Mast cell disorders range from benign proliferations to systemic diseases that cause anaphylaxis and other diverse symptoms to mast cell neoplasms with varied clinical outcomes. Mastocytosis is the pathologic process of the accumulation of abnormal mast cells in different organs, mostly driven by KIT mutations, and can present as cutaneous mastocytosis, systemic mastocytosis (SM), and mast cell sarcoma. The WHO 5th edition classification divides systemic mastocytosis into bone marrow mastocytosis, indolent systemic mastocytosis, smoldering systemic mastocytosis, aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm, and mast cell leukemia. The new ICC classifies SM slightly differently. The diagnosis of SM requires the integration of bone marrow morphologic, immunophenotypic, and molecular findings, as well as clinical signs and symptoms. Moreover, understanding the wide range of clinical presentations for patients with mast cell disorders is necessary for accurate and timely diagnosis. This review provides an updated overview of mast cell disorders, with a special emphasis on SM, including the latest approaches to diagnosis, prognostic stratification, and management of this rare disease.

Tyrosine kinase inhibitors (TKIs) have become invaluable in the treatment of human and canine malignancies, but their role in feline oncology is less defined. While toceranib phosphate and masitinib mesylate are licensed for use in dogs, no TKI is yet approved for cats. This review systematically maps the research conducted on the expression of tyrosine kinases in neoplastic and non-neoplastic domestic feline tissues, as well as the in vitro/in vivo use of TKIs in domestic cats. We identify and discuss knowledge gaps and speculate on the further research and potential indications for TKI use in cats. A comprehensive search of three electronic databases and relevant paper reference lists identified 139 studies meeting the inclusion criteria. The most commonly identified tumors were mast cell tumors (MCTs), mammary and squamous cell carcinomas and injection-site sarcomas. Based on the current literature, toceranib phosphate appears to be the most efficacious TKI in cats, especially against MCTs. Exploring the clinical use of TKIs in mammary carcinomas holds promise. Despite the progress, currently, the evidence falls short, underscoring the need for further research to discover new indications in feline oncology and to bridge the knowledge gaps between human and feline medicine.

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, most of which are sporadic, and familial GISTs with germline mutations are rarely seen. Here, we report a 26-year-old female with a germline p. W557R mutation in exon 11 of the KIT gene. The proband and her father and sister presented with multifocal GIST and pigmented nevi. All 3 patients underwent surgery and imatinib therapy. To date, only 49 kindreds with germline KIT mutations and 6 kindreds with germline PDGFRA mutations have been reported. Summarizing the reported kindreds, the majority of familial GISTs manifest as multiple primary GISTs complicated with special clinical manifestations, including cutaneous hyperpigmentation, dysphagia, mastocytosis, inflammatory fibrous polyps, and large hands. Familial GISTs are generally thought to exhibit TKI sensitivity similar to that of sporadic GISTs with the same mutation.

UNASSIGNED: We report the first case of pathologic complete response (pCR) to neoadjuvant imatinib in a gastric stromal tumor harboring KIT mutations in both exons 11 and 9. The significance of this co-occurrence is unknown and might increase the responsiveness of gastrointestinal stromal tumors (GISTs) to imatinib.
UNASSIGNED: pCR of GIST to neoadjuvant imatinib is rare. We report a case of pCR to neoadjuvant imatinib in a gastric stromal tumor that harbored co-occurrence of multiple KIT mutations in exons 11 and 9. This co-occurrence in exons 9 and 11 is the first to be reported in the English literature.

