Prognostic Significance of p14ARF, p15INK4b, and p16INK4a Inactivation in Malignant Peripheral Nerve Sheath Tumors

Endo, Makoto; Kobayashi, Chikashi; Setsu, Nokitaka; Takahashi, Yusuke; Kohashi, Kenichi; Yamamoto, Hidetaka; Tamiya, Sadafumi; Matsuda, Shuichi; Iwamoto, Yukihide; Tsuneyoshi, Masazumi; Oda, Yoshinao

doi:10.1158/1078-0432.ccr-10-2393

Cited by 54 publications

(43 citation statements)

References 44 publications

(48 reference statements)

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“…13 Other groups reported that decreased CDKN2A gene dosage was associated with metastases and poor survival among malignant peripheral nerve sheath tumors. 24 More recently, Endo et al 25 reported decreased (o50%) p16 expression by immunohistochemistry in a group of malignant peripheral nerve sheath tumors, which was associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

et al. 2015

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Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (Po0.001 for each). Expression of p75NTR was observed in 80% of malignant peripheral nerve sheath tumors compared with 31% of cellular schwannomas (Po0.001). Fourth, Ki-67 labeling indices Z20% were highly predictive of malignant peripheral nerve sheath tumor (87% sensitivity and 96% specificity). Taken together, the combinations of these histopathological and immunohistochemical features provide useful criteria to distinguish between malignant peripheral nerve sheath tumor and cellular schwannoma with high sensitivity and specificity. Additional retrospective and prospective multicenter studies with larger data sets will be required to validate these findings.

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Section: Discussionmentioning

confidence: 99%

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

et al. 2015

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“…INK4a (6,7), p53 (8), CHFR (9), CDK4, FOXM1 (10), hepatocyte growth factor (HGF; ref. 11), and MET (12) are necessary for the malignant transformation.…”

Section: Introductionmentioning

confidence: 99%

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

Endo

Yamamoto

Setsu

et al. 2013

Clinical Cancer Research

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120

100

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Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/ mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.Experimental Design: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/ mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.

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“…The loss of p15 INK4b expression was reported in nonepithelial malignancies including leukemias, malignant peripheral nerve sheeth tumors, meningioma, and Simon et al, 2001;Endo et al, 2011). Furthermore, in expression studies of p15 INK4b in epithelial cancers showed and co-workers reported p15 INK4b loss in more than 70% of advanced gastric cancers, especially the intestinal subtype (Sakellariou et al, 2008).…”

Section: Discussionmentioning

confidence: 92%

“…The cut-off level of 50% was according to Sakellariou et al (Sakellariou et al, 2008). p15 INK4b expression was nuclear and a scoring scale similar to the one described above with a 50% cut-off level was employed according to the published literature (Oda et al, 2005;Endo et al, 2011).…”

Section: Interpretation Of Staining Resultsmentioning

confidence: 99%

Loss of p15^INK4bExpression in Colorectal Cancer is Linked to Ethnic Origin

Abdel‐Rahman

Nieminen²,

Shoman³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Colorectal cancers remain to be a common cause of cancer-related death. Early-onset cases as well as those of various ethnic origins have aggressive clinical features, the basis of which requires further exploration. In a substantial number of cases, the loss was independent of SMAD4 but rather associated with p15 INK4b gene promotor hypermethylation and old age which could be related to different environmental exposures.

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Prognostic Significance of p14ARF, p15INK4b, and p16INK4a Inactivation in Malignant Peripheral Nerve Sheath Tumors

Cited by 54 publications

References 44 publications

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

Loss of p15^INK4bExpression in Colorectal Cancer is Linked to Ethnic Origin

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Prognostic Significance of p14ARF, p15INK4b, and p16INK4a Inactivation in Malignant Peripheral Nerve Sheath Tumors

Cited by 54 publications

References 44 publications

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

Morphologic and immunohistochemical features of malignant peripheral nerve sheath tumors and cellular schwannomas

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

Loss of p15INK4bExpression in Colorectal Cancer is Linked to Ethnic Origin

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Loss of p15^INK4bExpression in Colorectal Cancer is Linked to Ethnic Origin