Novel MIR143‐NOTCH fusions in benign and malignant glomus tumors
Juan‐Miguel MosqueraAndrea SbonerLei ZhangChun‐Liang ChenYun‐Shao SungHsiao‐Wei ChenNarasimhan P. AgaramDaniel BriskinBasma BashaSamuel SingerMark A. RubinThomas TuschlCristina R. Antonescu
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Abstract:
Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired‐end RNA‐seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT‐PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino‐nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1‐related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143 . Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1–3 rearrangements in benign and malignant, visceral, and soft tissue GTs. © 2013 Wiley Periodicals, Inc.Keywords:
Pathogenesis
Angioleiomyoma
Gene rearrangement
Glomus tumor
Angioleiomyoma is a benign tumor formed by the nodular growth of smooth muscle cells surrounding small arteries and small veins. It usually occurs in the intracutaneous or subcutaneous regions of the arms and legs and is rarely found in the oral area. We encountered a case of angioleiomyoma occurring in the palate. We describe this rare case and discuss other cases reported in the literature.
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Hard palate
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Angioleiomyoma is a rare benign tumor arising from the vascular smooth muscle cells and occurs most frequently on the lower limbs of middle-aged women. The prevalence of angioleiomyoma on the head and neck area is 8.5%. Unlike angioleiomyomas that occur on the lower extremities, pain is not common in patients with head and neck presentation. Making an initial diagnosis of angioleiomyoma is difficult at a location apart from the predilection sites because of its nature of having no clinical symptoms or diagnostic characteristics. We report a rare case of angioleiomyoma on the antihelix of the left ear and a review of the literature on such tumors.
Angioleiomyoma
Auricle
Presentation (obstetrics)
Benign tumor
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Perivascular neoplasms comprise traditionally glomus tumor and hemangiopericytoma (HPC). Whereas glomus tumor represents a well-defined entity, the existence of HPC as a separate entity has been questioned because a number of neoplasms of different lines of differentiation are characterized by a HPC-like vascular growth pattern. Myopericytoma represents a recently delineated entity showing a HPC-like vascular pattern. A large series of myopericytoma of skin and soft tissues has been analyzed to further characterize the clinicopathologic spectrum of this entity. Fifty-four cases of myopericytoma of skin and soft tissues were retrieved and the histology reviewed. Immunohistochemical stainings using alpha-smooth muscle actin (ASMA), desmin, and h-caldesmon antibodies were performed, and clinical data and follow-up information were obtained from referring pathologists. Thirty-four patients were male and 18 were female (gender was unknown in 2 cases). Patient age ranged from 13 to 87 years (median, 52 years). The lower extremities were most commonly affected (26 cases) followed by the upper extremities (16 cases), the head and neck region (4 cases), and the trunk (2 cases); exact location was unknown in 5 cases. In 20 cases, the neoplasms were confined to the dermis, in 6 cases an extension into the subcutis was seen, and 24 as well as 4 cases arose in subcutaneous and deep soft tissue, respectively. Two cases were multicentric; and in 1 of these patients, multiple anatomic regions were involved. Histologically, in all cases, numerous thin-walled vessels and a concentric, perivascular arrangement of ovoid, plump spindled to round myoid tumor cells was seen. However, a broad morphologic spectrum ranging from hypocellular, fibroma-like (3 cases), myofibroma-like (2 cases), angioleiomyoma-like (12 cases), and HPC-like neoplasms (13 cases) to classic myopericytomas (14 cases) and immature, cellular lesions (2 cases) was noted. In addition, 2 neoplasms with focal glomoid features, 5 intravascular, and 1 malignant myopericytomas were found. Prominent cytologic atypia and increased proliferative activity (>3 mitoses/10 high power fields) was seen in 4 and 2 cases, respectively. Immunohistochemically, all cases tested stained positively for ASMA. In addition, 29 of 32 cases tested stained positively for h-caldesmon, whereas desmin was only focally positive in 3 of 33 cases. Follow-up information was available in 46 cases (range, 7-168 months; median, 48 months). Despite marginal or incomplete excision in 23 of 46 cases, only 2 neoplasms (1 malignant and 1 intravascular myopericytoma) recurred locally (within 1 and 4 years, respectively). Despite overlapping morphologic features to angioleiomyoma and myofibroma, myopericytoma represents a distinct perivascular, myoid neoplasm of skin and soft tissues, characterized by a broad morphologic spectrum of concentrically, perivascularly growing myoid tumor cells that stain positively for ASMA and often for h-caldesmon, whereas desmin is usually negative. Most cases of myopericytoma behave in a benign fashion, but local recurrences and rarely metastases may occur in atypical and malignant neoplasms.
