Neurofibroma with glomus-like bodies: A novel association-Thoughts about origin.

A neurofibroma with focal glomus-like body differentiation is an unusual phenomenon recently encountered in an excision specimen from the right lateral distal forearm of a 26-year-old man. Glomus cells are modified smooth muscle cells normally present in glomus-like bodies but can also be found in glomus tumors (GT) or lesions considered in the spectrum of GT, including myopericytoma, myofibroma, and angiolipoma. Neurofibromas are peripheral nerve sheath tumors derived from the neural crest cells. While both GT and its variants and neurofibroma are thought to be derived from different cell types, there is growing evidence that glomus cells have a neural crest origin. This is based on multiple theories, with some overlapping pathways, including neural crest cell differentiation, Schwann cell reprogramming, VEGF expression, and NF1 gene biallelic inactivation. This report adds to the growing evidence of possible neural crest origin for glomus cells and would help explain finding glomus-like bodies scattered through a neurofibroma.

CARMN-NOTCH2 fusion transcript drives high NOTCH2 expression in glomus tumors of the upper digestive tract.

Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.

Clinicopathologic features and BRAF mutation status of tracheal glomus tumors - Characterization of 4 cases and the distinction from low-grade neuroendocrine tumors.

BACKGROUND: Glomus tumors are uncommon and mostly benign mesenchymal neoplasms of the perivascular family. To date, only a few cases of glomus tumors occurring in the trachea have been reported. Tracheal glomus tumors simulated low-grade neuroendocrine tumors on clinical and histomorphological examination, so the differential diagnosis between these two entities is very necessary. The latest studies showed that BRAF mutation may be associated with a malignant phenotype of glomus tumors. METHODS: We investigated the clinical, histopathologic, immunohistochemical, and BRAF V600E mutation status of four cases of tracheal glomus tumors. RESULTS: The cases showed a female predilection (male:female, 1:3) with a median age of 35.5. All of the cases had the typical morphological characteristics of glomus tumors, such as uniform round tumor cells with nest-like distribution surrounding thin-walled vessels; two of them met the malignant diagnostic criteria based on the 5th edition of WHO classification, including marked nuclear atypia and any level of mitotic activity. Immunohistochemistry showed diffusely positive for vimentin (4/4), α-SMA (4/4) and collagen IV (4/4), variably reactive for synaptophysin (3/4) and SSTR2 (2/2), and negative for AE1/AE3 (0/4) and chromogranin A (0/4). Three tested cases harbored no BRAF V600E mutation. Three follow-up cases were alive and free of disease with an average follow-up of 89.3 months. CONCLUSIONS: Tracheal glomus tumors are rare mesenchymal tumors that have overlapping morphologic and immunohistochemical features with neuroendocrine neoplasms. Our cases highlight the importance of careful histomorphological examination and comprehensive immunohistochemical study in reaching a correct diagnosis of glomus tumors of the trachea. Other than BRAF mutation, malignant glomus tumors may have a complex mutational profile.

Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface.

The approximately 300 human cullin-RING ligases (CRLs) are multisubunit E3s in which a RING protein, either RBX1 or RBX2, recruits an E2 to catalyze ubiquitination. RBX1-containing CRLs also can bind Glomulin (GLMN), which binds RBX1's RING domain, regulates the RBX1-CUL1-containing SCF(FBW7) complex, and is disrupted in the disease Glomuvenous Malformation. Here we report the crystal structure of a complex between GLMN, RBX1, and a fragment of CUL1. Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. The structure explains the basis for GLMN's selectivity toward RBX1 over RBX2, and how disease-associated mutations disrupt GLMN-RBX1 interactions. Our study reveals a mechanism for RING E3 ligase regulation, whereby an inhibitor blocks E2 access, and raises the possibility that other E3s are likewise controlled by cellular proteins that mask E2-binding surfaces to mediate inhibition.

The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin RING ligase-mediated turnover of Fbw7.

