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Jerzy Lasota - One of the best experts on this subject based on the ideXlab platform.

  • colonic adenocarcinomas harboring ntrk fusion genes a clinicopathologic and Molecular Genetic Study of 16 cases and review of the literature
    The American Journal of Surgical Pathology, 2020
    Co-Authors: Jerzy Lasota, Abbas Agaimy, Artur Kowalik, Malgorzata Chlopek, Jennifer Lamoureux, Jason Christiansen, Bartosz Wasąg, Anna Felisiakgoląbek, Wojciech Biernat, Vincenzo Canzonieri
    Abstract:

    This Study determined the frequency and the clinicopathologic and Genetic features of colorectal carcinomas driven by oncogenic fusions of the anaplastic lymphoma kinase gene (ALK). Of the 8150 screened tumors, 12 (0.15%) were immunohistochemically ALK-positive with D5F3 antibody. These cancers harbored CAD-ALK (n=1), DIAPH2-ALK (n=2), EML4-ALK (n=2), LOC101929227-ALK (n=1), SLMAP-ALK (n=1), SPTBN1-ALK (n=4), and STRN-ALK (n=1) fusions, as detected by an RNA-based next-generation sequencing assay. ALK fusion carcinomas were diagnosed mostly in older patients with a 9:3 female predominance (median age: 72 y). All tumors, except a rectal one, occurred in the right colon. Most tumors were stage T3 (n=7) or T4 (n=3). Local lymph node and distant metastases were seen at presentation in 9 and 2 patients. These tumors showed moderate (n=6) or poor (n=3) glandular differentiation, solid medullary growth pattern (n=2), and pure mucinous morphology (n=1). DNA mismatch repair-deficient phenotype was identified in 10 cases. Tumor-infiltrating lymphocytes were prominent in 9 carcinomas. In 4 carcinomas, tumor cells showed strong, focal (n=3), or diffuse programmed death-ligand 1 immunoreactivity. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 tumors. Four patients died of disease within 3 years, and 7 were alive with follow-up ranging from 1 to 8 years. No mutations in BRAF, RAS, and in genes encoding components of PI3K-AKT/MTOR pathway were identified. However, 1 tumor had a loss-of-function PTEN mutation. Aberration of p53 signaling, TP53 mutations, and/or nuclear accumulation of p53 protein was seen in 9 cases. ALK fusion colorectal carcinomas are a distinct and rare subtype of colorectal cancers displaying some features of mismatch repair-deficient tumors.

  • gist manifesting as a retroperitoneal tumor clinicopathologic immunohistochemical and Molecular Genetic Study of 112 cases
    The American Journal of Surgical Pathology, 2017
    Co-Authors: Markku Miettinen, Anna Felisiakgolabek, Shingo Inaguma, Zengfeng Wang, Jerzy Lasota
    Abstract:

    : Most gastrointestinal stromal tumors (GISTs) occur in the tubular gastrointestinal (GI) tract, but some present apparently outside the GI tract. In this Study, we analyzed 112 GISTs located in the retroperitoneum. These tumors occurred in 55 women and 57 men with a median age of 65 years (range: 21 to 89 y). On the basis of clinically or histologically detected connections to GI tract, 15 tumors were considered likely of gastric, 9 duodenal, and 13 of small intestinal origin. The remaining cases were categorized by location as peripancreatic (n=25), pelvic (n=11), mesenteric (n=4), and of unspecified/miscellaneous sites (n=35). The tumors varied in size 3 to 35 cm (median, 15 cm) and by mitotic rate per 5 mm, 0 to >100 (median, 10). Histologically the tumors apparently arising outside the GI tract had features of intestinal (n=41) and gastric GISTs (n=25); 9 cases had indeterminate histology. The histologic variants included spindled, epithelioid, vacuolated, nested, and myxoid potentially simulating other tumors such as liposarcoma and solitary fibrous tumor. Most GISTs were KIT-positive (106/112 cases), and the remaining 6 tumors were DOG1/Ano1-positive. Five cases showed focal nuclear positivity for MDM2. KIT mutations were detected in 42/59 cases, and PDGFRA mutations in 4/16 KIT wild-type and 3/5 of the KIT-negative tumors analyzed. One pelvic retroperitoneal GIST was succinate dehydrogenase deficient. All 79 patients were dead at last follow-up with a median survival of 14 months, with few survivals >5 years. Only operable versus inoperable tumor was a statistically favorable factor in univariate analysis (P 50/5 mm was significant for a shorter survival (hazard ratio, 5.25; 95% confidence interval, 1.65-16.8; P<0.01). Histologic and clinicopathologic similarity of extragastrointestinal retroperitoneal GISTs with GISTs of GI tract suggests their GI tract origin. Potentially overlapping features between GIST and other retroperitoneal tumors necessitate use of multiple diagnostic markers and Molecular Genetic studies.

