Abstract
In this paper we report a molecular study of a case of Primary Endometrial Squamous Carcinoma (PESC), in which a Human Papilloma Virus (HPV) infection had been previously excluded by Polymerase Chain Reaction (PCR). The studies performed in an effort to explain the carcinogenesis included immunohistochemical over-expression of p53 and p16 proteins as previously observed in our own papers, plus microsatellite analysis of D10S1765 at 10q23.3 (PTEN) and TP53 at 17p13.1 (P53) as well as the methylation status of the of BRCA1 and p16 promoters using specific PCRs. In this rare malignancy, we found allelic imbalance (AI) at 17p13.1 (P53). Instead, AI at D10S1765 (PTEN) gene was absent. The genetic alteration of p53, with hyper-expression of p53 protein and an absence of abnormalities in the PTEN gene are consistent with the similarities between Uterine Serous Carcinoma (USC) and our case of PESC. The aberrant methylation of both p16 and BCAR1 promoters was not detected in our case. This finding too could imply that ESC is more similar to Uterine Serous Carcinoma than Uterine Endometrioid Carcinoma (UEC). Moreover, the lack of aberrant methylation of p16, which is in accordance with over-expression of p16 immunoreactivity, in the absence of HPV infection may be related to other unknown genetic alterations. In our opinion, it is hard to reach any definite conclusion concerning the carcinogenesis of PESC, because of its rarity and the very few molecular studies reported in the literature. Further studies with more numerous cases and larger molecular analyses are mandatory for this malignancy, to confirm whether it is more closely related to papillary endometrial cancer than to endometrioid carcinoma.
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References
Klaes R, Friedrich T, Spitkovsky D et al (2001) Overexpression of p16ink4a as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276–284
Kataoka A, Nishida T, Sugiyama T, Hori K, Honda S, Yakushiji M (1997) Squamous cell carcinoma of the endometrium with human papillomavirus type 31 and without tumor suppressor gene p53 mutation. Gynecol Oncol 65:180–184
Pins MR, Young RH, Crum CP, Leach IH, Scully RE (1997) Cervical squamous cell carcinoma in situ with intraepithelial extension to the upper genital tract and invasion of tubes and ovaries: report of a case with human papilloma virus analysis. Int J Gynecol Pathol 16:272–278
Wang Z, Dong J, Eyzaguirre EJ, Tang WW, Eltorky MA, Qiu S (2009) Detection of human papilloma virus subtypes 16 and P16(ink4a) in invasive squamous cell carcinoma of the fallopian tube and concomitant squamous cell carcinoma in situ of the cervix. J Obstet Gynaecol Res 35:385–389
Bifulco G, Giampaolino P, Mandato VD, Morra I, Nappi C, Insabato L (2011) Primary squamous cell carcinoma of the endometrium: a case report. Eur J Gynaecol Oncol 32:350–352
Goodrich S, Kebria-Moslemi M, Broshears J, Sutton GP, Rose P. Primary squamous cell carcinoma of the endometrium: two cases and a review of the literature. Diagn Cytopathol. 2012 Jan 12. doi:10.1002/dc.22814. [Epub ahead of print]
Giordano G, D’Adda T, Merisio C, Gnetti L (2005) Primary squamous carcinoma of the endometrium: a case report with immunohistochemical and molecular study. Gynecol Oncol 96:876–879
Giordano G, Azzoni C, D’Adda T, Merisio C (2007) P16INK4a overexpression independent of Human Papilloma Virus (HPV) infection in rare subtypes of endometrial carcinomas. Pathol Res Pract 7:533–538
D’Adda T, Bottarelli L, Azzoni C et al (2005) Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors. Mod Pathol 18:795–805
Naidoo R, Chetty R (1998) The application of microsatellites in molecular pathology. Pathol Oncol Res 4:310–315
Herman JG, Graff JR, Myöhänen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826
Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159
Weissenbach J, Gyapay G, Dib C et al (1992) A second-generation linkage map of the human genome. Nature 359:794–801
Peltomaki P, Lothe RA, Aaltonen LA et al (1993) Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 53:5853–5855
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561
