Gastrointestinal stromal tumors (GISTs) and second malignancies A novel sentinel tumor? A monoinstitutional, STROBE-compliant observational analysis

M.G. Rodriquenz, S. Rossi, R. Ricci, M. Martini, Marilena Larocca, Angelo Dipasquale, M. Quirino, Giovanni Schinzari, Michele Basso, Ettore D'Argento, A. Strippoli, C. Barone, A. Cassano

Research output: Contribution to journalArticle

Abstract

Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis. A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-a genes was performed in all patients. Following the involvement of KRAS mutation in many tumors' pathogenesis, analysis of KRAS was performed in patients with also second neoplasms. Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-a mutation (n. 2) and exon 18 PDGFR-a mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P=0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months. The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis. © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.
Original languageEnglish
JournalMedicine (United States)
Volume95
Issue number38
DOIs
Publication statusPublished - 2016

Fingerprint

Gastrointestinal Stromal Tumors
Second Primary Neoplasms
Exons
Neoplasms
Mutation
vif Genes
cyhalothrin
Gastrointestinal Tract
Incidence
Health

Keywords

  • GIST
  • KIT
  • KRAS
  • PDGFR
  • Second malignancies
  • KRAS protein, human
  • platelet derived growth factor alpha receptor
  • protein p21
  • stem cell factor receptor
  • adult
  • aged
  • dna mutational analysis
  • exon
  • female
  • gastrointestinal stromal tumor
  • gastrointestinal tumor
  • genetics
  • human
  • immunohistochemistry
  • incidence
  • male
  • middle aged
  • mutation
  • Neoplasms, Second Primary
  • pathology
  • polymerase chain reaction
  • retrospective study
  • time factor
  • very elderly
  • young adult
  • Adult
  • Aged
  • Aged, 80 and over
  • DNA Mutational Analysis
  • Exons
  • Female
  • Gastrointestinal Neoplasms
  • Gastrointestinal Stromal Tumors
  • Humans
  • Immunohistochemistry
  • Incidence
  • Male
  • Middle Aged
  • Mutation
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-kit
  • Proto-Oncogene Proteins p21(ras)
  • Receptor, Platelet-Derived Growth Factor alpha
  • Retrospective Studies
  • Time Factors
  • Young Adult

Cite this

Gastrointestinal stromal tumors (GISTs) and second malignancies A novel sentinel tumor? A monoinstitutional, STROBE-compliant observational analysis. / Rodriquenz, M.G.; Rossi, S.; Ricci, R.; Martini, M.; Larocca, Marilena; Dipasquale, Angelo; Quirino, M.; Schinzari, Giovanni; Basso, Michele; D'Argento, Ettore; Strippoli, A.; Barone, C.; Cassano, A.

In: Medicine (United States), Vol. 95, No. 38, 2016.

