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Modern Pathology : An Official Journal... Mar 2023Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification....
Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification. These pericytic tumors form a continuous morphologic spectrum, including those with combined morphology. However, to our knowledge, no widely accepted criteria for classifying tumors with combined morphology are available. Recent studies have identified platelet-derived growth factor receptor-beta (PDGFRB) gene mutations in a subset of myofibromas, myopericytomas, and myopericytomatoses but not in angioleiomyomas. NOTCH receptor 3 (NOTCH3) mutations have been reported in a subset of infantile myofibromatosis. To assess their potential role in classifying pericytic tumors, we investigated PDGFRB and NOTCH3 mutations in 41 pericytic tumors of variable morphology, including some combined forms. Our results show these mutations to be present in a variety of pericytic tumors, such as myopericytomas (PDGFRB, 3/11; NOTCH3, 4/11), myopericytomatoses (1/2; 1/2), myofibromas (3/6; 0/6), angioleiomyomas (2/13; 3/13), and glomus tumors (5/9; 1/9). Point mutations were identified in 3 tumors in PDGFRB exon 12 (Y562C, S574F, and G576S), 12 tumors in PDGFRB exon 14 (M655I, H657L, and N666K), and 9 tumors in NOTCH3 exon 25 (A1480S/T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A). All PDGFRB mutations and NOTCH3 G1482S, T1490A, and G1494S mutations were classified as "deleterious/damaging" by ≥4 of 6 pathogenicity prediction tools in silico. Five-mutation-positive tumors, including 1 myopericytoma-angioleiomyoma, 2 myopericytomatoses-myofibroma, 1 myofibroma-myopericytoma and 1 angioleiomyoma-myopericytoma, were of combined morphology. Therefore, we found PDGFRB and NOTCH3 mutations to be detectable in a much wider variety of pericytic tumors than previously reported and confirmed myopericytomas, myofibromas, angioleiomyomas, and glomus tumors as members harboring PDGFRB or NOTCH3 mutations. Our results thus suggest that PDGFRB or NOTCH3 mutations are not useful for subclassifying members of the pericytic tumor family.
Topics: Humans; Myopericytoma; Angiomyoma; Glomus Tumor; Myofibroma; Receptor, Platelet-Derived Growth Factor beta; Mutation; Receptor, Notch3
PubMed: 36788105
DOI: 10.1016/j.modpat.2022.100070 -
Modern Pathology : An Official Journal... May 2023PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented...
PDGFRB-activating mutations have been reported in pediatric myofibroma and myofibromatosis. However, recurrent gain-of-function PDGFRB mutations have not been documented in sarcomas with myogenic differentiation. Driven by occasional sarcomas harboring PDGFRB mutations, we investigated their prevalence and clinicopathologic and genomic features in a large cohort of sarcomas. An institutional targeted DNA next-generation sequencing database was searched for sarcomas with myogenic differentiation harboring hotspot PDGFRB gene alterations. Among 3300 patients with sarcomas, 21 (0.6%) patients were identified (17 women, 4 men) with an age range of 35 to 88 years. The site distribution included 13 gynecologic tract (12 uteri, 1 vagina), 4 bone and soft tissue, and 4 viscera. All except 1 were high grade. Most patients were diagnosed as sarcomas with myogenic differentiation based on partial staining for 1 or more muscle markers, whereas 6 were labeled as leiomyosarcoma (LMS). Most tumors showed monomorphic spindle morphology, with either heterogeneous features of myofibroblastic and smooth muscle differentiation or an undifferentiated phenotype. Hormone receptors were negative in all uterine cases. PDGFRB immunostaining in all cases tested was strong and diffuse, whereas PDGFRA was negative/focal. The most frequent PDGFRB mutations were exon 12 (43%), exon 14 (N666K/S/T) (38%), and exon 18 (D850Y/H/V or insertion/deletion) (19%). The most frequent co-existing genetic alterations (26% to 37%) occurred in CDKN2A/B, TP53, TERT, and MED12. Moreover, PDGFRB-mutant sarcomas had an overall distinct genomic landscape compared with both uterine and soft tissue LMS control groups. These tumors were associated with a highly aggressive clinical course, with frequent distant metastases (81%) and death (76%), regardless of anatomic location, and worse overall survival compared with the 2 LMS control groups. This is the first study documenting recurrent hotspot PDGFRB alterations in high-grade sarcomas, which show a predilection for uterine location and myogenic differentiation that fall short of the diagnostic criteria for LMS. Further studies are needed to investigate the therapeutic potential of kinase inhibitors in this group of tumors.
Topics: Humans; Female; Receptor, Platelet-Derived Growth Factor beta; Sarcoma; Leiomyosarcoma; Mutation; Soft Tissue Neoplasms
PubMed: 36788091
DOI: 10.1016/j.modpat.2023.100104 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Feb 2023To investigate the clinicopathological features, diagnosis and differential diagnosis of pediatric myofibroma/myofibromatosis of the soft tissue and bone. All cases of...