Glomus tumor
Angioleiomyoma
Desmin
Hemangiopericytoma
Solitary Fibrous Tumor
Histology
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Angioleiomyoma (vascular leiomyoma) is a common benign smooth muscle tumor, often affecting the soft tissue of the extremities, head, and neck regions. However, testicular involvement is an exceedingly rare event. Herein, we present an unusual case of testicular angioleiomyoma. To the best of our knowledge, this is the third reported case in English literature.
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We report an angioleiomyoma developed within a cellular histiocytoma on the calf of a 77‐year‐old man. The lesion consisted of a spherical nodule with two well‐defined concentric areas. The outer circular area was a cellular histiocytoma and the inner central area consisted of an angioleiomyoma. Immunoperoxidase investigations for desmin demonstrated positivity in the angioleiomyoma, whereas the histiocytoma positivity in the angioleiomyoma, whereas the histiocytoma remained negative. Serial sections of the lesion failed to demonstrate a connection between the angioleiomyoma and a normal vein which could have been trapped by the histiocytoma. The angioleiomyoma may have originated from a vessel in the histiocytoma.
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Nodule (geology)
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Glomus tumors are relatively rare vascular tumors with reported incidence of 1.6% of all soft tissue tumors. It is variously regarded as a hamartoma or a neoplasm of neuromyoarterial glomus, which consists of dilated vascular channels, surrounded by proliferating glomus, nerve cells, and plays an important role in temperature regulation. We report the case of glomangioma in a 43-year-old male who came to dermatology OPD with a painful lesion over the right elbow of six months duration. Cutaneous examination revealed a single round reddish blue papule of about 0.5 cm in size on the flexor aspect of the right elbow. The papule was firm in consistency and tender. The excision biopsy showed stratified squamous lining with well circumscribed tumor in the dermis. The tumor consisted of sheets of uniform cells with pale cytoplasm; round to ovoid centrally placed punched out nuclei and well defined cell margins. There were numerous dilated thin walled vascular spaces surrounded by a layer of tumor cells and the histopathology was consistent with glomangioma.
Glomus tumor
Histopathology
Papule
Neurovascular bundle
Angioleiomyoma
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Angioleiomyoma is a solid benign tumor, which is often painful. It can be found in the dermis, subcutaneous fat and fascia. Peak incidence is during the fourth to sixth decades of life. Angioleiomyoma in the hand can be treated with simple excision, and is relatively rare in the hand. So far, there has been no report of angioleiomyoma in the hand in South Korea. The authors experienced two cases of angioleiomyoma in the hand; one in the second web space and the other in the fifth metacarpal region. Both patients were treated by simple excision. There was no evidence of recurrence at one-year follow up.
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Angioleiomyoma (vascular leiomyoma or angiomyoma) is a rare, benign smooth muscle tumor that originates in the tunica media of blood vessels.These tumors may be found anywhere in the body.They usually occur in the lower extremity.Auricular angioleiomyoma is very rare, and only a few cases have been reported.We describe here a 38-year-old male patient with angioleiomyoma on the left auricular helix.
Angioleiomyoma
Tunica media
Benign tumor
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Angioleiomyoma
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Angioleiomyoma
Hard palate
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