Utility of p16 Expression for Distinction of Uterine Serous Carcinomas From Endometrial Endometrioid and Endocervical Adenocarcinomas: Immunohistochemical Analysis of 201 Cases

Uterine serous carcinomas typically have a characteristic morphology (papillary architecture, high-grade nuclei) and immunoprofile (diffuse/strong p53 expression, loss of hormone receptor expression) that distinguish them from most endometrial endometrioid carcinomas. However, glandular variants of serous carcinoma can simulate Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) grade 2 endometrioid carcinomas, and some serous carcinomas lack p53 expression and retain hormone receptor expression, making classification difficult. P16 expression patterns distinguish endometrioid carcinomas (patchy) from human papillomavirus (HPV)-related endocervical adenocarcinomas (diffuse/strong) but utility for distinction of serous carcinomas from endometrioid carcinomas and endocervical adenocarcinomas has not been evaluated in a large series. Immunohistochemical analysis of p16 expression was performed on 201 uterine and endocervical adenocarcinomas in hysterectomy specimens, including 49 serous carcinomas, 101 endometrial endometrioid carcinomas (44 FIGO grade 1, 40 FIGO grade 2, and 17 FIGO grade 3), and 51 HPV-related endocervical adenocarcinomas. All serous carcinomas demonstrated diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 95%/100%). In contrast, endometrial endometrioid carcinomas exhibited less diffuse and less intense expression, with percent of positive tumor cells ranging from 10% to 90% (mean/median: 38%/30%; staining intensity: variable). Similar to serous carcinomas, all endocervical adenocarcinomas exhibited diffuse/moderate-strong p16 expression, with percentage of positive tumor cells ranging from 90% to 100% (mean/median: 94%/90%). P16 can serve as an additional diagnostic marker, used as part of an immunohistochemical panel, including p53 and hormone receptors, for distinction of uterine serous carcinomas from endometrioid carcinomas. Distinction of serous carcinomas from endocervical adenocarcinomas (HPV-related type), both of which share diffuse p16 expression and frequently lack hormone receptor expression, relies on morphology and diffuse/strong p53 expression in the former and detection of HPV in the latter.

[1]  J. Seidman,et al.  Endocervical Adenocarcinomas With Prominent Endometrial or Endomyometrial Involvement Simulating Primary Endometrial Carcinomas: Utility of HPV DNA Detection and Immunohistochemical Expression of p16 and Hormone Receptors to Confirm the Cervical Origin of the Corpus Tumor , 2009, The American journal of surgical pathology.

[2]  Dianne Miller,et al.  Endocervical Adenocarcinomas With Ovarian Metastases: Analysis of 29 Cases With Emphasis on Minimally Invasive Cervical Tumors and the Ability of the Metastases to Simulate Primary Ovarian Neoplasms , 2008, The American journal of surgical pathology.

[3]  I. Shih,et al.  Subdividing Ovarian and Peritoneal Serous Carcinoma Into Moderately Differentiated and Poorly Differentiated Does not Have Biologic Validity Based on Molecular Genetic and In Vitro Drug Resistance Data , 2008, The American journal of surgical pathology.

[4]  S. Nofech-Mozes,et al.  Immunophenotyping of serous carcinoma of the female genital tract , 2008, Modern Pathology.

[5]  M. Nucci,et al.  Histologic and immunohistochemical decision-making in endometrial adenocarcinoma , 2008, Modern Pathology.

[6]  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.

[7]  I. Shih,et al.  Assessment of TP53 mutation using purified tissue samples of ovarian serous carcinomas reveals a higher mutation rate than previously reported and does not correlate with drug resistance , 2007, International Journal of Gynecologic Cancer.

[8]  A. du Bois,et al.  Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group , 2007, British Journal of Cancer.

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

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

[11]  M. Mokni,et al.  p16INK4A overexpression and HPV infection in uterine cervix adenocarcinoma , 2006, Virchows Archiv.

[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]  Patrick Neven,et al.  Endometrial cancer. , 2005, Lancet.

[14]  H. Thaler,et al.  Serous Endometrial Cancers That Mimic Endometrioid Adenocarcinomas: A Clinicopathologic and Immunohistochemical Study of a Group of Problematic Cases , 2004, The American journal of surgical pathology.

[15]  J. O’Leary,et al.  P16INK4A positivity in benign, premalignant and malignant cervical glandular lesions: a potential diagnostic problem , 2004, Virchows Archiv.

[16]  R. Büttner,et al.  The diagnostic utility of human papillomavirus-testing in combination with immunohistochemistry in advanced gynaecologic pelvic tumours: a new diagnostic approach. , 2004, International journal of oncology.