To investigate the clinicopathological features, diagnosis and differential diagnosis of pediatric myofibroma/myofibromatosis of the soft tissue and bone. All cases of pediatric myofibroma/myofibromatosis of the soft tissue and bone diagnosed between January 2011 and December 2018 were retrieved from the surgical pathology records in the Department of Pathology, Beijing Jishuitan Hospital, Beijing, China. Clinical and radiological data were collected. H&E and immunohistochemistry were used to examine histological and immunophenotypic features and to make the diagnosis and differential diagnosis. The relevant literature was also reviewed. Twenty-eight cases of pediatric myofibroma/myofibromatosis of the soft tissue and bone were respectively collected. The patients' ages ranged from 2 months to 14 years, with a mean age of 7 years. There were 7 females and 21 males. There were 12 cases located in soft tissue, including the finger (=9), upper arm (=1) and foot (=2). There were 14 cases located in the bone of limb, including the femur (=8), tibia (=4), clavicle (=2), fibula (=2) and radius (=1). There were 2 cases of myofibromatosis involving multiple bones. Radiology showed lytic lesions in the bone. The proliferation of spindle-shaped myofibroblasts arranged in fascicles with indistinct eosinophilic cytoplasm and bland nuclei, with no pleomorphism and cytological atypia. The characteristic histologic structure was the biphasic nodular growth pattern with cellular and paucicellular regions. The tumors might arrange in a hemangiopericytoma-like pattern. The stroma varied between dense fibrosis and myxoid changes. The reactive new bone formation and inflammatory cell infiltration also existed. Immunohistochemical study showed that the SMA was positive. The surgical resections were performed. One of the patients had tumor recurrence as a result of 11-month follow-up. The pediatric myofibroma/myofibromatosis of the soft tissue and bone is a very rare benign tumor and has a good prognosis. It has a characteristic morphology and its differential diagnosis from other spindle cell tumors could be made with the immunohistochemical analysis.
Topics: Child; Female; Humans; Infant; Male; Bone and Bones; Diagnosis, Differential; Leiomyoma; Myofibroma; Myofibromatosis; Child, Preschool; Adolescent
PubMed: 36748135
DOI: 10.3760/cma.j.cn112151-20221017-00856 -
Cureus Nov 2022Solitary infantile myofibroma is a benign fibrous tumor occurring in early childhood. Although rare, it is the most common benign fibrous tumor of infancy. The clinical...
Solitary infantile myofibroma is a benign fibrous tumor occurring in early childhood. Although rare, it is the most common benign fibrous tumor of infancy. The clinical course of the disease is almost uniformly good since most tumors regress spontaneously. When indicated, conservative surgical excision is the treatment of choice, with a low recurrence rate. We present a case of solitary infantile myofibroma that recurred after three attempts of surgical excision, questioning the reported recurrence rate and the standard of care in recurrent solitary infantile myofibroma.
PubMed: 36514628
DOI: 10.7759/cureus.31300 -
Pediatric and Developmental Pathology :... 2023Perivascular tumors, which include myopericytoma and myofibroma, are rare benign soft tissue neoplasms composed of perivascular smooth muscle cells. Most demonstrate...
BACKGROUND
Perivascular tumors, which include myopericytoma and myofibroma, are rare benign soft tissue neoplasms composed of perivascular smooth muscle cells. Most demonstrate characteristic morphology and are readily diagnosed. However, a recently identified hypercellular subset shows atypical histologic features and harbor unique SRF gene fusions. These cellular perivascular tumors can mimic other more common sarcomas with myogenic differentiation.
METHODS
Clinical, radiological, morphological, immunohistochemical, and molecular findings were reviewed.
RESULTS
A slow-growing, fluctuant mass was noted within the philtrum at 16 months. Ultrasonography revealed a well-circumscribed cystic hypoechoic lesion. A small (1.0 cm), tan, well-circumscribed soft-tissue mass was excised after continued growth. Histologically, the encapsulated tumor was hypercellular and composed of spindle cells with predominantly-storiform architecture, focal perivascular condensation, dilated branching thin-walled vessels, increased mitoses, and a smooth muscle immunophenotype. An SRF::NCOA2 fusion was identified.
CONCLUSION
We report the first case of an SRF-rearranged cellular myopericytoma in the perioral region in a young child. This case expands the differential diagnosis of perioral soft tissue tumors with myogenic differentiation. We highlight key clinical, pathological, and molecular features. As we illustrate, these rare tumors pose a considerable diagnostic challenge, and risk misdiagnosis as sarcoma, most notably spindle cell rhabdomyosarcoma.
Topics: Humans; Child; Adult; Myopericytoma; Lip; Soft Tissue Neoplasms; Sarcoma; Myofibromatosis; Biomarkers, Tumor; Nuclear Receptor Coactivator 2
PubMed: 36457254
DOI: 10.1177/10935266221138896 -
JCO Precision Oncology Oct 2022
Topics: Carcinogenesis; Drug Monitoring; Humans; Imatinib Mesylate; Myofibromatosis; Receptor, Platelet-Derived Growth Factor beta
PubMed: 36201717
DOI: 10.1200/PO.22.00250 -
A Unique Presentation of Multicentric Myofibromatosis in the Masseter Muscle of a Pediatric Patient.Ear, Nose, & Throat Journal Sep 2022A 12-year-old female with a history of multicentric infantile myofibromatosis (IM) presented with a tender, enlarging cheek mass and trismus. Imaging identified an...
