High Prognostic Value of p16<sup><i>INK4</i></sup> Alterations in Gastrointestinal Stromal Tumors

Schneider‐Stock, Regine; Boltze, Carsten; Lasota, Jerzy; Miettinen, Markku; Peters, Brigitte; Pross, M.; Roessner, Albert; Günther, Thomas

doi:10.1200/jco.2003.08.101

Cited by 142 publications

(113 citation statements)

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“…This tumor occurs in both sexes equally (19,26,27) or slightly higher in men as observed in this study (8,23,32) . The primary site of tumors noted arise in the small bowel (40%) or in the stomach (32%) in contrast to others which this tumor commonly arise mostly in the stomach (60%-70%) and in the small intestine in a smaller frequency (26%-35%) (29) .…”

Section: Discussionsupporting

confidence: 71%

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Ki67 and p53 in gastrointestinal stromal tumors - GIST

Neves¹,

Oshima²,

Neto³

et al. 2009

Arq. Gastroenterol.

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-Context -Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor. Cellular proliferation and apoptosis is gaining importance for predicting prognosis in several cancers. Objective -To investigate the Ki67 and p53 immunostaining in GISTs. Methods -Specimens from 40 patients with GIST were assessed for immunohistochemical expression of Ki67 and p53. The tumors were divided according the risk of recurrence in two groups: I with high or intermediate risk and; II with low or very low risk. Results -Among the 40 patients, 21 were men, the mean age was 56 years, 16 occurred in the small intestine and 13 in the stomach, 5 in the retroperitonium, 4 in the colon or rectum and 2 in the mesenterium. Thirty two tumors were from group I and 8 from group II. Half of the patients developed recurrence, being 90% of the group I (P = 0.114). The tumor Ki67 labelling index ranged from 0.02 to 0.35 (mean level 0.12). This index was marginally higher in the group I patients with recurrence (P = 0.09) compared to the patients of the same group without recurrence. p53 staining was expressed in 65% of the GISTs. A higher frequency of p53 and Ki67 had been found in the group I tumors when compared to the other group (P = 0.022; OR = 8.00 -IC 95%: 1.32-48.65). Conclusion -The most common site was the small intestine and 80% had a malignant potential justifying the high recurrence observed. No significant correlation was found between p53 and overall outcome of the patients. In group I patients, the evaluation Ki67LI may be a marker of prognosis. The positivity of both markers is higher among the patients with worst prognosis than in the others. HEADINGS -Gastrointestinal stromal tumors. Ki-67 antigen. Tumor suppressor protein p53.

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Section: Discussionsupporting

confidence: 71%

“…This antigen provides information about the proportion of active cells in the cell cycle (15,29,32,35,37) .…”

Section: Introductionmentioning

confidence: 99%

Ki67 and p53 in gastrointestinal stromal tumors - GIST

Neves¹,

Oshima²,

Neto³

et al. 2009

Arq. Gastroenterol.

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“…Alterations of the G1/S-phase transition inhibitor p16 INK4A , which are frequently observed in high-risk/malignant GISTs, may contribute to this difference. 22,23 These findings are in line with our previous observation that the presence of epithelioid/mixed components in GISTs with biphasic pattern was associated with higher mitotic activity, higher expression of Ki67 and higher number of chromosomal copy number changes compared with the spindled component in the same tumor. 16 In that study, our observations suggested a clonal progression through sequential chromosomal alterations, with a shift in the histomorphological growth pattern from spindled to epithelioid/mixed phenotype.…”

Section: Discussionsupporting

confidence: 91%

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

et al. 2011

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In gastrointestinal stromal tumors (GISTs), the occurrence of an epithelioid/mixed phenotype has been correlated to PDGFRA mutations, gastric localization and favorable outcome. On the other hand, the prognostic significance of an epithelioid/mixed growth pattern occasionally observed in GISTs with KIT mutation is unclear. The aim of this study was to evaluate the prognostic significance of an epithelioid/mixed phenotype in correlation to anatomical localization, genotype, and expression of cell-cycle markers in a series of 116 primary GISTs with KIT mutation on a tissue microarray. Independent of their anatomical localization, the majority of KIT-mutated GISTs displayed a pure spindled phenotype (72%), with the remaining tumors showing an epithelioid/mixed growth pattern. In KIT-mutated GISTs from the stomach, the occurrence of an epithelioid/ mixed growth pattern was significantly correlated with larger tumor diameters (P ¼ 0.005), higher mitotic counts (P ¼ 0.0001), high-risk category (P ¼ 0.001), higher expression of the G2-phase cell-cycle marker cyclin B1 (P ¼ 0.04), higher expression of the G1 to M-phase proliferation marker Ki67 (P ¼ 0.02) and a significantly shorter disease-free survival (P ¼ 0.003) compared with tumors with pure spindled morphology. In contrast, there were no significant differences between pure spindled and epithelioid/mixed GISTs from the small/large bowel. Our findings indicate that the epithelioid/mixed phenotype in KIT-mutant gastric GISTs represents a secondary tumor growth pattern associated with tumor progression and adverse outcome, probably through accelerated G1/S-phase restriction point passage.

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“…Schneider-Stock et al 31 reported that p16 INK4A alteration was detected in benign, borderline and malignant GISTs but nevertheless was considered as an independent poor prognostic factor. The apparent discrepancy with our findings may relate to the difference in classification methods.…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity of chromosome 9p and loss of p16 expression are associated with malignant gastrointestinal stromal tumors

et al. 2004

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Gastrointestinal stromal tumors GISTs are distinctive KIT-positive mesenchymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well characterized. In this study, 21 cases of GISTs (eight low malignant potential, nine primary malignant and four intra-abdominal recurrences) were characterized by immunohistochemistry and evaluated for loss of heterozygosity of the short arm of chromosome 9, using six microsatellite markers. Loss of heterozygosity with at least one microsatellite marker at 9p region was a common finding in high-risk GISTs (malignant and recurrent group) but was absent in the low malignant potential group. Recurrent GISTs showed more frequent deletions than their primary tumors. All cases with loss of heterozygosity showed deletions at 9p21. Similarly, all low malignant potential GISTs were immunoreactive for p16, whereas malignant tumors were negative for p16. These results suggest that loss of p16 INK4A gene on 9p may contribute to the progression and/or malignant transformation of GISTs.

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High Prognostic Value of p16^INK4 Alterations in Gastrointestinal Stromal Tumors

Abstract: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.

Cited by 142 publications

References 30 publications

Ki67 and p53 in gastrointestinal stromal tumors - GIST

Ki67 and p53 in gastrointestinal stromal tumors - GIST

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

Loss of heterozygosity of chromosome 9p and loss of p16 expression are associated with malignant gastrointestinal stromal tumors

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High Prognostic Value of p16INK4 Alterations in Gastrointestinal Stromal Tumors

Abstract: We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.

Cited by 142 publications

References 30 publications

Ki67 and p53 in gastrointestinal stromal tumors - GIST

Ki67 and p53 in gastrointestinal stromal tumors - GIST

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

Loss of heterozygosity of chromosome 9p and loss of p16 expression are associated with malignant gastrointestinal stromal tumors

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High Prognostic Value of p16^INK4 Alterations in Gastrointestinal Stromal Tumors