Wirtz HC, Muller W, Noguchi T et al (1998) Prognostic value and clinicopathological profile of microsatellite instability in gastric cancer. Clin Cancer Res 4:1749–1754
Duggan BD, Felix JC, Muderspach LI, Tourgeman D, Zheng J, Shibata D (1994) Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst 86:1216–1221
Steele RJC, Thompson AM, Hall PA, Lane DP (1998) The p53 tumour suppressor gene. Br J Surg 85:1460–1467
Ziyaie D, Hupp TR, Thompson AM (2000) p53 and breast cancer. Breast 9:239–246
Rogel A, Popliker M, Webb CG, Oren M (1985) p53 cellular tumor antigen: analysis of mRNA levels in normal adult tissues, embryos, and tumors. Mol Cell Biol 5:2851–2855
Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine AJ (1988) Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol 8:531–539
Lakshmi S, Nair MB, Jayaprakash PG, Rajalekshmy TN, Nair MK, Pillai MR (1997) p53 protein and tumorigenesis in the uterine cervix. Gen Diagn Pathol 142:281–287
Reihsaus E, Kohler M, Kraiss S et al (1990) Regulation of the level of the oncoprotein p53 in non transformed and transformed cells. Oncogene 5:137–145
Munn KE, Walker RA, Menasce L, Varley JM (1996) Mutation of the TP53 gene and allelic imbalance at chromosome 17p13 in ductal carcinoma in situ. Br J Cancer 74:1578–1585
Steck PA, Perhouse MA, Jasser SA et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362
Li J, Yen C, Liaw D et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1946
Bussaglia E, del Rio E, Matias-Guiu X, Prat J (2000) PTEN mutations in endometrial carcinomas: a molecular and clinicopathologic analysis of 38 cases. Hum Pathol 31:312–317
Levine RL, Cargile CB, Blazes MS, van Rees B, Kurman RJ, Ellenson LH (1998) PTEN mutations and microsatellite instability in complex atypical hyperplasia, a precursor lesion to uterine endometrioid carcinoma. Cancer Res 58:3254–3258
Maxwell GL, Risinger JI, Gumbs C et al (1998) Mutation of the PTEN tumor suppressor gene in endometrial hyperplasias. Cancer Res 58:2500–2503
Mutter GL (2001) PTEN, a protean tumor suppressor. Am J Pathol 158:1895–1898
Omura-Minamisawa M, Diccianni MB, Chang RC et al (2001) p16/p14(ARF) cell cycle regulatory pathways in primary neuroblastoma: p16 expression is associated with advanced stage disease. Clin Cancer Res 7:3481–3490
Esteller M, Silva JM, Dominguez G et al (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92:564–569
Wong YF, Chung TK, Cheung TH et al (1999) Methylation of p16INK4A in primary gynecologic malignancy. Cancer Lett 136:231–235
Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71
Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182
Kerr P, Ashworth A (2001) New complexities for BRCA1 and BRCA2. Curr Biol 11:R668–R676
Shen S-X, Weaver Z, Xu X et al (1998) A targeted disruption of the murine BRCA1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene 17:3115–3124
Foray N, Randrianarison V, Mrot D, Perricaudet M, Lenoir G, Feunteun J (1999) Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2. Oncogene 18:7334–7342
Xu X, Wagner KU, Larson D et al (1999) Conditional mutation of BRCA1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat Genet 22:37–43
Bianco T, Chenevix-Trench G, Walsh DC, Cooper JE, Dobrovic A (2000) Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer. Carcinogenesis 21:147–151
Baldwin RL, Nemeth E, Tran H et al (2000) BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 60:5329–5333
Risinger JI, Hayes AK, Berchuck A, Barrett JC (1997) PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 57:4736–4738
Seeber LM, Zweemer RP, Marchionni L et al (2010) Methylation profiles of endometrioid and serous endometrial cancers. Endocr Relat Cancer 17:663–673
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The Authors wish to thank Professor Alex Gillan for his help with the English translation and Mrs Emilia Corradini for technical assistence.
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Giordano, G., Pizzi, S., Azzoni, C. et al. Primary Squamous Cell Carcinoma of the Endometrium Unrelated to Human Papilloma Virus: A Molecular Study. Pathol. Oncol. Res. 19, 495–499 (2013). https://doi.org/10.1007/s12253-013-9607-3
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DOI: https://doi.org/10.1007/s12253-013-9607-3