A 12-year-old female with a history of multicentric infantile myofibromatosis (IM) presented with a tender, enlarging cheek mass and trismus. Imaging identified an intramasseteric tumor. Given the unknown etiology of the tumor and her bothersome symptoms, the mass was excised using a transoral approach with concurrent facial nerve monitoring. Her pathology report confirmed the diagnosis of a myofibromatosis lesion embedded within the masseter muscle. While IM can often present with lesions in the head and neck region, the intramasseteric location is rare and presents unique considerations for surgical approach. Myofibromatosis lesions typically occur before two years of age, although there are some rare documented cases of multicentric myofibromatosis lesions presenting at older ages. Furthermore, this patient's family history of similar lesions suggests a familial variant, which may have implications for disease behavior and need for further work-up, monitoring, and management. Overall, this was an unusual presentation of IM given the patient's age, prevalent family history, and the location of the mass. This case report adds to the literature and discusses the clinical differential of a pediatric cheek mass, the surgical considerations for an intramasseteric tumor, and the natural history of infantile myofibromatosis.
PubMed: 36085035
DOI: 10.1177/01455613221125933 -
Pediatric and Developmental Pathology :... 2022Infantile fibrosarcoma (IF) is a well characterized pediatric malignancy marked by gene rearrangements involving members of the NTRK family. In this report, we present a...
Infantile fibrosarcoma (IF) is a well characterized pediatric malignancy marked by gene rearrangements involving members of the NTRK family. In this report, we present a case of IF that presented in the inguinal region-proximal thigh and was initially thought to be a kaposiform hemangioendothelioma (KHE) because it presented with a bleeding diathesis thought to be Kasabach-Merritt phenomenon (KMP). Subsequently, the placental examination showed a neoplasm in the perivascular-subendothelial space of stem villi, initially thought to be myofibromatosis. Ultimately, a biopsy of the thigh mass showed IF with an NTRK3-ETV6 fusion. Subsequent FISH analysis of the placenta showed an ETV6 rearrangement confirming that it was also IF. Review of the laboratory studies suggests that disseminated intravascular coagulation may have been more likely than KMP, highlighting the difficulty in making this distinction in some cases. We believe this to be the first report of an IF presenting in a soft tissue site and the placenta, and discuss the possible mechanisms that could have allowed the IF in the leg to spread to the placenta.
Topics: Pregnancy; Female; Humans; Placenta; Kasabach-Merritt Syndrome; Hemangioendothelioma; Sarcoma, Kaposi; Fibrosarcoma; Soft Tissue Neoplasms; Lung Neoplasms
PubMed: 35834223
DOI: 10.1177/10935266221114017 -
Journal Francais D'ophtalmologie Sep 2022
Topics: Diagnosis, Differential; Exophthalmos; Humans; Infant, Newborn; Myofibromatosis; Ophthalmologists
PubMed: 35764508
DOI: 10.1016/j.jfo.2022.02.022 -
Journal of Cellular and Molecular... Jul 2022Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and...
Penttinen syndrome is a rare progeroid disorder caused by mutations in platelet-derived growth factor (PDGF) receptor beta (encoded by the PDGFRB proto-oncogene) and characterized by a prematurely aged appearance with lipoatrophy, skin lesions, thin hair and acro-osteolysis. Activating mutations in PDGFRB have been associated with other human diseases, including Kosaki overgrowth syndrome, infantile myofibromatosis, fusiform aneurysms, acute lymphoblastic leukaemia and myeloproliferative neoplasms associated with eosinophilia. The goal of the present study was to characterize the PDGFRB p.Val665Ala variant associated with Penttinen syndrome at the molecular level. This substitution is located in a conserved loop of the receptor tyrosine kinase domain. We observed that the mutant receptor was expressed at a lower level but showed constitutive activity. In the absence of ligand, the mutant activated STAT1 and elicited an interferon-like transcriptional response. Phosphorylation of STAT3, STAT5, AKT and phospholipase Cγ was weak or undetectable. It was devoid of oncogenic activity in two cell proliferation assays, contrasting with classical PDGF receptor oncogenic mutants. STAT1 activation was not sensitive to ruxolitinib and did not rely on interferon-JAK2 signalling. Another tyrosine kinase inhibitor, imatinib, blocked signalling by the p.Val665Ala variant at a higher concentration compared with the wild-type receptor. Importantly, this concentration remained in the therapeutic range. Dasatinib, nilotinib and ponatinib also inhibited the mutant receptor. In conclusion, the p.Val665Ala variant confers unique features to PDGF receptor β compared with other characterized gain-of-function mutants, which may in part explain the particular set of symptoms associated with Penttinen syndrome.
Topics: Acro-Osteolysis; Aged; Humans; Interferons; Limb Deformities, Congenital; Myofibromatosis; Progeria; Receptor, Platelet-Derived Growth Factor beta; STAT1 Transcription Factor
PubMed: 35689379
DOI: 10.1111/jcmm.17427