Mitotic Count, Nuclear Atypia, and Immunohistochemical Determination of Ki-67, c-myc, p21-ras, c-erbB2, and p53 Expression in Granulosa Cell Tumors of the Ovary: Mitotic Count and Ki-67 Are Indicators of Poor Prognosis

King, Lynda A.; Okagaki, Takashi; Gallup, Donald G.; Twiggs, Leo B.; Messing, Mark J.; Carson, Linda F.

doi:10.1006/gyno.1996.0130

Cited by 71 publications

(72 citation statements)

References 6 publications

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“…This enables cumulus expansion, oocyte maturation, and ovulation (Park et al 2004). Similar to normal granulosa cells, EGFR protein is expressed in ovarian GCT cells (King et al 1996, Leibl et al 2006, Nosov et al 2009, Nofech-Mozes et al 2012, this study). Previously, high total EGFR protein expression has been reported to be prognostic as to GCT recurrence (Nosov et al 2009), but we did not find correlation between total or phosphorylated EGFR expression and the clinical parameters of the patients in our sample series.…”

Section: Discussionsupporting

confidence: 63%

“…Similar to these cells, GCT cells express follicle-stimulating hormone receptor, aromatase, and inhibin-subunit genes (Fuller et al 2002). Gene alterations commonly present in several human malignancies have not been identified in GCTs (King et al 1996, Jamieson et al 2004, Bittinger et al 2009, Jamieson & Fuller 2012. However, adult GCTs exhibit a highly specific somatic point mutation in the transcription factor FOXL2 gene, which is present in 93-97% of these tumors (Schrader et al 2009, Shah et al 2009, Jamieson et al 2010, Kim et al 2010a,b, Al-Agha et al 2011, Gershon et al 2011.…”

Section: Introductionmentioning

confidence: 99%

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Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

Andersson¹,

Anttonen²,

Färkkilä³

et al. 2014

Journal of Molecular Endocrinology

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Epidermal growth factor receptor (EGFR) is implicated in the progression of many human cancers, but its significance in ovarian granulosa cell tumor (GCT) pathobiology remains poorly understood. We assessed the EGFR gene copy number, surveyed the mRNA and protein expression patterns of EGFR in 90 adult GCTs, and assessed the in vitro sensitivity of GCTcells to EGFR inhibition. Low-level amplification of EGFR gene was observed in five GCTs and highlevel amplification in one sample. EGFR mRNA was robustly expressed in GCTs. Most tumors expressed both unphosphorylated and phosphorylated EGFR protein, but the protein expression did not correlate with clinical parameters, including the risk of recurrence. Smallmolecule EGFR inhibitors reduced the EGF-induced activation of EGFR and its downstream signaling molecules at nanomolar doses, but cell viability was reduced, and caspase-3/7 was activated in GCTcells only at micromolar doses. Based on the present results, EGFR is active and abundantly expressed in the majority of GCTs, but probably has only minor contribution to GCT cell growth. Given the high doses of EGFR inhibitors required to reduce GCT cell viability in vitro, they are not likely to be effective for GCT treatment as single agents; they should rather be tested as part of combination therapies for these malignancies.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

Andersson¹,

Anttonen²,

Färkkilä³

et al. 2014

Journal of Molecular Endocrinology

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“…48,61 DNA analyses have indicated that 5% to 20% of granulosa cell tumors are aneuploid. According to some investigators aneuploidy was not a predictor for recurrence, 58,[62][63][64] whereas others found that aneuploidy was associated with high risk for recurrence. [65][66][67][68] Similar conflicting results have been reported for p53 overexpression; some investigators demonstrated that this was an adverse prognostic factor, 62,69,70 whereas others showed no association with outcome.…”