  • frequency and clinicopathologic profile of pik3ca mutant gists Molecular Genetic Study of 529 cases
    Modern Pathology, 2016
    Co-Authors: Jerzy Lasota, Anna Felisiakgolabek, Zengfeng Wang, Tiffany Coates, Bartosz Wasag, Artur Kowalik, Sebastian Zieba, Malgorzata Chlopek, Janusz Kopczynski, Stanislaw Gozdz
    Abstract:

    Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors usually driven by the mutational activation of receptor tyrosine kinases, KIT, or PDGFRA. Oncogenic activation of phosphatidylinositide-3-kinase (PI3K), a downstream effector in the KIT signaling pathway, has been identified in different types of cancer, with the PI3K 110α subunit encoded by PIK3CA being a common mutational target. In this Study, the mutational hotspot in the PIK3CA kinase domain encoded by exon 20 was evaluated in 529 imatinib-naive GISTs using PCR amplification and Sanger sequencing. Eight mutations (two co-existing in one tumor) were identified. Subsequently, The cobas PIK3CA Mutation Test was employed to evaluate mutational hotspots in exons 1, 4, 7, and 9 in 119 PIK3CA exon 20-wild type tumors. In two cases, mutations in exons 1 and 9 were identified. In one GIST, previously undetected by Sanger sequencing, the exon 20 mutation was discovered. Altogether, eight primary and two metastatic GISTs carried PIK3CA mutations. The size of primary PIK3CA-mutant GISTs was ≥14 cm (mean size 17 cm), and mitotic activity varied from 0 to 72 per 50HPF (mean 5/50HPF). Follow-up data showed short survival in 6 of 7 studied cases. Detection of PIK3CA mutations in large or metastatic KIT-mutant GISTs may suggest that PIK3CA-mutant clones have a proliferative advantage during disease progression. Tyrosine kinase inhibitors have been successfully used in GIST treatment. However, resistance frequently develops due to secondary KIT mutations or activation of downstream to KIT signaling pathways, such as the PI3K/AKT/mTOR pathway. PIK3CA mutations similar to the ones detected in GISTs have been shown to cause such activation. Therefore, genotyping of PIK3CA in GISTs might help to pinpoint primary and metastatic tumors with the potential to develop resistance to tyrosine kinase inhibitors and guide therapy with PI3K inhibitors.

  • intranodal palisaded myofibroblastoma another mesenchymal neoplasm with ctnnb1 β catenin gene mutations clinicopathologic immunohistochemical and Molecular Genetic Study of 18 cases
    The American Journal of Surgical Pathology, 2015
    Co-Authors: William B Laskin, Anna Felisiakgolabek, Zengfeng Wang, Jerzy Lasota, John F Fetsch, Markku Miettinen
    Abstract:

    Intranodal palisaded myofibroblastoma is a benign, lymph node-based myofibroblastic tumor of unknown pathogenesis. We report the clinicopathological, immunohistochemical, and Genetic Molecular features of this rare entity. The Study cohort consisted of 14 males and 4 females ranging in age from 31 to 65 (mean, 47; median 49) years with tumors arising in inguinal lymph nodes (n=15), a neck lymph node (n=1), and undesignated lymph nodes (n=2). Most individuals presented with a painless mass or lump. Possible trauma/injury to the inguinal region was documented in four cases. Tumors ranged in size from 1.0 to 4.2 (mean, 3.1; median; 3.0) cm. Microscopically, the process presented as a well-circumscribed, often times pseudoencapsulated nodule (n=17) or nodules (n=1). Tumors consisted of a cellular proliferation of cytologically bland, spindled cells arranged in short fascicles and whorls within a finely collagenous(n=11) or myxocollagenous(n=7) matrix. In 12 tumors, scattered fibromatosis-like fascicles of spindled cells were noted. Histological features characteristic of the process included nuclear palisades (n=16 cases), collagenous bodies (n=15), and perinuclear intracytoplasmic hyaline globules (n=10). Mitotic activity ranged from 0 to 8 (mean,2; median, 1) mitotic figures/50 high-powered fields with no atypical division figures identified. Immunohistochemically, all tumors tested expressed (vimentin (n=3), smooth-muscle actin and/or muscle-specific actin (n=5, each), and nuclear beta-catenin and cyclin D1 (n=8, each). The latter two results prompted a screening for mutations in the beta-catenin gene glycogen synthase kinase-3 beta phosphorylation mutational “hotspot” region in exon 3 using PCR amplification and Sanger sequencing. Single nucleotide substitutions leading to missense mutations at the protein level were identified in 7 of 8 (88%) analyzed tumors and are responsible for the abnormal expression of beta-catenin and cyclin D1. These results demonstrate that mutational activation of the beta-catenin gene is likely a pivotal event in the pathogenesis of intranodal palisaded myofibroblastoma.

