Increased p16 Expression in High-grade Serous and Undifferentiated Carcinoma Compared With Other Morphologic Types of Ovarian Carcinoma

There are several morphologic types of ovarian carcinoma. It has been shown that p16 is overexpressed in high-grade serous carcinoma but there has been little detailed comparison of p16 expression in the common types of ovarian carcinoma. The aim of this study was to compare p16 expression in ovarian carcinomas of serous, endometrioid, clear cell, and mucinous type with a view to ascertaining whether high expression in a primary ovarian carcinoma is specific for a serous neoplasm. We included problematic cases, which are difficult to type, such as poorly differentiated and undifferentiated carcinomas and serous carcinomas with clear cells. In these problematic groups, we compared p16 expression with that of WT1, which is known to be relatively specific for a serous phenotype. Cases of ovarian high-grade serous carcinoma (n=38), endometrioid carcinoma (n=15), clear cell carcinoma (n=12), and mucinous carcinoma (n=10) were stained with p16. Cases were scored both with respect to distribution of immunoreactivity (0–5) and intensity (0–3). An immunohistochemical composite score was also calculated (0–15) by multiplying the distribution and intensity scores. Serous carcinomas typically exhibited high p16 expression; there was statistically significant higher p16 expression in serous carcinomas compared with the other morphologic types. There was high p16 and WT1 expression in most undifferentiated carcinomas and in serous carcinomas with clear cells, suggesting that these represent variants of serous carcinoma. We have demonstrated that p16 is highly expressed in high-grade serous and undifferentiated carcinomas compared with other morphologic types of ovarian carcinoma. This may be useful, in conjunction with WT1, in the classification of problematic neoplasms. p16 may be involved in the pathogenesis of high-grade ovarian serous carcinomas, possibly through inactivation of retinoblastoma protein.

[1]  R. Soslow,et al.  Histologic subtypes of ovarian carcinoma: an overview. , 2008, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[2]  M. von Knebel Doeberitz,et al.  No Metastatic Cervical Adenocarcinomas in a Series of p16INK4a-Positive Mucinous or Endometrioid Advanced Ovarian Carcinomas: An Analysis of the AGO Ovarian Cancer Study Group , 2008, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[3]  J. H. Price,et al.  An immunohistochemical and morphological analysis of post-chemotherapy ovarian carcinoma , 2007, Journal of Clinical Pathology.

[4]  W. McCluggage,et al.  My approach to and thoughts on the typing of ovarian carcinomas , 2007, Journal of Clinical Pathology.

[5]  C. Comin,et al.  h-Caldesmon, Calretinin, Estrogen Receptor, and Ber-EP4: A Useful Combination of Immunohistochemical Markers for Differentiating Epithelioid Peritoneal Mesothelioma From Serous Papillary Carcinoma of the Ovary , 2007, The American journal of surgical pathology.

[6]  H. Tsuda,et al.  Immunohistochemical detection of hepatocyte nuclear factor 1beta in ovarian and endometrial clear-cell adenocarcinomas and nonneoplastic endometrium. , 2007, Human pathology.

[7]  G. Nuovo,et al.  Immunohistochemical Overexpression of p16 and p53 in Uterine Serous Carcinoma and Ovarian High-grade Serous Carcinoma , 2007, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[8]  A. Malpica,et al.  High‐grade ovarian serous carcinoma exhibits significantly higher p16 expression than low‐grade serous carcinoma and serous borderline tumour , 2007, Histopathology.

[9]  A. Gown,et al.  p16 Expression in Primary Ovarian Mucinous and Endometrioid Tumors and Metastatic Adenocarcinomas in the Ovary: Utility for Identification of Metastatic HPV-Related Endocervical Adenocarcinomas , 2007, The American journal of surgical pathology.

[10]  A. Hummer,et al.  Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis , 2006, Modern Pathology.

[11]  W. McCluggage,et al.  p16 Expression in the Female Genital Tract and Its Value in Diagnosis , 2006, Advances in anatomic pathology.

[12]  M. de Silva,et al.  Abnormalities of the RB1 Pathway in Ovarian Serous Papillary Carcinoma as Determined by Overexpression of the p16(INK4A) Protein , 2005, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[13]  K. Cooper,et al.  p16INK4A Immunoexpression and HPV In Situ Hybridization Signal Patterns: Potential Markers of High-Grade Cervical Intraepithelial Neoplasia , 2005, The American journal of surgical pathology.

[14]  L. Cope,et al.  Patterns of p53 Mutations Separate Ovarian Serous Borderline Tumors and Low- and High-grade Carcinomas and Provide Support for a New Model of Ovarian Carcinogenesis: A Mutational Analysis With Immunohistochemical Correlation , 2005, The American journal of surgical pathology.