Fbw7, a substrate receptor for Cul1-RING-ligase (CRL1), facilitates the ubiquitination and degradation of several proteins, including Cyclin E and c-Myc. In spite of much effort, the mechanisms underlying Fbw7 regulation are mostly unknown. Here, we show that Glomulin (Glmn), a protein found mutated in the vascular disorder glomuvenous malformation (GVM), binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity. Loss of Glmn in a variety of cells, tissues, and GVM lesions results in decreased levels of Fbw7 and increased levels of Cyclin E and c-Myc. The increased turnover of Fbw7 is dependent on CRL and proteasome activity, indicating that Glmn modulates the E3 activity of CRL1(Fbw7). These data reveal an unexpected functional connection between Glmn and Rbx1 and demonstrate that defective regulation of Fbw7 levels contributes to GVM.

[Gastric glomus tumors expressing synaptophysin: clinicopathologic and immunohistochemical analyses].

Objective: To investigate the clincopathologic and immunohistochemical features of gastric glomus tumors and their differences from gastric neuroendocrine neoplasms. Methods: Six cases of gastric glomus tumors, 8 cases of glomus tumors in other sites and 7 cases of gastric neuroendocrine neoplasms were collected from the Department of Pathology, Taizhou Hospital. The clinicopathological and immunohistochemical characteristics of these tumors were analyzed retrospectively. Results: The gastric glomus tumors were located in the muscularis propria of the antrum and most cases strongly expressed synaptophysin (5/6). However, no synaptophysin expression was seen in glomus tumors of other organs.Most gastric neuroendocrine neoplasms were located in the mucosa or submucosa of the fundus and corpus. In addition to the strong expression of synaptophysin (7/7), CgA (6/7) and CD56(5/7) were strongly positive, although SMA was negative. Conclusions: Gastric glomus tumors and neuroendocrine neoplasms have similar morphological characteristics and both show strongly expression of synaptophysin. However, the location and immunohistochemical characteristics of gastric glomus tumors differ from those of the neuroendocrine neoplasms.

Glomus tumors in individuals with neurofibromatosis type 1.

BACKGROUND: Glomus tumors have recently been reported in individuals with the neurofibromatosis type 1 (NF1) cancer disposition syndrome. We compare the clinical and molecular features of these painful hamartomas in a series of sporadic and NF1-associated cases. OBJECTIVE: We sought to evaluate the association of NF1 with glomus tumors and to compare NF1-associated glomus tumors with sporadic glomus tumors. METHODS: We conducted a retrospective cohort study of all individuals with a histopathologic diagnosis of glomus tumor at a large tertiary care center from January 1998 to January 2013. Charts were reviewed for a coexisting diagnosis of NF1. RESULTS: A total of 42 glomus tumors were identified in 34 individuals. Twelve (28.6%) were found in 6 patients with NF1. In 28 individuals with 30 sporadic tumors, there was no coexisting medical condition. Although multifocal tumors (16.7%) and tumor recurrence (33.3%) were more common in association with NF1, these trends did not reach statistical significance. NF1-associated glomus tumors exhibited no neurofibromin immunoreactivity, whereas their sporadic counterparts retained neurofibromin expression. LIMITATIONS: The retrospective design resulted in incomplete data capture. CONCLUSIONS: Detection of glomus tumors should raise suspicion for a concurrent diagnosis of NF1.

Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting.

Glomuvenous malformations (OMIM 138000) are hamartomas presenting in childhood as multiple, bluish papules and nodules in the skin, which are characterized histopathologically by irregular vascular spaces surrounded by typical glomus cells. Glomuvenous malformations are caused by autosomal dominant mutations of the GLMN gene. A 34-year-old woman and her 16-year-old son presented with bluish papules and nodules since childhood. Biopsy specimens from both patients showed histopathologic features of glomuvenous malformations, unusually in consistent and close association with smooth muscle, hair follicles and eccrine glands. Sequencing of the GLMN gene revealed the p.C36X (c.108C>A) mutation in germline DNA from both patients. This is probably the first report describing the hamartomatous features of familial glomuvenous malformations consistently associated with a prominent smooth muscle component and eccrine glands.