  • no kras mutations found in gastrointestinal stromal tumors gists Molecular Genetic Study of 514 cases
    Modern Pathology, 2013
    Co-Authors: Jerzy Lasota, Zengfeng Wang, Tiffany Coates, Rashonda Dennis, Moses O Evbuomwan, Mark Raffeld, Markku Miettinen
    Abstract:

    No KRAS mutations found in gastrointestinal stromal tumors (GISTs): Molecular Genetic Study of 514 cases

Markku Miettinen - One of the best experts on this subject based on the ideXlab platform.

  • gist manifesting as a retroperitoneal tumor clinicopathologic immunohistochemical and Molecular Genetic Study of 112 cases
    The American Journal of Surgical Pathology, 2017
    Co-Authors: Markku Miettinen, Anna Felisiakgolabek, Shingo Inaguma, Zengfeng Wang, Jerzy Lasota
    Abstract:

    : Most gastrointestinal stromal tumors (GISTs) occur in the tubular gastrointestinal (GI) tract, but some present apparently outside the GI tract. In this Study, we analyzed 112 GISTs located in the retroperitoneum. These tumors occurred in 55 women and 57 men with a median age of 65 years (range: 21 to 89 y). On the basis of clinically or histologically detected connections to GI tract, 15 tumors were considered likely of gastric, 9 duodenal, and 13 of small intestinal origin. The remaining cases were categorized by location as peripancreatic (n=25), pelvic (n=11), mesenteric (n=4), and of unspecified/miscellaneous sites (n=35). The tumors varied in size 3 to 35 cm (median, 15 cm) and by mitotic rate per 5 mm, 0 to >100 (median, 10). Histologically the tumors apparently arising outside the GI tract had features of intestinal (n=41) and gastric GISTs (n=25); 9 cases had indeterminate histology. The histologic variants included spindled, epithelioid, vacuolated, nested, and myxoid potentially simulating other tumors such as liposarcoma and solitary fibrous tumor. Most GISTs were KIT-positive (106/112 cases), and the remaining 6 tumors were DOG1/Ano1-positive. Five cases showed focal nuclear positivity for MDM2. KIT mutations were detected in 42/59 cases, and PDGFRA mutations in 4/16 KIT wild-type and 3/5 of the KIT-negative tumors analyzed. One pelvic retroperitoneal GIST was succinate dehydrogenase deficient. All 79 patients were dead at last follow-up with a median survival of 14 months, with few survivals >5 years. Only operable versus inoperable tumor was a statistically favorable factor in univariate analysis (P 50/5 mm was significant for a shorter survival (hazard ratio, 5.25; 95% confidence interval, 1.65-16.8; P<0.01). Histologic and clinicopathologic similarity of extragastrointestinal retroperitoneal GISTs with GISTs of GI tract suggests their GI tract origin. Potentially overlapping features between GIST and other retroperitoneal tumors necessitate use of multiple diagnostic markers and Molecular Genetic studies.

  • intranodal palisaded myofibroblastoma another mesenchymal neoplasm with ctnnb1 β catenin gene mutations clinicopathologic immunohistochemical and Molecular Genetic Study of 18 cases
    The American Journal of Surgical Pathology, 2015
    Co-Authors: William B Laskin, Anna Felisiakgolabek, Zengfeng Wang, Jerzy Lasota, John F Fetsch, Markku Miettinen
    Abstract:

    Intranodal palisaded myofibroblastoma is a benign, lymph node-based myofibroblastic tumor of unknown pathogenesis. We report the clinicopathological, immunohistochemical, and Genetic Molecular features of this rare entity. The Study cohort consisted of 14 males and 4 females ranging in age from 31 to 65 (mean, 47; median 49) years with tumors arising in inguinal lymph nodes (n=15), a neck lymph node (n=1), and undesignated lymph nodes (n=2). Most individuals presented with a painless mass or lump. Possible trauma/injury to the inguinal region was documented in four cases. Tumors ranged in size from 1.0 to 4.2 (mean, 3.1; median; 3.0) cm. Microscopically, the process presented as a well-circumscribed, often times pseudoencapsulated nodule (n=17) or nodules (n=1). Tumors consisted of a cellular proliferation of cytologically bland, spindled cells arranged in short fascicles and whorls within a finely collagenous(n=11) or myxocollagenous(n=7) matrix. In 12 tumors, scattered fibromatosis-like fascicles of spindled cells were noted. Histological features characteristic of the process included nuclear palisades (n=16 cases), collagenous bodies (n=15), and perinuclear intracytoplasmic hyaline globules (n=10). Mitotic activity ranged from 0 to 8 (mean,2; median, 1) mitotic figures/50 high-powered fields with no atypical division figures identified. Immunohistochemically, all tumors tested expressed (vimentin (n=3), smooth-muscle actin and/or muscle-specific actin (n=5, each), and nuclear beta-catenin and cyclin D1 (n=8, each). The latter two results prompted a screening for mutations in the beta-catenin gene glycogen synthase kinase-3 beta phosphorylation mutational “hotspot” region in exon 3 using PCR amplification and Sanger sequencing. Single nucleotide substitutions leading to missense mutations at the protein level were identified in 7 of 8 (88%) analyzed tumors and are responsible for the abnormal expression of beta-catenin and cyclin D1. These results demonstrate that mutational activation of the beta-catenin gene is likely a pivotal event in the pathogenesis of intranodal palisaded myofibroblastoma.

