Molecular pathology of endometrial carcinoma

This review paper discusses the main molecular alterations of endometrial carcinoma, the most common cancer of the female genital tract. Two clinicopathological variants are recognized: the oestrogen‐related (type I, endometrioid carcinoma) and the non‐oestrogen‐related (type II, non‐endometrioid carcinoma). Whereas type I shows microsatellite instability and mutations in PTEN, PIK3CA, K‐RAS and CTNNB1 (beta‐catenin), type II exhibits TP53 mutations and chromosomal instability. Recent investigations regarding the role of non‐coding RNA have provided important information regarding tumour progression. Understanding pathogenesis at the molecular level is essential for identifying biomarkers of potential use in targeted therapies.     

DNA replication error in endometrial carcinoma and complex atypical endometrial hyperplasia.

We attempted to define the relation between DNA replication errors (RERs) in endometrial carcinomas and the precancerous lesion complex atypical endometrial hyperplasia (ATH) and clinicopathological characteristics. Tissue samples from 93 patients with endometrial carcinoma diagnosed as endometrioid adenocarcinoma and 26 patients with ATH (including 21 in whom endometrial carcinoma also was found) were prepared as formalin-fixed, paraffin-embedded sections. The samples were examined for the presence of RERs by the polymerase chain reaction with the use of five microsatellite markers. RERs were observed at > or = 1 loci in 32 endometrial carcinoma patients (34%); all 26 ATH patients were RER negative. RERs were observed in 25% of stage I and stage II cancer patients (16/64) and in 55% of stage III and stage IV cancer patients (16/29) (P = 0.009), as well as in 63% (10/16) of cancer patients with and in 27% (20/75) of patients without lymph-node metastases (P = 0.013). The incidence of RERs was not related to patient age, histological tumor grade, or prognosis. These results suggest that RER may be involved in the advanced rather than the early stages of endometrioid adenocarcinoma. There appears to be little association between RER and ATH.     

Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints

This article reviews the main molecular alterations involved in endometrial carcinoma. Five molecular features (microsatellite instability, and mutations in the PTEN, k-RAS, PIK3CA and beta-catenin genes) are characteristic of endometrioid carcinomas, whereas non-endometrioid carcinomas show alterations of p53, loss of heterozygosity (LOH) on several chromosomes, as well as other molecular alterations (STK15, p16, E-cadherin and C-erb B2). The review also covers the phenomenon of apoptosis resistance, as well as the results obtained from cDNA array studies, and the perspectives for targeted therapies. A group of practical applications of molecular pathology techniques are also mentioned: diagnosis of hereditary non-polyposis colon cancer syndrome in patients with endometrial carcinoma; evaluation of precursor lesions; prognosis; diagnosis, particularly for synchronous endometrioid carcinomas of the uterus and the ovaries; and targeted therapies.     

Expression of cyclin D1 in endometrial hyperplasia and endometrial carcinoma

This study investigates the role of cyclin D1 in 30 uterine surgical resection and endometrial biopsy specimens from 30 patients with simple hyperplasia (10 cases), complex hyperplasia (6 cases) and endometrial carcinoma (14 cases). Cyclin D1 immunohistochemistry was performed on 2-4 mm thick paraffin sections using labelled streptavidin biotin kit. Cyclin D1 expression was present in 2/6 (33%) cases of complex hyperplasia, 7/14 (50%) cases of endometrial carcinoma and none in simple hyperplasia. Difference in cyclin D1 immunopositivity in simple hyperplasia and endometrial carcinoma was statistically significant (p = 0.018) but the difference in cyclin D1 immunopositivity between complex hyperplasia and endometrial carcinoma was not statistically significant. Our study suggests that cyclin D1 over-expression may be an early event in endometrial carcinogensis. Since there was no difference in extent and intensity of cyclin D1 expression between complex hyperplasia and endometrial carcinoma, it appears that deregulation is maximal in complex hyperplasia.     

Problems in the differential diagnosis of endometrial hyperplasia and carcinoma.