Functional study in a yeast model of a novel succinate dehydrogenase subunit B gene germline missense mutation (C191Y) diagnosed in a patient affected by a glomus tumor.

Mutations of succinate dehydrogenase (SDH) subunits B, C and D are associated to pheochromocytoma/paraganglioma (PGL) development. The mechanisms linking SDH mutations to tumorigenesis are currently unknown. We report a novel germline missense SDHB mutation (C191Y) in a patient affected by a glomus tumor. The missense mutation hits an amino acid residue conserved from mammals to the yeast Saccharomyces cerevisiae. The pathogenic significance of the human mutation was validated in a yeast model. SDH2(C184Y) mutant allele equivalent to human SDHB(C191Y) did not restore the OXPHOS phenotype of the Deltasdh2 null mutant. In the mutant, SDH activity was also abolished along with a reduction in respiration. Sensitivity to oxidative stress was increased in the mutant, as revealed by reduced growth in the presence of menadione. Remarkably, the frequency of petite colony formation was increased in the mutant yeast strain, indicating an increased mtDNA mutability. Histochemistry demonstrates that SDH activity was selectively absent in the patient tumor tissue. Overall, our results demonstrate that the C191Y SDHB mutation suppresses SDH enzyme activity leading to increased ROS formation and mtDNA mutability in our yeast model. These findings further our understanding of the mechanisms underlying PGL development and point to the yeast model as a valid tool to investigate on the possible pathogenic relevance of SDH novel mutations and/or rare polymorphism.

A novel mutation of the glomulin gene in an Italian family with autosomal dominant cutaneous glomuvenous malformations.

Glomuvenous malformations (GVM) are hamartomas characterized histologically by glomus cells, which should be distinguished from glomus tumors. Familial GVM are rare, often present as multiple lesions, and exhibit familial aggregation, with autosomal dominant transmission. GVM are caused by mutations of the glomulin (GLMN) gene on chromosome 1p21-p22. Their development is thought to follow the 'two-hit' hypothesis, with a somatic mutation required in addition to the inherited germline mutation. We describe a novel GLMN mutation in an Italian family with GVM in which some members present with the less commonly observed phenotype of solitary lesions. A second somatic 'hit' mutation in GLMN was not discovered in our family. We further provide histological, immunohistochemical and electron microscopic data exhibiting the classic features of GVM. The diagnosis of GVM is critical because of distinction from venous malformations and blue rubber bleb nevus syndrome, which may demonstrate clinical similarities but require different treatment.

Sclerotic glomus tumor.

We report an unusual histopathological variant of a glomus tumor that arose in a peculiar topographic site, a sclerotic glomus tumor. Unlike conventional glomus tumors or glomangiomas that have a loose fibrous stroma with variable hyaline and myxoid changes, the case reported herein had a diffuse, hyalinized, sclerotic stroma. A further difference was that the majority of glomus tumors and glomangiomas occur in the subungual area, trunk, or extremities, whereas the present tumor occurred on the ear. Due to the peculiar histological features and location, other tumors were considered in the differential diagnosis to include Merkel cell carcinoma, primitive neuroectodermal tumor, and small cell melanoma. This article illustrates a unique variant of a glomus tumor, which to our knowledge has not been previously described.

Immunohistochemical analysis and biological behaviour of gastric glomus tumours: a case report and review of the literature.

Gastric glomus tumours are rare and clinically recognized as benign. Nevertheless, some show biological behaviour similar to that of malignant lesions. During the last 40 years, we have encountered only one gastric glomus tumour. Analysis of frozen sections of this tumour suggested a mesenchymal tumour with malignant potential. Three mitoses per 50 high-power fields, with no cytological abnormalities, were observed. Tumour cells were positive for α-smooth muscle actin, vimentin and actin but negative for CD117, S-100 protein, creatine kinase, desmin, CD68, collagen type IV, CD34 and p53. The post-operative period was uneventful. During 37 months' follow-up, no recurrence or metastasis was detected and a benign course was considered likely. Literature on the immunohistochemistry and biological behaviour of gastric glomus tumours was also reviewed. Immunohistochemical studies are helpful in the differential diagnosis of gastric glomus tumours: although most are benign, malignancy cannot be excluded. Thus, long-term follow-up of the patient is necessary.