  • no kras mutations found in gastrointestinal stromal tumors gists Molecular Genetic Study of 514 cases
    Modern Pathology, 2013
    Co-Authors: Jerzy Lasota, Zengfeng Wang, Tiffany Coates, Rashonda Dennis, Moses O Evbuomwan, Mark Raffeld, Markku Miettinen
    Abstract:

    No KRAS mutations found in gastrointestinal stromal tumors (GISTs): Molecular Genetic Study of 514 cases

  • succinate dehydrogenase deficient gists a clinicopathologic immunohistochemical and Molecular Genetic Study of 66 gastric gists with predilection to young age
    The American Journal of Surgical Pathology, 2011
    Co-Authors: Markku Miettinen, Zengfeng Wang, Maarit Sarlomorikala, Czeslaw Osuch, Piotr Rutkowski, Jerzy Lasota
    Abstract:

    Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this Study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients 50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.

  • true smooth muscle tumors of the small intestine a clinicopathologic immunhistochemical and Molecular Genetic Study of 25 cases
    The American Journal of Surgical Pathology, 2009
    Co-Authors: Markku Miettinen, Leslie H Sobin, Jerzy Lasota
    Abstract:

    Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this Study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [ or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.

Leslie H Sobin - One of the best experts on this subject based on the ideXlab platform.

  • true smooth muscle tumors of the small intestine a clinicopathologic immunhistochemical and Molecular Genetic Study of 25 cases
    The American Journal of Surgical Pathology, 2009
    Co-Authors: Markku Miettinen, Leslie H Sobin, Jerzy Lasota
    Abstract:

    Gastrointestinal stromal tumors (GISTs) comprise a great majority of small intestinal mesenchymal tumors previously designated as smooth muscle tumors (SMTs), but true SMTs occur with a low-frequency encompassing both leiomyomas and leiomyosarcomas (LMSs). In this Study, we analyzed 25 tumors in the spectrum of primary SMTs of the small intestine. Metastatic tumors and those with external attachment only were excluded. These tumors occurred in 15 men and 10 women of median age of 62 years (range: 18 to 80 y). There were 9 well-differentiated SMTs with no atypia and low mitotic activity [ or =35 mitoses/50 HPFs. Four of 5 such LMSs with follow-up recurred or metastasized, and at least 3 patients died of disease; several others had a short survival but cause of death could not be determined. One patient, an 18-year-old woman, who died of LMS, was a survivor of a Wilms tumor radiated in infancy. All 6 LMSs studied for GIST-specific KIT and platelet-derived growth factor receptor alpha mutations showed wild-type sequences. This series demonstrates that primary small intestinal SMTs are rare (estimated frequency 1 SMT for 36 GISTs). A majority of these are mitotically active tumors with atypia warranting the diagnosis of LMS, and have a high malignant potential. The number of LMS cases is too small for stratification for risk assessment. True SMTs of small intestine should be separated from GISTs because of different pathogenesis and treatment.

  • synovial sarcoma of the stomach a clinicopathologic immunohistochemical and Molecular Genetic Study of 10 cases
    The American Journal of Surgical Pathology, 2008
    Co-Authors: Hala R Makhlouf, Leslie H Sobin, Will Ahrens, Beamon Agarwal, Nancy Dow, Josephine J Marshalleck, Edward L Lee, Jorge Dotto, Pei Hui, Andre M Oliveira
    Abstract:

    Only a few synovial sarcomas arising in the gastrointestinal tract have been reported, most of them are from the esophagus. We report clinical, histopathologic, and immunohistochemical features of 10 gastric synovial sarcomas. These tumors occurred in 4 males and 6 females with mean and median age of 52 years (range, 29 to 68 y). None of the patients had evidence of synovial sarcoma elsewhere. The tumor sizes ranged from 0.8 to 15 cm (mean, 3 cm). Two tumors were large transmural masses of 8 and 15 cm, and 8 were 0.8 to 6 cm, ulcerated cuplike or plaquelike or oval lesions predominantly involving the luminal side. Histologically, 9 tumors were monophasic one also having a poorly differentiated round cell component, and one was biphasic. Microscopic calcifications were present in 2 tumors. At least focal keratin (AE1/AE3 cocktail, keratin 7) and/or epithelial membrane antigen-positivity were detected in all tumors, and there was no CD34 or KIT-immunoreactivity. SYT-SSX fusion transcripts were demonstrated in 7 cases studied by a polymerase chain reaction-based fusion transcript assay. Five patients had a partial gastrectomy, and 5 underwent wedge or segmental resections. Two patients had received chemotherapy after surgery, but none had postoperative radiation. Four patients with plaquelike or cuplike tumors < or =3 cm were alive and well 1, 2, 2, and 18.5 years after surgery. Two patients died of tumor 25 and 29 months after surgery. One of them had a large 8-cm tumor, and another had a 2-cm tumor with a poorly differentiated component. Two patients were alive with recurrences 6 and 48 months after diagnosis. Synovial sarcoma rarely occurs as a gastric primary tumor. It has a variable prognosis depending on tumor size and differentiation, and should be considered in the differential diagnosis of KIT-negative gastric spindle cell neoplasms.

  • gastrointestinal stromal tumors of the jejunum and ileum a clinicopathologic immunohistochemical and Molecular Genetic Study of 906 cases before imatinib with long term follow up
    The American Journal of Surgical Pathology, 2006
    Co-Authors: Markku Miettinen, Leslie H Sobin, Hala R Makhlouf, Jerzy Lasota
    Abstract:

    Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. This Study analyzed 1091 tumors originally classified as smooth muscle tumors of the small intestine (including jejunum or ileum and excluding duodenum), and found that 906 (83%) of these were GISTs. The GIST patients had 55:45 male-to-female ratio with a median age of 59 years (range, 13-94 years). Only 0.6% of tumors occurred before the age of 21 years and 13.6% before the age of 40 years. The tumors varied from 0.3 to 40 cm (median, 7.0 cm) and most commonly presented with GI bleeding or acute abdomen; 18% were incidentally detected. Histologically, the tumors were relatively monotypic with spindle cell (86%), epithelioid (5%), or mixed patterns (9%). Skeinoid fibers were present in 44% of cases, and their presence was associated with a favorable course. Most epithelioid tumors were malignant, and this morphology sometimes emerged from less cellular and less mitotically active spindle cell tumors, suggesting that it represented a transformation. KIT was immunohistochemically detected in 98%, CD34 in 40%, smooth muscle actin in 34%, desmin in 0.2%, and S-100 protein in 14% of the tumors tested. Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only 10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity 5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.

  • gastrointestinal stromal tumors in patients with neurofibromatosis 1 a clinicopathologic and Molecular Genetic Study of 45 cases
    The American Journal of Surgical Pathology, 2006
    Co-Authors: Markku Miettinen, Leslie H Sobin, John F Fetsch, Jerzy Lasota
    Abstract:

    Gastrointestinal stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, most commonly occur sporadically, but there seems to be some increased tendency for these tumors to develop in patients with neurofibromatosis 1 (NF1). The clinicopathologic profile, KIT, and PDGFRA mutation status and long-term prognosis of patients with GIST in NF1 are incompletely characterized. In this Study, we analyzed 45 patients who had NF1 and GIST. There were 26 females and 19 males with a median age of 49 years (10 years lower than the median age of GIST patients in general). A great majority of tumors occurred in the jejunum or ileum, with multiple tumors occurring in 28 cases. Ten patients had a duodenal and one had a gastric GIST. The most common presentations were gastrointestinal bleeding and anemia, and many patients had intermittent bleeding over several years. The majority of the tumors were small and mitotically inactive; only 7 had mitotic activity >5/50 HPFs and 15 tumors were >5 cm. Associated Cajal cell hyperplasia was common. One patient had an intraabdominal peri-intestinal neurofibroma. Five of 35 patients with follow-up died of metastatic disease; all of these had a tumor >5 cm, mitotic rate >5/50 HPFs, or both; three of these tumors were located in the duodenum. The presence of multiple small tumors was not associated with progressive disease. Most patients with long-term follow-up enjoyed a good prognosis; 2 died of other NF1-associated tumors (malignant peripheral nerve sheath tumors, brain tumor). None of the 16 tumors from 15 patients had a KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as is typically seen in sporadic GISTs, indicating that GISTs in NF1 patients have a different pathogenesis than sporadic GISTs.

  • gastrointestinal stromal tumors in patients with neurofibromatosis 1 a clinicopathologic and Molecular Genetic Study of 45 cases
    The American Journal of Surgical Pathology, 2006
    Co-Authors: Markku Miettinen, Leslie H Sobin, John F Fetsch, Jerzy Lasota
    Abstract:

    Abstract:Gastrointestinal stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, most commonly occur sporadically, but there seems to be some increased tendency for these tumors to develop in patients with neurofibromatosis 1 (NF1). The clinicopathologic profile, KI

Andrew L Folpe - One of the best experts on this subject based on the ideXlab platform.

