Synovial sarcoma is a high-grade soft tissue sarcoma that can be challenging to diagnose on the basis of histology alone. It is defined by a characteristic translocation t(X;18) that produces the ...fusion oncogene SYT-SSX. The current diagnostic gold standard for synovial sarcoma is the demonstration of the translocation by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or cytogenetics, in an appropriate histologic context. TLE1 encodes a transcriptional corepressor that is overexpressed in synovial sarcomas. Gene and tissue microarray studies have identified TLE1 as an excellent bio-marker for distinguishing the synovial sarcoma from other soft tissue malignancies. We prospectively evaluated incoming soft tissue tumor cases where the histology and clinical setting made synovial sarcoma a real consideration in the differential diagnosis. TLE1, Bcl2, epithelial membrane antigen, and cytokeratin expression were assessed using commercially available antibodies. TLE1 gave intense, diffuse nuclear staining in 35 of 35 molecularly confirmed synovial sarcoma cases, and was rare to absent in the 73 other soft tissue tumors examined (positive staining was found only in 1 of 43 malignant peripheral nerve sheath tumors, the 1 tested fibrosarcoma, and 1 pleomorphic sarcoma). TLE1 was more sensitive and specific for synovial sarcoma than other currently available immunohistochemical markers including Bcl2, epithelial membrane antigen and cytokeratins, and had a positive predictive value of 92% and a negative predictive value of 100% in this clinical setting. Our findings confirm, in a prospective diagnostic context, that TLE1 is more sensitive and specific for synovial sarcoma than any other currently available immunohistochemical stains, and in some cases may preclude the need for molecular testing.
Kinase inhibitors such as imatinib have dramatically improved outcomes for patients with gastrointestinal stromal tumor (GIST), but many patients develop resistance to these treatments. Although in ...some patients this event corresponds with mutations in the GIST driver oncogenic kinase KIT, other patients develop resistance without KIT mutations. In this study, we address this patient subset in reporting a functional dependence of GIST on the FGF receptor FGFR3 and its crosstalk with KIT in GIST cells. Addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment, allowing sensitive cells to proliferate in the presence of the drug. FGF2 expression was increased in imatinib-resistant GIST cells, the growth of which was blocked by RNAi-mediated silencing of FGFR3. Moreover, combining KIT and FGFR3 inhibitors synergized to block the growth of imatinib-resistant cells. Signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. Clinically, an IHC analysis of tumor specimens from imatinib-resistant GIST patients revealed a relative increase in FGF2 levels, with a trend toward increased expression in imatinib-naïve samples consistent with possible involvement in drug resistance. Our findings provide a mechanistic rationale to evaluate existing FGFR inhibitors and multikinase inhibitors that target FGFR3 as promising strategies to improve treatment of patients with GIST with de novo or acquired resistance to imatinib.
Cutaneous myxoma (CM) is an uncommon benign neoplasm of skin, which may be sporadic or arise in association with syndromes such as Carney complex. There has been only one large case series describing ...CM. We report 54 additional cases of CM; patients had a mean age of 55 years (range = 7–91), with a female-to-male ratio of 1.3. Most occurred on the trunk (n = 19), with the back being the most common site. The remainder presented on the lower extremity (n = 18), head and neck (n = 10), and arm (n = 7). Histopathologically, they were relatively circumscribed, nodular, and centered in the dermis. All had abundant myxoid stroma, a thin, arborizing vascular network, and spindled to stellate cells with no to mild atypia without mitotic activity. Follicular induction, stromal neutrophils, and intranuclear inclusions were present in 35%, 25%, and 61% of cases, respectively. Collagen trapping, splitting of collagen fibers, and encircling of hair follicles or eccrine glands were encountered in a subset. Thirty-nine cases were treated with shave excision, whereas 12 cases underwent wide local excision. Follow-up data were available for 28 of 54 cases (mean = 50 months). Only one case recurred at 36 months. This study suggests CM has a lower risk of local recurrence than previously reported.
•Cutaneous myxoma is a benign myxoid neoplasm of skin•This is the largest clinicopathologic study of cutaneous myxoma till date.•We compared the clinicopathologic features of the cases in our series with the features described in the previous studies and also with a pooled data group of case reports of cutaneous myxoma between 1996-2020.•This study revealed a lower local recurrence rate in cutaneous myxoma compared to previous studies.
Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to ...have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p = 0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.
The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we ...sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.
The activities of YAP and TAZ, the end effectors of the Hippo pathway, are consistently altered in cancer, and this dysregulation drives aggressive tumor phenotypes. While the actions of these two ...proteins aid in tumorigenesis in the majority of cancers, the dysregulation of these proteins is rarely sufficient for initial tumor development. Herein, we present a unique TAZ-driven cancer, epithelioid hemangioendothelioma (EHE), which harbors a WWTR1(TAZ)–CAMTA1 gene fusion in at least 90% of cases. Recent investigations have elucidated the mechanisms by which YAP/TAP-fusion oncoproteins function and drive tumorigenesis. This review presents a critical evaluation of this recent work, with a particular focus on how the oncoproteins alter the normal activity of TAZ and YAP, and, concurrently, we generate a framework for how we can target the gene fusions in patients. Since EHE represents a paradigm of YAP/TAZ dysregulation in cancer, targeted therapies for EHE may also be effective against other YAP/TAZ-dependent cancers.
