to consider when determining the appropriate patient treatment direction and histopathological examination.

Caractéristiques échographiques et tomodensitométriques de mastocytomes intestinaux imitant un lymphome alimentaire chez 2 chiens. Deux chiens shih tzu ont été référés à notre clinique en raison d'une hématochézie et de vomissements. L'échographie abdominale a révélé une masse focale, asymétrique et exophytique de l'intestin grêle avec perte de stratification pariétale et épaississement de la couche musculaire de l'intestin adjacent. La tomodensitométrie (TDM) chez les deux chiens a révélé une masse jéjunale et duodénale exophytique focale, asymétrique, homogène et contrastée avec une couche muqueuse intacte et une lymphadénopathie généralisée. Les métastases et les ulcérations n'ont pas été détectées par TDM. Le diagnostic initial d'imagerie était un lymphome chez les deux chiens; cependant, l'examen histopathologique a révélé la présence de mastocytomes intestinaux (iMCT). Malgré sa similitude avec le lymphome alimentaire, l'iMCT doit être considérée comme un diagnostic possible, basé sur les caractéristiques de l'imagerie, afin de garantir la sélection des traitements appropriés. Il s'agit du premier rapport vétérinaire décrivant les caractéristiques échographiques et tomodensitométriques détaillées des iMCT.Message clinique clé :Il s'agit du premier rapport de cas vétérinaire démontrant les caractéristiques échographiques et tomodensitométriques de l'iMCT canin, qui peuvent être diagnostiquées à tort comme un lymphome alimentaire. Ce rapport fournit un autre diagnostic différentiel à prendre en compte lors de la détermination de l'orientation thérapeutique et de l'examen histopathologique appropriés du patient.(Traduit par Dr Serge Messier).

Mast Cells in Aspirin-Exacerbated Respiratory Disease.

PURPOSE OF REVIEW: Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. RECENT FINDINGS: Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.

Genetic Changes in Mastocytes and Their Significance in Mast Cell Tumor Prognosis and Treatment.

Mast cell tumors are a large group of diseases occurring in dogs, cats, mice, as well as in humans. Systemic mastocytosis (SM) is a disease involving the accumulation of mast cells in organs. KIT gene mutations are very often seen in abnormal mast cells. In SM, high KIT/CD117 expression is observed; however, there are usually no KIT gene mutations present. Mastocytoma (MCT)-a form of cutaneous neoplasm-is common in animals but quite rare in humans. KIT/CD117 receptor mutations were studied as the typical changes for human mastocytosis. In 80% of human cases, the KIT gene substitution p.D816H was present. In about 25% of MCTs, metastasis was observed. Changes in the gene expression of certain genes, such as overexpression of the DNAJ3A3 gene, promote metastasis. In contrast, the SNORD93 gene blocks the expression of metastasis genes. The panel of miR-21-5p, miR-379, and miR-885 has a good efficiency in discriminating healthy and MCT-affected dogs, as well as MCT-affected dogs with and without nodal metastasis. Further studies on the pathobiology of mast cells can lead to clinical improvements, such as better MCT diagnosis and treatment. Our paper reviews studies on the topic of mast cells, which have been carried out over the past few years.

Predictors of Clonality and Underlying Mastocytosis in Mast Cell Activation Syndromes.

PURPOSE OF REVIEW: Mast cell (MC) activation can present with a wide range of symptoms. The mechanisms that cause such activation are varied. One of them is the presence of clonal MCs which is defined, within other possible changes, by the presence of a somatic, activating mutation in the KIT gene. The clinical course and prognosis of patients with this underlying disease may be different from other causes of MC activation (MCA). For this reason, it is important to early diagnose, or at least suspect, which patients with MCA are due to clonal MCs. RECENT FINDINGS: The diagnosis of clonality must be made in a comprehensive manner. However, this paper reviews chronologically each of the stages from the patient's first visit to the doctor's office which can be indicative of clonality: clinical presentation of MCA, physical examination, analytical determinations of tryptase, and/or KIT mutational analysis and bone involvement, among others. The different clonality predictive scores proposed are also reviewed and compared. Although the gold standard for the diagnosis of certainty of MC clonality is the performance of a bone marrow (BM) biopsy, there are clinical symptoms, signs, and biological parameters suggestive of clonality, as well as predictive scores, which can guide (or rule out) an early diagnosis and avoid unnecessary BM biopsies.

Mastocytosis in the skin in dogs: A multicentric case series.