  • prrx1 ncoa1 rearranged fibroblastic tumor clinicopathologic immunohistochemical and Molecular Genetic Study of 6 cases of a potentially under recognized distinctive mesenchymal tumor
    Histopathology, 2021
    Co-Authors: Josephine K Dermawan, Elizabeth M Azzato, Judith Jebastin Thangaiah, Sandra Gjorgovagjeorgievski, Brian P Rubin, Andrew L Folpe, Abbas Agaimy, Karen Fritchie
    Abstract:

    AIMS PRRX1-NCOA1 rearranged fibroblastic tumor is a recently described, rare mesenchymal tumor. Only 4 cases have been previously reported. We report 6 additional cases of this unusual mesenchymal neoplasm with emphasis on its differential diagnosis. MATERIALS AND RESULTS The six cases were from 3 females and 3 males (aged 20-49 years; median 42). Three tumors were located on the abdominal wall; two from the shoulder/axillary areas; one on the lateral hip. All presented as slow-growing subcutaneous nodules, ranging from 2.6 to 5.5 cm (median 4.0 cm). The tumors consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinized and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibers were present, as were irregularly dilated, "gaping", "crescent-shaped" or "staghorn-like" thin-walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100 protein, MUC4 and STAT6 was consistently negative. RNA-sequencing revealed PRRX1-NCOA1 fusions in all cases. Of the 4 cases with limited follow-up (1.5-4 months), none recurred following local surgical excision. CONCLUSIONS The morphologic features of PRRX1-NCOA1 rearranged fibroblastic tumor overlap with those of RB1-deficient soft tissue tumors, solitary fibrous tumor, and low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphologic Study and application of a panel of immunostains, although Molecular Genetic Study is most definitive. The natural history of PRRX1-NCOA1 rearranged fibroblastic tumor appears quite favorable, although longer term Study of larger number of cases is warranted.

  • smarcb1 deficient vulvar neoplasms a clinicopathologic immunohistochemical and Molecular Genetic Study of 14 cases
    The American Journal of Surgical Pathology, 2015
    Co-Authors: Andrew L Folpe, Kenneth J Schoolmeester, Glenn W Mccluggage, Lisa M Sullivan, Katharine Castagna, William A Ahrens, Esther Oliva, Jaclyn A Biegel, Petur G Nielsen
    Abstract:

    Loss of expression of the SMARCB1 (INI1/BAF47/SNF5) tumor-suppressor protein, originally identified in pediatric malignant rhabdoid tumors, has been noted in significant percentages of epithelioid sarcomas of classical and proximal-type and in myoepithelial carcinomas. Epithelioid sarcoma and myoepithelial carcinoma are very rare in the vulvar region, and few of these cases have been evaluated for SMARCB1 protein loss by immunohistochemistry (IHC) or for SMARCB1 gene alterations by Molecular Genetic techniques. We studied the clinicopathologic, IHC, and Molecular Genetic features of 14 SMARCB1-deficient vulvar neoplasms. All available routinely stained sections were reexamined, and IHC analysis for wide-spectrum cytokeratins, high-Molecular weight cytokeratins, epithelial membrane antigen, S100 protein, CD34, smooth muscle actin, desmin, and SMARCB1 was performed. Multiplex ligation-dependent probe amplification and DNA sequencing of the SMARCB1 gene was performed on 12 cases with sufficient available tissue. The 14 vulvar tumors occurred in adult women (mean age 46 y, range 22 to 62 y) and measured 1.1 to 8.8 cm in size (mean 4.7 cm). Tumors were classified as classical-type epithelioid sarcoma (N=1), proximal-type epithelioid sarcoma (N=6), myoepithelial carcinoma (N=4), and "SMARCB1-deficient vulvar sarcoma, not otherwise specified" (N=3) on the basis of combined histopathologic and IHC findings. One myoepithelial carcinoma showed divergent rhabdomyoblastic differentiation. All tested cases showed partial or complete SMARCB1 deletions (homozygous: 9 cases; heterozygous: 3 cases). One case with a heterozygous deletion also showed a c.528delC mutation in exon 5. Fluorescence in situ hybridization for EWSR1 rearrangement was performed for 3 cases classified as myoepithelial carcinoma and was negative. Follow-up (13 patients, range 5 to 72 mo, mean 31 mo) data showed 3 patients dead of disease, 1 alive with unresectable metastatic disease, 1 alive with radiographic evidence of extensive lymph nodal disease, and 8 alive without disease. We conclude that SMARCB1-deficient vulvar neoplasms chiefly comprise epithelioid sarcoma and myoepithelial carcinoma, although some defy easy classification. No association was seen between clinical behavior and the type of SMARCB1 alteration.