Gastrointestinal stromal tumors (GISTs) have a significant risk of metastasis, although the degree varies in each case. The present report describes a case of late recurrence of GIST that was diagnosed 30 years after the primary tumor resection. An 80-year-old man was transported to Sanjo General Hospital (Sanjo, Japan) with hemorrhagic shock from gastrointestinal bleeding. Abdominal contrast-enhanced computed tomography revealed an 11.7-cm heterogenous tumor in the retroperitoneum adjacent to the third portion of the duodenum. The patient had a medical history of resection of \'leiomyoma\' of the upper jejunum when he was 50 years old. Pathological examination using archival pathological samples revealed that the previously excised tumor was GIST because the tumor cells showed positive immunoreactivity for KIT and DOG1. Treatment was started with imatinib, a selective KIT tyrosine inhibitor, even though endoscopy failed to provide biopsy specimens. Positron emission tomography conducted on the 28th treatment day revealed that imatinib completely shut down 18F-fluorodeoxyglucose uptake in the tumor, confirming that the tumor was imatinib-sensitive. A literature review yielded 12 GIST cases wherein metastases were diagnosed >10 years after primary tumor resection. Of the 12, four were originally diagnosed as benign. Clinicians should keep in mind that GISTs were formerly confused with non-GIST tumors and that there is a risk of relapse 10 years or later after curative surgery.

It is well recognized that the primary KIT or PDGFRA variant of a gastrointestinal stromal tumour (GIST) can predict sensitivity to imatinib. However, these data are currently spread across a wide range of publications and have not been collated as one reference. A broad-ranging literature search was therefore performed to assemble such a database which should help optimize imatinib-based management of GIST patients henceforth. Having excluded wild type GISTs and results for imatinib used as adjuvant therapy, 79 publications (dated August 2001 to March 2022) underwent data extraction. These data on imatinib sensitivity were either derived from in vitro studies, predicted by in silico analysis or based on in vivo clinical patient response. Data interpretation carried some caveats: there was a potential for replication of patient-derived data between older and new publications; only predicted protein sequences were presented; the criteria used to record clinical response were not uniform across all publications; and imatinib dosage could vary between different clinical publications. However, these data showed broad agreement of imatinib sensitivity amongst similar subtypes of KIT or PDGFRA variant. There was also agreement between in vivo versus in vitro/in silico derived sensitivity data for most variants when both data types were available.

UNASSIGNED: KIT is a proto-oncogene that is involved in the proliferation, survival, and regulation of melanocytes, mast cells, and the interstitial cells of Cajal. Mutations of KIT have been reported to be associated with hyperpigmentation and lentigines, mastocytosis, and gastrointestinal stromal tumors (GISTs). Some hotspot mutations of KIT have been reported to be associated with mastocytosis and GISTs, while the relationship between KIT mutations and hyperpigmentation and lentigines has not been fully elucidated.
UNASSIGNED: In this study, we presented a three-generation Chinese pedigree with progressive hyperpigmentation and generalized lentigines inherited in an autosomal dominant pattern. High-throughput sequencing was performed to capture genetic variations in peripheral blood samples of the proband. Also, Sanger sequencing was performed to further verify the result. We also reviewed previous literature on KIT mutations with hyperpigmentation and lentigines.
UNASSIGNED: A missense mutation of the KIT gene was identified: c. 2485G > C, which was co-segregated in the proband and his insulted father. Germline KIT mutations presenting as generalized hyperpigmentation and lentigines without systemic disorders are rare, with only two reports of c. 2485G > C mutation associated with this phenotype in previous literature.
UNASSIGNED: Our pedigree, together with those two reports, indicates a possible phenotype-genotype correlation of this germline KIT mutation, which might be helpful for genetic counseling, further functional segregation of KIT, and design of targeted therapy in the future.