The differential diagnosis of endometrial hyperplasia and well-differentiated endometrioid adenocarcinoma is complicated not only by the resemblance of these lesions to each other, but also by their tendency to be overdiagnosed (particularly hyperplasia) on the background of polyps, endometritis, artifacts, and even normally cycling endometrium. Atypical hyperplasia may also be overdiagnosed when epithelial metaplastic changes occur in simple or complex hyperplasia without atypia. Low-grade adenocarcinomas are best recognized by architectural evidence of stromal invasion, usually in the form of stromal disappearance, desmoplasia, necrosis, or combinations of these findings between adjacent glands. Endometrioid adenocarcinomas are usually Type 1 cancers associated with manifestations of endogenous or exogenous hyperestrogenic stimulation and a favorable prognosis. Subtypes include adenocarcinomas with squamous differentiation and secretory, ciliated cell and villoglandular variants. Rules and pitfalls in the grading of endometrioid adenocarcinomas and the estimation and reporting of myometrial invasion are presented.     

子宫内膜增生及内膜癌中PTEN、Ki-67蛋白的表达

目的　研究子宫内膜增生组织及内膜癌组织中PTEN、Ki 6 7蛋白的异常表达 ,探讨其与子宫内膜癌变的关系及作为早期癌变生物学标志的可能性。方法　应用免疫组化S P法对 12例正常增生期子宫内膜组织、4 0例子宫内膜增殖症组织、4 2例内膜腺癌组织中PTEN、Ki 6 7蛋白的表达进行研究。结果　在正常增生期子宫内膜、子宫内膜增殖症 (单纯增生、复杂型增生、不典型增生 )、子宫内膜腺癌组织中PTEN蛋白的阳性表达率呈递减趋势 ;Ki 6 7蛋白的阳性表达率呈递增趋势。等级相关分析结果显示PTEN、Ki 6 7表达异常与子宫内膜组织学分级均显著相关 (相关系数r分别为 - 0 5 4 1和 0 4 96 ,P值均<0 0 1)。子宫内膜癌与除不典型增生外的子宫内膜增殖症组织及正常增生期子宫内膜组织的PTEN、Ki 6 7蛋白表达差异有显著性 ,正常增生期子宫内膜、单纯增生与不典型增生组织的PTEN蛋白表达差异有显著性 ,不典型增生与单纯增生组织的Ki 6 7蛋白表达差异有显著性。PTEN、Ki 6 7蛋白表达存在负相关性 (r =- 0 4 2 8,P <0 0 1)。PTEN、Ki 6 7蛋白的表达与子宫内膜癌的手术分期、组织学分级、肌层浸润无关 (P >0 0 5 )。结论　PTEN、Ki 6 7蛋白的异常表达与子宫内膜的癌变过程相关 ,PTEN基因表达异常及细胞增殖异常与子宫内膜     

Molecular pathology of gastric carcinoma

Gastric carcinoma (GC) is a biologically heterogeneous disease involving numerous genetic and epigenetic alterations. A very small proportion of GCs can be caused by a specific germ-line mutation of the E-cadherin gene (CDH1). Sporadic GC is developed through multistep processes that begin with Helicobacter pylori-induced atrophic gastritis. Epstein-Barr virus is another infectious cause of GC, and the above two infection-associated GCs are characterized by global CpG island methylation in the promoter region of cancer-related genes. Mutations of tumor protein p53 (TP53) and β-catenin (CTNNB1) genes occur early in the development of GC and contribute to gastric carcinogenesis. Furthermore, significant numbers of GCs show loss of Runx3 due to hemizygous deletion and hypermethylation of the promoter region. Aberrant Cdx2 expression has been shown in precancerous lesions as well as GC. However, it remains unclear whether Cdx2 plays an oncogenic role in gastric carcinogenesis. GC with microsatellite instability is also a well-defined subset exhibiting distinctive clinicopathologic features. Targeted therapy against GC with ERBB2 amplification recently improved the prognosis of patients with advanced GC. In addition, epigenetic changes in GC could be attractive targets for cancer treatment with modulators. A genome-wide search has been undertaken to identify novel methylation-silenced genes in GC, which will help us understand the overall molecular features of GC and further provide novel opportunities in the treatment of GC.     