  • synovial sarcoma of the kidney a clinicopathologic immunohistochemical and Molecular Genetic Study of 16 cases
    The American Journal of Surgical Pathology, 2014
    Co-Authors: John K Schoolmeester, John C Cheville, Andrew L Folpe
    Abstract:

    We report the clinicopathologic and immunohistochemical features of 16 cases of Genetically confirmed primary synovial sarcoma of the kidney. The cases occurred in 9 men and 7 women ranging in age from 17 to 78 years (mean, 46 y). The tumors were grossly large, solid, and variably cystic (2.2 to 19.0 cm; mean 8.6 cm). Microscopically, all tumors were of the monophasic type and diffusely immunoreactive for TLE1 and BCL-2. Focal pankeratin positivity was found in just under half. Ten cases carried an SS18-SSX2 fusion transcript, and 5 cases showed an SS18-SSX1 transcript by reverse transcription polymerase chain reaction. The remaining case demonstrated SS18 rearrangement by fluorescence in situ hybridization. Clinical follow-up information was available for 12 patients (range, 1 to 77 mo; mean, 32.5 mo). Fourteen patients underwent radical nephrectomy, and 3 patients had lung metastases at presentation. Six patients died of disease within 1 to 58 months (mean, 31 mo) of their diagnosis. Five patients were alive without evidence of disease 12 to 77 months (mean, 39 mos) after surgery. A single patient was alive with metastases to the spine 11 months after surgery. We conclude that renal synovial sarcoma is an aggressive tumor, with adverse patient outcome in >50% of cases. Synovial sarcoma must be distinguished from morphologically similar lesions of the kidney.

  • spindle epithelial tumor with thymus like differentiation a morphologic immunohistochemical and Molecular Genetic Study of 11 cases
    The American Journal of Surgical Pathology, 2009
    Co-Authors: Andrew L Folpe, Ricardo V Lloyd, Carlos E Bacchi, Juan Rosai
    Abstract:

    Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare tumor of the thyroid and neck, first described by Chan and Rosai. SETTLE is a low-grade malignancy, with potential for late lung, lymph node, and other visceral metastases. The clinicopathologic features of SETTL

Hala R Makhlouf - One of the best experts on this subject based on the ideXlab platform.

  • calcifying nested stromal epithelial tumors of the liver a clinicopathologic immunohistochemical and Molecular Genetic Study of 9 cases with a long term follow up
    The American Journal of Surgical Pathology, 2009
    Co-Authors: Hala R Makhlouf, Hala M Abdulal, Guanghua Wang, Zachary Goodman
    Abstract:

    There is a rare primary liver tumor that has been reported as “ossifying stromal-epithelial tumor” (3 cases), “desmoplastic nested spindle cell tumor” (4 cases), and “nested stromal-epithelial tumor” (6 cases). Herein we report 9 cases of this tumor, including 3 previously reported, from the files o

  • synovial sarcoma of the stomach a clinicopathologic immunohistochemical and Molecular Genetic Study of 10 cases
    The American Journal of Surgical Pathology, 2008
    Co-Authors: Hala R Makhlouf, Leslie H Sobin, Will Ahrens, Beamon Agarwal, Nancy Dow, Josephine J Marshalleck, Edward L Lee, Jorge Dotto, Pei Hui, Andre M Oliveira
    Abstract:

    Only a few synovial sarcomas arising in the gastrointestinal tract have been reported, most of them are from the esophagus. We report clinical, histopathologic, and immunohistochemical features of 10 gastric synovial sarcomas. These tumors occurred in 4 males and 6 females with mean and median age of 52 years (range, 29 to 68 y). None of the patients had evidence of synovial sarcoma elsewhere. The tumor sizes ranged from 0.8 to 15 cm (mean, 3 cm). Two tumors were large transmural masses of 8 and 15 cm, and 8 were 0.8 to 6 cm, ulcerated cuplike or plaquelike or oval lesions predominantly involving the luminal side. Histologically, 9 tumors were monophasic one also having a poorly differentiated round cell component, and one was biphasic. Microscopic calcifications were present in 2 tumors. At least focal keratin (AE1/AE3 cocktail, keratin 7) and/or epithelial membrane antigen-positivity were detected in all tumors, and there was no CD34 or KIT-immunoreactivity. SYT-SSX fusion transcripts were demonstrated in 7 cases studied by a polymerase chain reaction-based fusion transcript assay. Five patients had a partial gastrectomy, and 5 underwent wedge or segmental resections. Two patients had received chemotherapy after surgery, but none had postoperative radiation. Four patients with plaquelike or cuplike tumors < or =3 cm were alive and well 1, 2, 2, and 18.5 years after surgery. Two patients died of tumor 25 and 29 months after surgery. One of them had a large 8-cm tumor, and another had a 2-cm tumor with a poorly differentiated component. Two patients were alive with recurrences 6 and 48 months after diagnosis. Synovial sarcoma rarely occurs as a gastric primary tumor. It has a variable prognosis depending on tumor size and differentiation, and should be considered in the differential diagnosis of KIT-negative gastric spindle cell neoplasms.