UNASSIGNED: Mast cell leukemia (MCL) is a highly life-threatening and extremely rare subtype of systemic mastocytosis (SM). MCL often genetically contains one or more somatic mutations, particularly activating mutations of KIT. This study reported on an acute MCL patient who had a rare phenotype and genetic mutants with a history of primary malignant mediastinal germ cell tumor (GCT).
UNASSIGNED: A 30-year-old Asian male patient who underwent two rounds of surgery and chemotherapy with a history of primary mediastinal GCT (PM-GCTs) was admitted to our hospital due to persistent chest pain and severe fatigue. The diagnosis of acute MCL was confirmed via morphology analysis and chemical staining of marrow aspirate, as well as via marrow biopsy, with the addition of C-findings that included splenomegaly and cytopenia. The atypical MCs were phenotypically positive for CD117 and CD9 but weakly positive for CD2 and negative for CD25. Next-generation sequencing of the marrow aspirate identified heterozygous mutations in TP53 P301Qfs*44, FLT3 R973X, SETBP1 N272D, and JAK3 I688F, whereas mutations in KIT were not found. Although the initial therapy of corticosteroids, ruxolitinib, and dasatinib-based regimens was effective, he died of acute respiratory distress syndrome after the first cycle of chemotherapy with cladribine and cytarabine. The patient\'s survival time was 2.4 months after the initial presentation of MCL.
UNASSIGNED: In this case, MCL preceded by PM-GCTs had similar clinical symptoms and morphological manifestations but distinctly different genetic profiles than primary MCL. The characteristic morphology of MCL provides the most pivotal evidence that led our diagnosis in the correct direction. A competing hypothesis is that there is a common embryonal cancer stem cell between PM-GCTs and secondary MCL, and the latter is gradually developed in the context of additional \"driver mutations\".

BACKGROUND: Extraskeletal myxoid chondrosarcomas (EMCs) are solid tumors that have been genetically and biologically characterized. Only a few studies have discussed the role of the KIT gene or CD117 expression in EMCs, identified by immunohistochemical (IHC) staining. Herein, we present a novel case of cellular EMC exhibiting an EWSR1-NR4A3 fusion, KIT exon 13 mutations and strong diffuse expression of CD117.
METHODS: A 69-year-old man presented with a fist-sized tumor on his left shoulder. CT revealed a tumor in the left thoracic and dorsal muscle space. The tumor was completely resected. Histologically, the tumor cells had a nodular structure and infiltrated the peripheral fat and muscle tissues. The tumor cells were uniform in size with round nuclei, well-defined nucleoli and eosinophilic cytoplasm. Immunohistochemically, the tumor cells were positive for CD117, vimentin, CD56 and NSE and focally expressed desmin; the cells were negative for myogenin, S-100, SYN, INSM1, CD34, STAT6, INI-1, Brachyury, ERG, TLE1, AE1/AE3, WT-1, CD99 and SMA. NGS revealed an EWSR1-NR4A3 fusion and KIT exon 13 mutations. The patient had no further treatment after surgery, and no recurrence or metastasis occurred during the ~ 10 month follow-up period.
CONCLUSIONS: Molecular detection is an indispensable technique for diagnosing cellular EMCs. The KIT mutations noted in this case report may offer fresh insights into EMCs treatment options.

Activating genomic alterations of the receptor tyrosine kinase KIT are found preferentially in certain melanoma subtypes such as acral and mucosal melanoma or melanoma arising in chronically sun-damaged skin. However, the therapeutic value of c-Kit inhibitors for these subtypes currently remains unclear.
The objective of this study was to summarise the efficacy and safety of c-Kit inhibitors for unresectable or metastatic mucosal, acral or chronically sun-damaged melanoma.
We performed a systematic literature research in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers and conference abstracts for eligible trials until 23rd June 2020. Results were pooled using a random-effects model to calculate pooled proportions of objective response rates (ORRs) and severe adverse events (sAEs) from unselected KIT mutant or amplified cohorts.
Nineteen single-arm studies with an overall sample size of 601 patients were included. The studies investigated imatinib (n = 8), nilotinib (n = 7), dasatinib (n = 3) and sunitinib (n = 1). The pooled ORR for all inhibitors was 15% (95% confidence interval [CI]: 12-18%). Subgroup analysis revealed the highest ORR (20%; 95% CI: 14-26%) for nilotinib. The ORR for mucosal melanoma was 14% (95% CI: 6-24%) and 22% for acral lentiginous melanoma (95% CI: 14-30%). At least one sAE was reported in 42% of patients (95% CI: 34-50%).
c-Kit inhibitors represent a valuable treatment option for patients with KIT-mutant melanoma, in particular for mutations of exons 11 and 13. Furthermore, high-quality trials are urgently needed to investigate putative combinations of specific targeted therapies with immunotherapy.