Research output: Contribution to journalArticle

Rodriquenz, MG, Rossi, S, Ricci, R, Martini, M, Larocca, M, Dipasquale, A, Quirino, M, Schinzari, G, Basso, M, D'Argento, E, Strippoli, A, Barone, C & Cassano, A 2016, 'Gastrointestinal stromal tumors (GISTs) and second malignancies A novel sentinel tumor? A monoinstitutional, STROBE-compliant observational analysis', Medicine (United States), vol. 95, no. 38. https://doi.org/10.1097/MD.0000000000004718
Rodriquenz, M.G. ; Rossi, S. ; Ricci, R. ; Martini, M. ; Larocca, Marilena ; Dipasquale, Angelo ; Quirino, M. ; Schinzari, Giovanni ; Basso, Michele ; D'Argento, Ettore ; Strippoli, A. ; Barone, C. ; Cassano, A. / Gastrointestinal stromal tumors (GISTs) and second malignancies A novel sentinel tumor? A monoinstitutional, STROBE-compliant observational analysis. In: Medicine (United States). 2016 ; Vol. 95, No. 38.
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abstract = "Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis. A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-a genes was performed in all patients. Following the involvement of KRAS mutation in many tumors' pathogenesis, analysis of KRAS was performed in patients with also second neoplasms. Forty-six out of 128 GIST patients (35.9{\%}) had a second neoplasm. Most second tumors (52{\%}) raised from gastrointestinal tract and 19.6{\%} from genitourinary tract. Benign neoplasms were also included (21.7{\%}). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-a mutation (n. 2) and exon 18 PDGFR-a mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P=0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months. The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis. {\circledC} 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.",
keywords = "GIST, KIT, KRAS, PDGFR, Second malignancies, KRAS protein, human, platelet derived growth factor alpha receptor, protein p21, stem cell factor receptor, adult, aged, dna mutational analysis, exon, female, gastrointestinal stromal tumor, gastrointestinal tumor, genetics, human, immunohistochemistry, incidence, male, middle aged, mutation, Neoplasms, Second Primary, pathology, polymerase chain reaction, retrospective study, time factor, very elderly, young adult, Adult, Aged, Aged, 80 and over, DNA Mutational Analysis, Exons, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Humans, Immunohistochemistry, Incidence, Male, Middle Aged, Mutation, Polymerase Chain Reaction, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), Receptor, Platelet-Derived Growth Factor alpha, Retrospective Studies, Time Factors, Young Adult",
author = "M.G. Rodriquenz and S. Rossi and R. Ricci and M. Martini and Marilena Larocca and Angelo Dipasquale and M. Quirino and Giovanni Schinzari and Michele Basso and Ettore D'Argento and A. Strippoli and C. Barone and A. Cassano",
note = "Export Date: 22 March 2017 CODEN: MEDIA Correspondence Address: Rossi, S.; Department of Medical Oncology, Humanitas Clinical and Research Center, Via Manzoni, 56, Italy; email: sbrn.rossi85@gmail.com Chemicals/CAS: protein p21, 85306-28-1; KRAS protein, human; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins p21(ras); Receptor, Platelet-Derived Growth Factor alpha References: Duffaud, F., Blay, J.Y., Gastrointestinal stromal tumors: Biology and treatment (2003) Oncology, 65, pp. 187-197; Miettinen, M., Lasota, J., Gastrointestinal stromal tumors (GISTs): Definition, occurrence, pathology, differential diagnosis and molecular genetics (2003) Pol J Pathol, 54, pp. 3-24; Joensuu, H., Vehtari, A., Riihimaki, J., Risk of recurrence of gastrointestinal stromal tumor after surgery: An analysis of pooled population-based cohorts (2012) Lancet Oncol, 13, pp. 265-274; Lau, S., Tam, K.F., Imaging of gastrointestinal stromal tumor (GIST) (2004) Clin Radiol, 59, pp. 487-498; Hirota, S., Isozaki, K., Moriyama, Y., Gain of function mutations of c-kit in human gastrointestinal stromal tumors (1998) Science, 297, pp. 577-580; Joensuu, H., Roberts, P.J., Sarlomo-Rikala, M., Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor (2001) N Engl J Med, 344, pp. 1052-1056; Gupta, P., Tewari, M., Shukla, H.S., Gastrointestinal stromal tumor (2008) Surg Oncol, 17, pp. 129-138; Fuller, C.E., Williams, G.T., Gastrointestinal stromal tumor (2008) Surg Oncol, 17, pp. 129-138; Carney, J.A., The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma: A five-year review (1983) Medicine (Baltimore), 62, pp. 159-169; Corless, C.L., Barnett, C.M., Heinrich, M.C., Gastrointestinal stromal tumors: Origin and molecular oncology (2011) Nat Rev Cancer, 11, pp. 865-878; Roberts, W.M., Look, A.T., Roussel, M.F., Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes (1989) Cell, 55, pp. 655-661; West, R.B., Corless, C.L., Chen, X., The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT e PDGFRA mutational status (2004) Am J Pathol, 165, pp. 107-113; Ricci, R., Dei Tos, A.P., Rindi, G., GISTogram: A graphic presentation of the growing GIST complexity (2013) Virchows Arch, 463, pp. 481-487; Sarlomo-Rikala, M., Kovatich, A.J., Barusevicius, A., CD117: A sensitive marker for gastrointestinal stromal tumors that is more specific than CD34 (1998) Mod Pathol, 11, pp. 728-734; Heinrich, M.C., Corless, C.L., Duensing, A., PDGFRA activating mutations in gastrointestinal stromal tumors (2003) Science, 299, pp. 708-710; Maertens, O., Prenen, H., Debiec-Rychter, M., Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients (2006) Hum Mol Gent, 15, pp. 1015-1023; Pantaleo, M.A., Astolfi, A., Indio, V., SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing (2011) J Natl Cancer Inst, 103, pp. 983-987; Miranda, C., Nucifora, M., Molinari, F., KRAS and BRAF mutations predict primary resistance to imatinib in gatrointestinal stromal tumors (2012) Clin Cancer Res, 26, pp. 1769-1776; Agaimy, A., Wunsch, P.H., Miettinen, M., Occurrence of other malignancies in patients with gastrointestinal stromal tumors (2006) Semin Diagn Pathol, 23, pp. 120-129; Vassos, N., Agaimy, A., Hohenberger, W., Coexistence of gastrointestinal stromal tumors (GIST) and malignant neoplasms of different origin: Prognostic implications (2014) Int J Surg, 12, pp. 371-377; Scheiman, J., Cutler, A., Helicobacter pylori and gastric cancer (1999) Am J Med, 106, pp. 222-226; Moss, S.F., Malfertheiner, P., Helicobacter and gastric malignancies (2007) Helicobacter, 12, pp. 23-30; Cohen, A., Geller, S.A., Horowitz, L.S., Experimental models for gastric leiomyosarcoma. The effects of N-methyl-N-nitrsoguanidine in combination with stress, aspirin, or sodium taurocholate (1984) Cancer, 53, pp. 1088-1092; Au, W.Y., Ho, K.M., Shek, T.W., Papillary renal cell carcinoma and gastrointestinal stromal tumor: A unique association (2004) Ann Oncol, 15, pp. 843-844; Miettinen, M., Lasota, J., Gastrointestinal stromal tumors: Pathology and prognosis at different sites (2006) Semin Diagn Pathol, 23, pp. 669-676; Miettinen, M., Lasota, J., Review on morphology, molecular pathology, prognosis and differential diagnosis (2006) Arch Pathol Lab Med, 130, pp. 1466-1478; Ricci, R., Martini, M., Cenci, T., Case of rectal GI stromal tumor demonstrating that KIT and PDGFRA mutations are not always mutually exclusive (2016) J Clin Oncol, 34, pp. e107-e109; Basso, M., Strippoli, A., Orlandi, A., KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients (2013) Br J Cancer, 108, pp. 115-120; Agaimy, A., Terracciano, L.M., Dirnhofer, S., V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours (2009) J Clin Pathol, 62, pp. 613-616; Pantaleo, M.A., Astolfi, A., Indio, V., SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing (2011) J Natl Cancer Inst, 103, pp. 983-987; Miettinen, M., Sobin, L.H., Lasota, J., Gastrointestinal stromal tumors of the stomach: A clinopathological and molecular genetic study of 1765 cases with long term follow-up (2005) Am J Surg Pathol, 29, pp. 52-68; Kramer, K., Wolf, S., Mayer, B., Frequence, spectrum and prognostic impact of additional malignancies in patients with gastrointestinal stromal tumors (2015) Neoplasia, 1, pp. 134-140; Hechtman, J.F., DeMatteo, R., Nafa, K., Additional primary malignancies in patients with gastrointestinal stromal tumor (GIST): A clinicopathologic study of 260 patients with molecular analysis and review of the literature (2015) Ann Surg Oncol, 22, pp. 2633-2639; Ricci, R., Martini, M., Cenci, T., PDGFRA-mutant syndrome (2015) Mod Pathol, 28, pp. 954-964; Lasota, J., Xi, L., Coates, T., No KRAS mutations found in gastrointestinal stromal tumors (GISTs): Molecular genetic study of 514 cases (2013) Mod Pathol, 26, pp. 1488-1491; Hechtman, J.F., DeMatteo, R., Nafa, K., Additional primary malignancies in patients with gastrointestinal stromal tumor (GIST): Clinicopathologic study of 260 patients with molecular analysis and review of the literature (2015) Ann Surg Oncol, 22, pp. 2633-2639; Rodriquenz, M.G., Ricci, R., Iezzi, M., Martini, M., Basso, M., Dadduzio, V., Larocca, L.M., Cassano, A., 1431P Gastroin-testinal Stromal Tumors (GIST) and Second Malignancies: A Novel 'Sentinel Tumor{"}?",
year = "2016",
doi = "10.1097/MD.0000000000004718",
language = "English",
volume = "95",
journal = "Medicine; analytical reviews of general medicine, neurology, psychiatry, dermatology, and pediatries",
issn = "0025-7974",
publisher = "Lippincott Williams and Wilkins",
number = "38",