Uterine adenosarcomas are mesenchymal neoplasms Piscuoglio, Salvatore; Burke, Kathleen A; Ng, Charlotte KY ...
The Journal of pathology,
February 2016, Letnik:
238, Številka:
3
Journal Article
Human Cancers Express a Mutator Phenotype Bielas, Jason H.; Loeb, Keith R.; Rubin, Brian P. ...
Proceedings of the National Academy of Sciences - PNAS,
11/2006, Letnik:
103, Številka:
48
Journal Article
Recenzirano
Odprti dostop
Cancer cells contain numerous clonal mutations, i.e., mutations that are present in most or all malignant cells of a tumor and have presumably been selected because they confer a proliferative ...advantage. An important question is whether cancer cells also contain a large number of random mutations, i.e., randomly distributed unselected mutations that occur in only one or a few cells of a tumor. Such random mutations could contribute to the morphologic and functional heterogeneity of cancers and include mutations that confer resistance to therapy. We have postulated that malignant cells exhibit a mutator phenotype resulting in the generation of random mutations throughout the genome. We have recently developed an assay to quantify random mutations in human tissue with unprecedented sensitivity. Here, we report measurements of random single-nucleotide substitutions in normal and neoplastic human tissues. In normal tissues, the frequency of spontaneous random mutations is exceedingly low, less than 1 x 10⠻⠸ per base pair. In contrast, tumors from the same individuals exhibited an average frequency of 210 x 10⠻⠸ per base pair, an elevation of at least two orders of magnitude. Our data document tumor heterogeneity at the single-nucleotide level, indicate that accelerated mutagenesis prevails late into tumor progression, and suggest that elevation of random mutation frequency in tumors might serve as a novel prognostic indicator.
Inflammatory myofibroblastic tumors (IMTs) are neoplastic mesenchymal proliferations featuring an inflammatory infiltrate composed primarily of lymphocytes and plasma cells. The myofibroblastic cells ...in some IMTs contain chromosomal rearrangements involving the
ALK receptor tyrosine-kinase locus region (chromosome band 2p23). ALK—which is normally restricted in its expression to neural tissues—is expressed strikingly in the IMT cells with 2p23 rearrangements. We now report a recurrent oncogenic mechanism, in IMTs, in which tropomyosin (TPM) N-terminal coiled-coil domains are fused to the ALK C-terminal kinase domain. We have cloned two
ALK fusion genes,
TPM4-ALK and
TPM3-ALK, which encode ∼95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphorylation. Immunohistochemical and molecular correlations, in other IMTs, implicate non-TPM ALK oncoproteins that are predominantly cytoplasmic or pre- dominantly nuclear, presumably depending on the subcellular localization of the ALK fusion partner. Notably, a
TPM3-ALK oncogene was reported recently in anaplastic lymphoma, and
TPM3-ALK is thereby the first known fusion oncogene that transforms,
in vivo, both mesenchymal and lymphoid human cell lineages.
Well-differentiated liposarcoma/atypical lipomatous tumor and dedifferentiated liposarcoma can be difficult to distinguish from benign lipomatous neoplasms and other high-grade sarcomas, ...respectively. Cytogenetics in these tumors has identified ring and giant chromosomes composed of 12q13-15 amplicons including the MDM2 gene. Identifying MDM2 amplification by fluorescence in situ hybridization may prove an adjunctive tool in the diagnosis of lipomatous neoplasms. Dual color fluorescence in situ hybridization employing a laboratory-developed BAC label probe cocktail specific for MDM2 (12q15) and a probe for the centromeric region of chromosome 12 (Abbott Molecular, DesPlaines, IL) was performed on formalin-fixed and paraffin-embedded tissue including whole sections from atypical lipomatous tumors (n=13), dedifferentiated liposarcomas (n=14), benign lipomatous tumors (n=30), and pleomorphic sarcoma, not otherwise specified (n=10), and a tissue microarray containing a variety of high-grade sarcomas (n=63). An MDM2/chromosome 12 ratio ≥2.0 was considered amplified, <2.0 nonamplified, and cases displaying >2 signals of both probes and an MDM2 ratio <2.0 polysomic for chromosome 12. Of the well-differentiated and dedifferentiated liposarcomas, 100% showed amplification of MDM2. Chromosome 12 polysomy was noted in 89% of spindle cell/pleomorphic lipomas, while all angiolipomas and lipomas were nonamplified and eusomic. MDM2 amplification was observed in 40% of pleomorphic sarcomas and a small subset of high-grade sarcomas (3/63). MDM2/chromosome 12 fluorescence in situ hybridization is a sensitive and specific tool (both 100%) in evaluating low-grade lipomatous neoplasms. The specificity decreases in high-grade sarcomas, as MDM2 amplification was observed in a small portion of pleomorphic sarcomas and high-grade sarcomas other than dedifferentiated liposarcomas. Importantly, none of the benign lipomatous lesions were MDM2 amplified and even cells in areas of well-differentiated liposarcomas with minimal cytologic atypia were amplified, making the probe a valuable tool in the diagnosis of even limited biopsy samples of well-differentiated lipomatous neoplasms.
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