Canine cutaneous mastocytosis (CM) is rare in contrast to canine mast cell tumours. In humans, CM commonly affects children and is usually indolent with possible spontaneous resolution. Systemic mastocytosis (SM) with bone marrow involvement typically affects adults, can have a poor outcome, and often includes skin lesions. 'Mastocytosis in the skin' (MIS) is the preferred term of skin lesions, if bone marrow evaluations are not available, which is often the cases in dogs. In human SM and CM, KIT mutations are often detected. The veterinary literature suggests clinical resemblances between human and canine MIS, but data is limited, and KIT mutations are rarely assessed. This retrospective study describes clinicopathological findings, treatment and outcome of 11 dogs with suspected MIS. Dogs with multiple mast cell tumours were excluded. Histopathology reports (n = 5) or slides (n = 6) were reviewed. KIT mutation analysis including exons 8, 9, 11, 14 and 17 were analysed in eight dogs. Median age at diagnosis was 4 years (range, 1-12). Typical clinical signs included multifocal to generalised nodules and papules. Histologically, skin lesions were characterised by dermal infiltration of well-differentiated mast cells. KIT mutations were detected in 3/8 dogs (exon 9: n = 2; exon 11: n = 1). One dog had mastocytaemia suggesting possible SM. Glucocorticoids were mostly successful with lesion improvement in all treated dogs (n = 8). This cohort highlights resemblances between human and canine MIS. Further studies are required to confirm these findings and establish diagnostic criteria for CM and MIS associated with SM in dogs.

Prognostic role of macrophages and mast cells in the microenvironment of hepatocellular carcinoma after resection.

BACKGROUND: The prognostic significance of mast cells and different phenotypes of macrophages in the microenvironment of hepatocellular carcinoma (HCC) following resection is unclear. We aimed in this study to assess the local distribution of infiltrating macrophages and mast cells of specific phenotypes in tissues of HCC and to evaluate their prognostic values for survival of post-surgical patients. METHODS: The clinicopathological and follow-up data of 70 patients with HCC, who underwent curative resection of tumor from 1997 to 2019, were collected. The infiltration of CD68+ and CD163+ macrophages and CD117+ mast cells was assessed immunohistochemically in representative resected specimens of HCC and adjacent tissues. The area fraction (AF) of positively stained cells was estimated automatically using QuPath image analysis software in several regions, such as tumor center (TC), inner margin (IM), outer margin (OM), and peritumor (PT) area. The prognostic significance of immune cells, individually and in associations, for time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: High AF of CD68+ macrophages in TC and IM and high AF of mast cells in IM and PT area were associated with a longer DFS. High AF of CD163+ macrophages in PT area correlated with a shorter DFS. Patients from CD163TChigh & CD68TClow group had a shorter DFS compared to all the rest of the groups, and cases with CD163IMlow & CD68IMhigh demonstrated significantly longer DFS compared to low AF of both markers. Patients from CD68IMhigh & CD163PTlow group, CD117IMhigh & CD163PTlow group, and CD117PThigh & CD163PTlow group had a significantly longer DFS compared to all other combinations of respective cells. CONCLUSIONS: The individual prognostic impact of CD68+ and CD163+ macrophages and mast cells in the microenvironment of HCC after resection depends on their abundance and location, whereas the cumulative impact is built upon combination of different cell phenotypes within and between regions.

Quantification of Mucosal Mast Cells in the Gastrointestinal Tract: A Primer for Practicing Pathologists.

CONTEXT.­: Mast cells are essential components of the immune system and play crucial pathogenetic roles in several digestive diseases, including mastocytic enterocolitis and eosinophilic gastrointestinal disorders. Pathologists have rarely been asked to evaluate the distribution and density of mast cells in gastrointestinal (GI) biopsy specimens. However, such requests are becoming more common because of an increasing awareness of the role of mast cells in functional GI disease and in both esophageal and nonesophageal eosinophilic gastrointestinal disorders. OBJECTIVE.­: To provide pathologists with tools to incorporate the assessment of mast cells in the evaluation of esophageal, gastric, and intestinal specimens by developing a systematic approach to their evaluation, counting, and reporting. DESIGN.­: This study consisted of a review of the literature followed by multiple consensus sessions to decide where to count mast cells and what a countable mast cell is. RESULTS.­: We reviewed 135 papers addressing the content of mast cells in the digestive tract, selected 21 that detailed how cells were counted (microscope lens, area of high-power fields, locations evaluated, type of cells considered as countable), and summarized their data in a table. Then, drawing from both the acceptable literature and our own extensive experience, we reached a tentative consensus on: (1) the normal numbers in the different segments of the GI tract; (2) the morphology of countable mast cells; and (3) the locations and strategies for counting them. CONCLUSIONS.­: The result is a set of suggestions for reporting mast cell counts, their distribution, and their location in a way clinicians can understand and use for management decisions.