  • gastrointestinal stromal tumors of the jejunum and ileum a clinicopathologic immunohistochemical and Molecular Genetic Study of 906 cases before imatinib with long term follow up
    The American Journal of Surgical Pathology, 2006
    Co-Authors: Markku Miettinen, Leslie H Sobin, Hala R Makhlouf, Jerzy Lasota
    Abstract:

    Gastrointestinal (GI) stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are the most common mesenchymal tumors of the GI tract. This Study analyzed 1091 tumors originally classified as smooth muscle tumors of the small intestine (including jejunum or ileum and excluding duodenum), and found that 906 (83%) of these were GISTs. The GIST patients had 55:45 male-to-female ratio with a median age of 59 years (range, 13-94 years). Only 0.6% of tumors occurred before the age of 21 years and 13.6% before the age of 40 years. The tumors varied from 0.3 to 40 cm (median, 7.0 cm) and most commonly presented with GI bleeding or acute abdomen; 18% were incidentally detected. Histologically, the tumors were relatively monotypic with spindle cell (86%), epithelioid (5%), or mixed patterns (9%). Skeinoid fibers were present in 44% of cases, and their presence was associated with a favorable course. Most epithelioid tumors were malignant, and this morphology sometimes emerged from less cellular and less mitotically active spindle cell tumors, suggesting that it represented a transformation. KIT was immunohistochemically detected in 98%, CD34 in 40%, smooth muscle actin in 34%, desmin in 0.2%, and S-100 protein in 14% of the tumors tested. Outcome was strongly dependent on tumor size and mitotic activity, with an overall 39% tumor-related mortality, twice that for gastric GISTs. Only 10 cm and >5 mitoses/50 HPF metastasized. In stark contrast to corresponding gastric tumors, tumors >10 cm with mitotic activity 5/50 HPF had a high metastatic rate (>50%); tumors >5 cm < or = 10 cm with low mitotic rate had a 24% metastatic rate. The median survival times of patients with low mitotic rate tumors who died of disease decreased by increasing tumor size. KIT exon 11 mutations were detected in 90 cases, exon 9 mutation in 17 cases, and exon 17 mutation in 1 case; the presence of mutation or mutation type was not prognostically significant. There were no PDGFRA exon 12 or 8 mutations. Systematic data on prognosis of small intestinal GISTs of various size and mitotic activity categories can be helpful in management and surveillance of patients with these tumors.

  • gastrointestinal stromal tumors intramural leiomyomas and leiomyosarcomas in the duodenum a clinicopathologic immunohistochemical and Molecular Genetic Study of 167 cases
    The American Journal of Surgical Pathology, 2001
    Co-Authors: Markku Miettinen, Leslie H Sobin, Janusz Kopczynski, Hala R Makhlouf, Maarit Sarlomorikala, Hajnalka Gyorffy, Allen P Burke, Jerzy Lasota
    Abstract:

    In this Study we analyzed the clinicopathologic features of duodenal smooth muscle or stromal tumors, including 156 GISTs, 6 leiomyomas (LMs), and 5 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. GISTs were documented as KIT positive (n = 109); 47 tumors were also included because of their histologic identity to KIT-positive cases. GIST-specific c-kit gene mutations were documented in exon 11 in 9 of 30 cases (30%) and exon 9 in 4 of 30 cases (13%). The GISTs occurred in patients with an age range of 10-88 years (median 56 years); 54% were male. Ten patients had neurofibromatosis type I; six of them had multiple GISTs. The GISTs ranged from small asymptomatic intramural or external nodules to large masses that extended into the retroperitoneum (median size 4.5 cm). They were mostly spindle cell tumors; three malignant GISTs had an epithelioid morphology, and 81 cases had skeinoid fibers. The tumors often coexpressed CD34 and KIT (54%) and were variably positive for smooth muscle actin (39%) and S-100 protein (20%) but never for desmin. A total of 86% of patients with tumors >5 cm with >5 mitoses/50 high power fields (HPF) (n = 21) died of disease, whereas no tumor <2 cm with <5 mitoses/50 HPF (n = 12) recurred or caused death. Long latency was common between primary operation and recurrences or metastases; either one occurred in 49 of 140 patients with follow-up (35%). No formula could accurately predict metastases, which occasionally developed even if mitotic activity was <5/50 HPF and size <5 cm. Metastases were in the abdominal cavity, liver, and rarely in bones and lungs but never in lymph nodes. Four actin- and desmin-positive and KIT-negative benign intramural LMs were similar to those more often seen in the esophagus. There were five LMSs, one of which formed a polypoid intraluminal mass; all were actin positive and KIT negative. The great majority of duodenal mesenchymal tumors are GISTs, which have a spectrum from small indolent tumors to overt sarcomas. LMs and LMSs are rare.