[15]  E. Oliva,et al.  An Immunohistochemical Analysis of Ovarian Small Cell Carcinoma of Hypercalcemic Type , 2004, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[16]  Chung-Liang Ho,et al.  Mutations of BRAF and KRAS Precede the Development of Ovarian Serous Borderline Tumors , 2004, Cancer Research.

[17]  S. Russell,et al.  A multistep model for ovarian tumorigenesis: the value of mutation analysis in the KRAS and BRAF genes , 2004, The Journal of pathology.

[18]  I. Shih,et al.  Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. , 2004, The American journal of pathology.

[19]  W. McCluggage.  WT1 is of value in ascertaining the site of origin of serous carcinomas within the female genital tract. , 2004, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[20]  K. Shah,et al.  Distinction of Endocervical and Endometrial Adenocarcinomas: Immunohistochemical p16 Expression Correlated With Human Papillomavirus (HPV) DNA Detection , 2004, The American journal of surgical pathology.

[21]  W. McCluggage,et al.  WT‐1 assists in distinguishing ovarian from uterine serous carcinoma and in distinguishing between serous and endometrioid ovarian carcinoma , 2004, Histopathology.

[22]  Brigitte M. Ronnett,et al.  The Histologic Type and Stage Distribution of Ovarian Carcinomas of Surface Epithelial Origin , 2004, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[23]  A. Folpe,et al.  Immunoprofile of Ovarian Tumors With Putative Transitional Cell (Urothelial) Differentiation Using Novel Urothelial Markers: Histogenetic and Diagnostic Implications , 2003, The American journal of surgical pathology.

[24]  D. O’Rourke,et al.  A Panel of Immunohistochemical Stains Assists in the Distinction Between Ovarian and Renal Clear Cell Carcinoma , 2003, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[25]  D. Jenkins,et al.  p16 Immunoreactivity May Assist in the Distinction Between Endometrial and Endocervical Adenocarcinoma , 2003, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[26]  I. Shih,et al.  Mutational Analysis of K-ras Segregates Ovarian Serous Carcinomas into Two Types: Invasive MPSC (Low-grade Tumor) and Conventional Serous Carcinoma (High-grade Tumor) , 2003, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[27]  P. Maxwell,et al.  Immunohistochemical staining with MIB1, bcl2 and p16 assists in the distinction of cervical glandular intraepithelial neoplasia from tubo-endometrial metaplasia, endometriosis and microglandular hyperplasia. , 2002, Histopathology.

[28]  D. Schmidt,et al.  Distinction between endometrial and endocervical adenocarcinoma. , 2002, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[29]  I. Shih,et al.  Diverse tumorigenic pathways in ovarian serous carcinoma. , 2002, The American journal of pathology.

[30]  B. Quade,et al.  Ki-67, Cyclin E, and p16 INK4 Are Complimentary Surrogate Biomarkers for Human Papilloma Virus-Related Cervical Neoplasia , 2001, The American journal of surgical pathology.

[31]  S. Riethdorf,et al.  Expression of cyclin-dependent kinase inhibitors p16MTS1, p21WAF1, and p27KIP1 in HPV-positive and HPV-negative cervical adenocarcinomas , 2001, Virchows Archiv.

[32]  I. Konishi,et al.  Immunohistochemical Detection of the Wilms' Tumor Gene (WT1) in Epithelial Ovarian Tumors , 2000, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[33]  A. Stemmer-Rachamimov,et al.  Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[34]  T. Nakajima,et al.  Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. , 1998, The American journal of pathology.

[35]  C. Fisher,et al.  Further evaluation of reproducibility and prognostic value of histologic typing and grading in FIGO stage I ovarian cancer patients without systemic locoregional adjuvant treatment , 1994, International Journal of Gynecologic Cancer.

[36]  S. Tsugane,et al.  Observer disagreement in histological classification of ovarian tumors in Japan. , 1994, Gynecologic oncology.

[37]  K. Bertelsen,et al.  Reproducibility and prognostic value of histologic type and grade in early epithelial ovarian cancer , 1992, International Journal of Gynecologic Cancer.

[38]  B. Lund,et al.  Reproducibility of histopathological evaluation in epithelial ovarian carcinoma. Clinical implications , 1991, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[39]  T. Ulbright,et al.  Evaluation of the reproducibility of the World Health Organization classification of common ovarian cancers. With emphasis on methodology. , 1987, Archives of pathology & laboratory medicine.

[40]  F. A. Langley,et al.  Interpathologist and intrapathologist disagreement in ovarian tumor grading and typing. , 1986, Analytical and quantitative cytology and histology.

[41]  T. Motoyama,et al.  Expression of hepatocyte nuclear factor-1beta (HNF-1beta) in clear cell tumors and endometriosis of the ovary , 2006, Modern Pathology.

[42]  J. H. Price,et al.  Morphological effects of chemotherapy on ovarian carcinoma. , 2002, Journal of clinical pathology.