[17]  D. Huntsman,et al.  Interpretation of p53 Immunoreactivity in Endometrial Carcinoma: Establishing a Clinically Relevant Cut-Off Level , 2004, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[18]  Joan G. Jones,et al.  Differential Expression of WT1 and p53 in Serous and Endometrioid Carcinomas of the Endometrium , 2004, International Journal of Gynecological Pathology.

[19]  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.

[20]  G. Sterrett,et al.  The value of HPV DNA typing in the distinction between adenocarcinoma of endocervical and endometrial origin , 2003, Pathology.

[21]  E. Wilander,et al.  Adenocarcinoma of the uterine cervix: the presence of human papillomavirus and the method of detection , 2003, Acta obstetricia et gynecologica Scandinavica.

[22]  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.

[23]  L. D. A. de Ângelo Andrade,et al.  p53, estrogen and progesterone receptors in diagnostic curettage for endometrial adenocarcinoma and their correlation with morphological data and disease stage at hysterectomy. , 2003, Sao Paulo medical journal = Revista paulista de medicina.

[24]  S. Caldeira,et al.  The role of TP53 in Cervical carcinogenesis , 2003, Human mutation.

[25]  A. Haitel,et al.  p16INK4a Is a Useful Marker for the Diagnosis of Adenocarcinoma of the Cervix Uteri and Its Precursors: An Immunohistochemical Study With Immunocytochemical Correlations , 2003, The American journal of surgical pathology.

[26]  E. Wilander,et al.  Types of human papillomavirus revealed in cervical adenocarcinomas after DNA sequencing. , 2003, Oncology reports.

[27]  P. Clement,et al.  Endocervical adenocarcinoma and its variants: their morphology and differential diagnosis , 2002, Histopathology.

[28]  M. Sherman,et al.  Hormone Receptor Immunohistochemistry and Human Papillomavirus In Situ Hybridization Are Useful for Distinguishing Endocervical and Endometrial Adenocarcinomas , 2002, The American journal of surgical pathology.

[29]  C. Isacson,et al.  Early Uterine Serous Carcinoma: Clonal Origin of Extrauterine Disease , 2001, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[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]  M. von Knebel Doeberitz,et al.  Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri , 2001, International journal of cancer.

[32]  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.

[33]  E. Pirog,et al.  Prevalence of human papillomavirus DNA in different histological subtypes of cervical adenocarcinoma. , 2000, The American journal of pathology.

[34]  S. Finkelstein,et al.  Well-Differentiated Villoglandular Adenocarcinoma of the Uterine Cervix: Oncogene/Tumor Suppressor Gene Alterations and Human Papillomavirus Genotyping , 2000, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[35]  R. Slebos,et al.  The frequency of p53, k‐ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma , 2000, Cancer.

[36]  R. Kurman,et al.  Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression. , 1998, Human pathology.

[37]  M. Carcangiu,et al.  Stage IA uterine serous carcinoma: a study of 13 cases. , 1997, The American journal of surgical pathology.

[38]  Kathleen R. Cho,et al.  Microsatellite instability is uncommon in uterine serous carcinoma. , 1997, The American journal of pathology.

[39]  Kathleen R. Cho,et al.  p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. , 1997, The American journal of pathology.

[40]  R. Zappatore,et al.  Human papillomavirus types 16 and 18 infection in infiltrating adenocarcinoma of the cervix: PCR analysis of 138 cases and correlation with histologic type and grade. , 1996, American journal of clinical pathology.

[41]  M. Lehtinen,et al.  Human papillomavirus DNA in uterine cervix squamous cell carcinoma and adenocarcinoma detected by polymerase chain reaction , 1996, Cancer.

[42]  M. Sherman,et al.  p53 in endometrial cancer and its putative precursors: evidence for diverse pathways of tumorigenesis. , 1995, Human pathology.

[43]  M. Carcangiu,et al.  Early pathologic stage clear cell carcinoma and uterine papillary serous carcinoma of the endometrium: comparison of clinicopathologic features and survival. , 1995, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[44]  M. Inoue,et al.  Clinicopathological characteristics of p53 overexpression in endometrial cancers , 1994, International journal of cancer.

[45]  N. Muñoz,et al.  p53 gene mutations and MDM2 amplification are uncommon in primary carcinomas of the uterine cervix. , 1993, The American journal of pathology.

[46]  Carl W. Miller,et al.  Mutations of p53 and human papillomavirus infection in cervical carcinoma , 1993, Cancer.

[47]  M. Carcangiu,et al.  Uterine papillary serous carcinoma: a study on 108 cases with emphasis on the prognostic significance of associated endometrioid carcinoma, absence of invasion, and concomitant ovarian carcinoma. , 1992, Gynecologic oncology.

[48]  H. Bartsch,et al.  International Agency for Research on Cancer. , 1969, WHO chronicle.