Spitz Tumors With ROS1 Fusions: A Clinicopathological Study of 6 Cases, Including FISH for Chromosomal Copy Number Alterations and Mutation Analysis Using Next-Generation Sequencing

Donati, Michele; Kastnerova, Liubov; Martínek, Petr; Grossmann, P.; Sticová, Eva; Hadravský, Ladislav; Torday, Tomas; Kyclová, Jitka; Michal, Michal; Kazakov, Dmitry V.

doi:10.1097/dad.0000000000001499

Cited by 37 publications

(26 citation statements)

References 57 publications

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“…RNA NGS analysis, performed to further characterise the type of fusion, revealed three different fusion partners. A fusion between PPFIBP1 and ROS1 , which has already been observed in spitzoid tumours, 7,10,11 was identified in an AST. The same patient, at the age of 3 years, had presented with another AST on the cheek, which FISH showed to be also rearranged, but the specific fusion was not identified.…”

Section: Discussionmentioning

confidence: 55%

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ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in‐situ hybridisation and next‐generation sequencing analysis

et al. 2021

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Aims Spitzoid tumours have been shown to harbour exclusive kinase fusions. Few studies have analysed substantial numbers of ROS1‐rearranged lesions. The aim of the present study was to investigate also their immunohistochemical profile. Methods and results Among a group of 35 spitzoid tumours, of which 34 were consecutively diagnosed in a 3‐year period, we found 11 ROS1 cases that were immunohistochemically positive, from 10 patients, eight of whom were female and two of whom were male, and who were aged 3–52 years (median, 29 years); most lesions (eight) were localized on the lower extremities. Four patterns of immunostaining were observed: cytoplasmic granular diffuse (six cases), sparse cytoplasmic granules (three cases), paranuclear dots (one case), and nuclear (one case). Fluorescence in‐situ hybridisation (FISH) analysis showed all cases to be rearranged (cut‐off of >15%). RNA next‐generation sequencing (NGS) analysis showed specific fusions of ROS1 in four cases: two with PWWP2A, one with PPFIBP1, and one with ZCCHC8. DNA NGS analysis showed in five cases, specific mutations of AKT, EGFR, NRAS, MYC, ALK, and KIT. ROS1 lesions belonged predominantly to the ‘atypical Spitz tumour’ group, and showed mainly a nested histological pattern. Interestingly, one patient developed two ROS1‐positive lesions. Conclusions Immunohistochemistry showed 100% sensitivity and specificity as compared with the FISH results, corresponding to ROS1 rearrangement in 31% of cases studied. These observations shed new light on the value of immunohistochemical evaluation of ROS1 in spitzoid tumours. ROS1 patterns of immunostaining probably reflect different subcellular localisations of ROS1 fusions, although no specific correlations were found in the cases studied. Immunohistochemistry and FISH were the most sensitive techniques for detecting ROS1 rearrangement in this subset of neoplasms.

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Section: Discussionmentioning

confidence: 55%

“…Among them, an AST from the helix of a 52‐year‐old patient showed a specific NRAS mutation. A ROS1 ‐rearranged spitzoid tumour with a NRAS mutation was reported by Donati et al 10 . NRAS is mutated in approximately 15–20% of melanomas 28 .…”

Section: Discussionmentioning

confidence: 85%

ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in‐situ hybridisation and next‐generation sequencing analysis

et al. 2021

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“…PCR amplification of the whole coding sequence using in-house designed primers and Sanger Sequencing of BAP1 were performed. The primers and PCR conditions were reported elsewhere 22 . From eight patients, either peripheral blood or saliva was tested for germline BAP1 mutations after obtaining the patient's written consent.…”

Section: Molecular Analysismentioning

confidence: 99%

Novel insights into the BAP1-inactivated melanocytic tumor

et al. 2022

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BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.

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“…Illumina TruSight Tumor 170 assay The commercially available TruSight Tumor 170 assay from Illumina was performed according to the manufacturer's instructions, and the library was sequenced on an Illumina platform as described previously [8].…”

Section: Targeted Next-generation Sequencingmentioning

confidence: 99%

Inflammatory leiomyosarcoma shows frequent co-expression of smooth and skeletal muscle markers supporting a primitive myogenic phenotype: a report of 9 cases with a proposal for reclassification as low-grade inflammatory myogenic tumor

et al. 2020

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Inflammatory leiomyosarcoma (ILMS) is a very rare soft tissue tumor that usually follows an indolent clinical course, but long-term follow-up studies are lacking. Recent publications primarily focused on its genetic profile characterized by a near haploid genome. One study also showed these tumors to have upregulation of genes known to be crucial for skeletal muscle differentiation. Nevertheless, immunohistochemical expression of skeletal muscle markers, as well as markers that would help to distinguish ILMS from a long list of relevant differential diagnostic entities, has not been extensively studied. Nine cases of ILMS were collected and stained by a broad IHC panel which, besides others, contained MyoD1, myogenin, and PAX-7. A subset of cases was also analyzed by 2 different NGS assays and by MDM2 fluorescence in situ hybridization. Five male and 4 female patients ranged in age from 25 to 54 years (mean, 36 years). The tumors showed a predilection for intramuscular sites of the lower limbs (n = 4) and back (n = 2), whereas the remaining 3 cases affected an unspecified skeletal muscle, lung, and omentum. Follow-up with an average length of 10.6 years (range 0.5-22) was available for 8 patients. The omental tumor spread locally within the abdominal cavity, but the patient has been free of disease 7 years after treatment. None of the 5 patients with somatic soft tissue tumors (and follow-up longer than 1.5 years) had either recurrence or metastasis. Immunohistochemical studies revealed a substantial expression of skeletal muscle markers in almost all cases. This phenotype coupled with a highly characteristic genotype and significantly more indolent clinical behavior as compared with conventional leiomyosarcoma of deep soft tissue offers a strong rationale to change the current nomenclature. Based on the clinicopathological features and gene expression profile, we propose the name low-grade inflammatory myogenic tumor.

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Spitz Tumors With ROS1 Fusions: A Clinicopathological Study of 6 Cases, Including FISH for Chromosomal Copy Number Alterations and Mutation Analysis Using Next-Generation Sequencing

Cited by 37 publications

References 57 publications

ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in‐situ hybridisation and next‐generation sequencing analysis

ROS1 pattern of immunostaining in 11 cases of spitzoid tumour: comparison with histopathological, fluorescence in‐situ hybridisation and next‐generation sequencing analysis

Novel insights into the BAP1-inactivated melanocytic tumor

Inflammatory leiomyosarcoma shows frequent co-expression of smooth and skeletal muscle markers supporting a primitive myogenic phenotype: a report of 9 cases with a proposal for reclassification as low-grade inflammatory myogenic tumor

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