}

TY - JOUR

T1 - Gastrointestinal stromal tumors (GISTs) and second malignancies A novel sentinel tumor? A monoinstitutional, STROBE-compliant observational analysis

AU - Rodriquenz, M.G.

AU - Rossi, S.

AU - Ricci, R.

AU - Martini, M.

AU - Larocca, Marilena

AU - Dipasquale, Angelo

AU - Quirino, M.

AU - Schinzari, Giovanni

AU - Basso, Michele

AU - D'Argento, Ettore

AU - Strippoli, A.

AU - Barone, C.

AU - Cassano, A.

N1 - Export Date: 22 March 2017 CODEN: MEDIA Correspondence Address: Rossi, S.; Department of Medical Oncology, Humanitas Clinical and Research Center, Via Manzoni, 56, Italy; email: sbrn.rossi85@gmail.com Chemicals/CAS: protein p21, 85306-28-1; KRAS protein, human; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins p21(ras); Receptor, Platelet-Derived Growth Factor alpha References: Duffaud, F., Blay, J.Y., Gastrointestinal stromal tumors: Biology and treatment (2003) Oncology, 65, pp. 187-197; Miettinen, M., Lasota, J., Gastrointestinal stromal tumors (GISTs): Definition, occurrence, pathology, differential diagnosis and molecular genetics (2003) Pol J Pathol, 54, pp. 3-24; Joensuu, H., Vehtari, A., Riihimaki, J., Risk of recurrence of gastrointestinal stromal tumor after surgery: An analysis of pooled population-based cohorts (2012) Lancet Oncol, 13, pp. 265-274; Lau, S., Tam, K.F., Imaging of gastrointestinal stromal tumor (GIST) (2004) Clin Radiol, 59, pp. 487-498; Hirota, S., Isozaki, K., Moriyama, Y., Gain of function mutations of c-kit in human gastrointestinal stromal tumors (1998) Science, 297, pp. 577-580; Joensuu, H., Roberts, P.J., Sarlomo-Rikala, M., Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor (2001) N Engl J Med, 344, pp. 1052-1056; Gupta, P., Tewari, M., Shukla, H.S., Gastrointestinal stromal tumor (2008) Surg Oncol, 17, pp. 129-138; Fuller, C.E., Williams, G.T., Gastrointestinal stromal tumor (2008) Surg Oncol, 17, pp. 129-138; Carney, J.A., The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma: A five-year review (1983) Medicine (Baltimore), 62, pp. 159-169; Corless, C.L., Barnett, C.M., Heinrich, M.C., Gastrointestinal stromal tumors: Origin and molecular oncology (2011) Nat Rev Cancer, 11, pp. 865-878; Roberts, W.M., Look, A.T., Roussel, M.F., Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes (1989) Cell, 55, pp. 655-661; West, R.B., Corless, C.L., Chen, X., The novel marker, DOG1, is expressed ubiquitously in gastrointestinal stromal tumors irrespective of KIT e PDGFRA mutational status (2004) Am J Pathol, 165, pp. 107-113; Ricci, R., Dei Tos, A.P., Rindi, G., GISTogram: A graphic presentation of the growing GIST complexity (2013) Virchows Arch, 463, pp. 481-487; Sarlomo-Rikala, M., Kovatich, A.J., Barusevicius, A., CD117: A sensitive marker for gastrointestinal stromal tumors that is more specific than CD34 (1998) Mod Pathol, 11, pp. 728-734; Heinrich, M.C., Corless, C.L., Duensing, A., PDGFRA activating mutations in gastrointestinal stromal tumors (2003) Science, 299, pp. 708-710; Maertens, O., Prenen, H., Debiec-Rychter, M., Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients (2006) Hum Mol Gent, 15, pp. 1015-1023; Pantaleo, M.A., Astolfi, A., Indio, V., SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing (2011) J Natl Cancer Inst, 103, pp. 983-987; Miranda, C., Nucifora, M., Molinari, F., KRAS and BRAF mutations predict