Section: Prognostic Factorsmentioning

confidence: 99%

Granulosa Cell Tumor of the Ovary: Tumor Review

et al. 2008

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Granulosa cell tumors of the ovary are rare neoplasms that originate from sex-cord stromal cells. The long natural history of granulosa cell tumors and their tendency to recur years after the initial diagnosis are the most prominent of their characteristics. The secretion of estradiol is the reason for signs at presentation such as vaginal bleeding and precocious puberty. Abdominal pain and hemoperitoneum, which occasionally can occur, are attributable to tumor rupture. The most common finding in pelvic examination is a tumor mass, which is subsequently confirmed with imaging techniques. Surgery is the mainstay of initial management for histological diagnosis, appropriate staging, and debulking. A more conservative unilateral salpingo-oophorectomy is indicated in patients with stage I disease and patients of reproductive age. Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the appropriate surgical treatment for postmenopausal women and those with more advanced disease. The stage of disease is the most important prognostic factor associated with the risk of relapse. There are no clear conclusions regarding the role of postoperative chemotherapy or radiotherapy in stage I disease and in those with completely resected tumor. The use of adjuvant chemotherapy or radiotherapy has sometimes been associated with prolonged disease-free survival and possibly overall survival. Chemotherapy is the treatment of choice for patients with advanced, recurrent, or metastatic disease, and BEP (bleomycin, etoposide, and cisplatin) is the preferred regimen. Although the overall rate of response to treatment is high, the impact of treatment on disease-free or overall survival is unknown. Prolonged surveillance is mandatory because tumors tend to recur years after the initial diagnosis.

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“…In the study by MildeLangosch et al, (1995) on vulvar cancer, loss of p53 function was associated with a high risk of progression and an unfavourable prognosis. In the literature the prognostic value of p53 seems to be controversial, because in some studies p53 is considered prognostic relevant (Charpin et al, 1995;Esrig et al, 1994;Florenes et al, 1994;Shurbaji et al, 1995;Sun et al, 1992;Vogt et al, 1997), whereas in other studies it is not King et al, 1996;Ofner et al, 1995;Xerri et al, 1994;Younes et al, 1995). It may be that the prognostic value of p53 depends on whether mutation of p53 occurs during carcinogenesis, progression or metastasis of the tumour.…”

Section: Discussionmentioning

confidence: 99%

In squamous cell carcinoma of the vulva, overexpression of p53 is a late event and neither p53 nor mdm2 expression is a useful marker to predict lymph node metastases

et al. 1999

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SummaryTo offer more tailored treatment to individual patients with squamous cell carcinoma of the vulva, more accurate prediction of lymph node metastases is required. As p53 and mdm2 are genes known to be involved in the development of other tumours, we studied expression of p53 and mdm2 in carcinogenesis of squamous cell carcinoma of the vulva and their clinical relevance. Archival material of 141 T1 and T2 vulvar tumours were used. Of the 141 primary tumours, the corresponding 39 lymph node metastases (LNM) were studied, and in 90 cases the pre-existent epithelia adjacent to the tumour (EAT) and in 14 cases vulvar intraepithelial neoplasia adjacent to the tumour (VIN) was also investigated. Detection of p53 and mdm2 protein was immunohistochemically performed. Scoring categories were: negative (1); weakly positive (2); moderately to markedly positive (3); and markedly positive (4). Overexpression of p53 was seen in 56% of the LNM, 39% of the primary tumours, 21% of the VIN lesions and 0% in the group of EAT. No relation was found between overexpression of p53 in the primary tumour and LNM. Expression of mdm2 was seen in 14% of the primary tumours, of which four cases were marked positive. In the group of LNM no mdm2-positive staining was observed. In the group of EAT, 25% was mdm2-positive, of which six cases were marked positive. In the group of VIN, 36% showed moderate (score 3) mdm2 expression. No relation was found between expression of mdm2 and LNM. In squamous cell carcinoma, overexpression of p53 is a late event in carcinogenesis. Marked expression of mdm2 is rarely seen in vulvar carcinomas, indicating that aberrant p53 cannot induce mdm2 expression. LNM cannot be predicted by detection of these proteins.

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Mitotic Count, Nuclear Atypia, and Immunohistochemical Determination of Ki-67, c-myc, p21-ras, c-erbB2, and p53 Expression in Granulosa Cell Tumors of the Ovary: Mitotic Count and Ki-67 Are Indicators of Poor Prognosis

Cited by 71 publications

References 6 publications

Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

Sensitivity of human granulosa cell tumor cells to epidermal growth factor receptor inhibition

Granulosa Cell Tumor of the Ovary: Tumor Review

In squamous cell carcinoma of the vulva, overexpression of p53 is a late event and neither p53 nor mdm2 expression is a useful marker to predict lymph node metastases

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