Symplastic glomus tumor - a rare but distinct benign histological variant with analogy to other 'ancient' benign skin neoplasms.

A 78-year-old woman presented with a nail deformity of the index finger of the left hand associated with paroxysmal pain upon cold exposure. Histologically, a well-circumscribed tumor of 3 mm diameter was found in the dermis. The neoplastic cells in some areas were of pronouncedly variable size and cytomorphology, mostly epithelioid in shape, with eosinophilic cytoplasm and indistinctly defined cell borders. Pronounced nuclear pleomorphism and atypia were striking features, but no mitotic figures were noted. Multinuclear cells were present as were numerous small-to-medium vessels throughout the tumor. The tumor stroma showed myxoid areas. Immunohistochemistry showed cytoplasmic and membranous expression of smooth muscle actin and vimentin. The histological features and immunoprofile were consistent with the diagnosis of symplastic glomus tumor, a rare histological variant, which has been defined as a glomus tumor exhibiting marked nuclear atypia, in the absence of any other criteria for malignancy. The biological behavior of the tumor is benign. It is essential to differentiate this entity from malignant glomus tumor, which has metastatic potential. Even prominent cellular atypia and nuclear pleomorphism in a glomus tumor as in our case is not a marker of malignancy in the absence of additional criteria.

Symplastic glomus tumor: a case report.

Symplastic glomus tumors are defined as glomus tumors with a high-grade nuclear pleomorphism in the absence of any other malignant features, such as large size, deep location, infiltrative growth, mitotic activity, or necrosis. Only 11 cases have been reported so far in the English literature. It could be a challenge for pathologists who have no experience with it because the tumor can show marked nuclear atypia and pleomorphism. Despite its high nuclear grade, a symplastic glomus tumor itself has a benign biologic behavior. Hereby, the authors report a case of a symplastic glomus tumor on the right index finger tip of a 44-year-old woman with a literature review.

Malignant cutaneous glomus tumor presenting as a rapidly growing leg mass in a pregnant woman.

A 21-year-old pregnant woman presented with a rapidly growing >2 cm nodule on her right leg, involving dermis and subcutaneous tissue. Histologically, the tumor was composed of sheets and nests of neoplastic cells with variable cytomorphology, including typical round to ovoid glomus cells with clear cytoplasm and well-defined cell borders, small cells and spindle cells. Numerous medium to large vessels were present throughout the tumor. Moderate- to high cellularity, nuclear atypia and frequent mitotic figures (42 MF/50 High power field (HPF)) were noted. Immunohistochemistry showed cytoplasmic and membranous expression of actin (HHF-35) and membranous expression of type IV collagen. The histologic features and immunoprofile were consistent with the diagnosis of malignant glomus tumor, a rare soft tissue neoplasm that typically arises on the extremities. Histologic features that infer malignancy in glomus tumors include the combination of large size (>2 cm) and deep location, or atypical mitotic figures, or moderate to severe cytologic atypia with high mitotic activity (>5 mitoses /50 HPF). Although our case was superficially located, the nuclear atypia and mitotic rate, as well as the large size, fulfilled the criteria for a malignant glomus tumor.

Glomus tumor of the mesentery with atypical features: a case report.

Glomus tumors usually occur in the acral soft tissue and rarely in visceral locations, such as the stomach, intestines, mediastinum, lung, pancreas, bladder, and vagina. The authors present a 74-year-old woman with an exceptionally large glomus tumor of the mesentrium with malignant features. Previously reported cases of intraabdominal glomus tumor in the abdominal cavity exhibited benign behavior and few cases with metastatic disease. Criteria for malignancy in acral glomus tumors, such as unusually large size, infiltrative growth, necrosis, nuclear atypia, and mitotic activity, seem not to translate to abdominal glomus tumors. As very few intraabdominal glomus are described, the malignant potential of these tumors stays uncertain for longer period.