primary resistance to imatinib in gatrointestinal stromal tumors (2012) Clin Cancer Res, 26, pp. 1769-1776; Agaimy, A., Wunsch, P.H., Miettinen, M., Occurrence of other malignancies in patients with gastrointestinal stromal tumors (2006) Semin Diagn Pathol, 23, pp. 120-129; Vassos, N., Agaimy, A., Hohenberger, W., Coexistence of gastrointestinal stromal tumors (GIST) and malignant neoplasms of different origin: Prognostic implications (2014) Int J Surg, 12, pp. 371-377; Scheiman, J., Cutler, A., Helicobacter pylori and gastric cancer (1999) Am J Med, 106, pp. 222-226; Moss, S.F., Malfertheiner, P., Helicobacter and gastric malignancies (2007) Helicobacter, 12, pp. 23-30; Cohen, A., Geller, S.A., Horowitz, L.S., Experimental models for gastric leiomyosarcoma. The effects of N-methyl-N-nitrsoguanidine in combination with stress, aspirin, or sodium taurocholate (1984) Cancer, 53, pp. 1088-1092; Au, W.Y., Ho, K.M., Shek, T.W., Papillary renal cell carcinoma and gastrointestinal stromal tumor: A unique association (2004) Ann Oncol, 15, pp. 843-844; Miettinen, M., Lasota, J., Gastrointestinal stromal tumors: Pathology and prognosis at different sites (2006) Semin Diagn Pathol, 23, pp. 669-676; Miettinen, M., Lasota, J., Review on morphology, molecular pathology, prognosis and differential diagnosis (2006) Arch Pathol Lab Med, 130, pp. 1466-1478; Ricci, R., Martini, M., Cenci, T., Case of rectal GI stromal tumor demonstrating that KIT and PDGFRA mutations are not always mutually exclusive (2016) J Clin Oncol, 34, pp. e107-e109; Basso, M., Strippoli, A., Orlandi, A., KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients (2013) Br J Cancer, 108, pp. 115-120; Agaimy, A., Terracciano, L.M., Dirnhofer, S., V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours (2009) J Clin Pathol, 62, pp. 613-616; Pantaleo, M.A., Astolfi, A., Indio, V., SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing (2011) J Natl Cancer Inst, 103, pp. 983-987; Miettinen, M., Sobin, L.H., Lasota, J., Gastrointestinal stromal tumors of the stomach: A clinopathological and molecular genetic study of 1765 cases with long term follow-up (2005) Am J Surg Pathol, 29, pp. 52-68; Kramer, K., Wolf, S., Mayer, B., Frequence, spectrum and prognostic impact of additional malignancies in patients with gastrointestinal stromal tumors (2015) Neoplasia, 1, pp. 134-140; Hechtman, J.F., DeMatteo, R., Nafa, K., Additional primary malignancies in patients with gastrointestinal stromal tumor (GIST): A clinicopathologic study of 260 patients with molecular analysis and review of the literature (2015) Ann Surg Oncol, 22, pp. 2633-2639; Ricci, R., Martini, M., Cenci, T., PDGFRA-mutant syndrome (2015) Mod Pathol, 28, pp. 954-964; Lasota, J., Xi, L., Coates, T., No KRAS mutations found in gastrointestinal stromal tumors (GISTs): Molecular genetic study of 514 cases (2013) Mod Pathol, 26, pp. 1488-1491; Hechtman, J.F., DeMatteo, R., Nafa, K., Additional primary malignancies in patients with gastrointestinal stromal tumor (GIST): Clinicopathologic study of 260 patients with molecular analysis and review of the literature (2015) Ann Surg Oncol, 22, pp. 2633-2639; Rodriquenz, M.G., Ricci, R., Iezzi, M., Martini, M., Basso, M., Dadduzio, V., Larocca, L.M., Cassano, A., 1431P Gastroin-testinal Stromal Tumors (GIST) and Second Malignancies: A Novel 'Sentinel Tumor"?

PY - 2016

Y1 - 2016

N2 - Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis. A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-a genes was performed in all patients. Following the involvement of KRAS mutation in many tumors' pathogenesis, analysis of KRAS was performed in patients with also second neoplasms. Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-a mutation (n. 2) and exon 18 PDGFR-a mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P=0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months. The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis. © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.

AB - Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis. A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-a genes was performed in all patients. Following the involvement of KRAS mutation in many tumors' pathogenesis, analysis of KRAS was performed in patients with also second neoplasms. Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-a mutation (n. 2) and exon 18 PDGFR-a mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P=0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months. The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis. © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.

KW - GIST

KW - KIT

KW - KRAS

KW - PDGFR

KW - Second malignancies

KW - KRAS protein, human

KW - platelet derived growth factor alpha receptor

KW - protein p21

KW - stem cell factor receptor

KW - adult

KW - aged

KW - dna mutational analysis

KW - exon

KW - female

KW - gastrointestinal stromal tumor

KW - gastrointestinal tumor

KW - genetics

KW - human

KW - immunohistochemistry

KW - incidence

KW - male

KW - middle aged

KW - mutation

KW - Neoplasms, Second Primary

KW - pathology

KW - polymerase chain reaction

KW - retrospective study

KW - time factor

KW - very elderly

KW - young adult

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - DNA Mutational Analysis

KW - Exons

KW - Female

KW - Gastrointestinal Neoplasms

KW - Gastrointestinal Stromal Tumors

KW - Humans

KW - Immunohistochemistry

KW - Incidence

KW - Male

KW - Middle Aged

KW - Mutation

KW - Polymerase Chain Reaction

KW - Proto-Oncogene Proteins c-kit

KW - Proto-Oncogene Proteins p21(ras)

KW - Receptor, Platelet-Derived Growth Factor alpha

KW - Retrospective Studies

KW - Time Factors

KW - Young Adult

U2 - 10.1097/MD.0000000000004718

DO - 10.1097/MD.0000000000004718

M3 - Article

VL - 95

JO - Medicine; analytical reviews of general medicine, neurology, psychiatry, dermatology, and pediatries

JF - Medicine; analytical reviews of general medicine, neurology, psychiatry, dermatology, and pediatries

SN - 0025-7974

IS - 38

ER -