Molecular pathology of gastric carcinoma: progress and prospects.

Gastric carcinoma is the fourth most common malignancy in Western Europe and a major cause of cancer morbidity and mortality worldwide, particularly in the Far East and in areas of South America. The natural history of the disease is not fully established, and there is a need to elucidate the molecular mechanisms of gastric carcinogenesis in order to understand its pathogenesis and to develop molecular markers for clinical diagnostic use. Molecular analysis of colonic carcinogenesis has increased our understanding of its pathogenesis and has demonstrated multistage carcinogenesis in a human cancer. Research in gastric carcinoma has not achieved such significant progress, although a start has been made. We analyze some of the interpretation problems in molecular pathology affecting progress that are of interest to the histopathologist and review recent studies on the molecular biology of gastric carcinoma involving flow cytometry, cytogenetics, allele loss analysis, and transfection. We also summarize current knowledge about each of the major oncogenes and suppressor genes, attempting, in particular, to correlate gene abnormalities with morphologic appearances. The expanding field of cell proliferation and growth factors is outlined, gastric and colon carcinomas are compared, and gastric carcinoma is considered as a model system for the study of differentiation. This report concludes by suggesting directions for future research.     

Immunomorphologic features of epithelial-stromal relationships at hyperplasia and endometrial carcinoma

The results of a immunomorphologic comprehensive study of epithelial-stromal relationships in the uterus hyperplasia and endometrial cancer suggest that the suppressor gene of cancer (PTEN) plays a key role in the process of neoplastic transformation of endometrial hyperplasia and adenocarcinoma development. For the first time the existence of two highly differentiated endometrial adenocarcinoma immunophenotype were detected The first one is a PTEN-negative endometrial aedenocarcinoma, characterized by an almost complete inhibition of tumor suppressor gene PTEN in the epithelium of the glands and stromal cell of the tumor The second type is a PTEN-positive endometrial adenocarcinoma, in which epithelial and stromal tumor suppressor gene PTEN activity has retained Based on these results we have formulated a hypothesis about the different types of endometrial hyperplasia morphogenesis and its possible transfer to cervical cancer associated with features of tumor suppressor gene PTEN.     

钙磷脂结合蛋白Ⅰ及其相关基因蛋白在子宫内膜增殖症、不典型增生和子宫内膜腺癌中的表达和意义

目的：研究钙磷脂结合蛋白Ⅰ（Annexin-Ⅰ，AX－Ⅰ）在子宫内膜病变中的表达及在交界病变鉴别诊断中的意义。方法：收集37份子宫内膜不同病变标本，经HE染色，在光镜下按国内及国际妇产科联合会（FIGO）标准分类，AX－Ⅰ、 雌激素受体、孕激素受体、表达生长因子受体、胰岛素样生长因子－Ⅰ受体与c-erbB-2的免疫组织化学染色采用LSAB法。结果：腺囊性子宫内膜增殖症12例、子宫内膜不典型增生（ATH）10例、子宫内膜癌（EC）15例。免疫组织化学AX－Ⅰ在腺囊性增殖症中，除，除1例弱阳性外，均为阴性，在不典型增生组9组为强阳性，1例弱阳性；内膜癌则7例弱阳性，8例阴性；内膜鳞化或鳞癌区呈强阳性。c-erbB-2蛋白在不典型增生组9例为阳性。1例阴性。表皮生长因子受体（EGFR）均呈强阳性，胰岛素样生长因子－Ⅰ受体的表达弱且无规律，P53表达在EC组较ATH组略强。结论：AX－Ⅰ基因蛋白可能在肿瘤的发病初期起作用，癌变后其表达下降，甚至消失；AX－Ⅰ强阳性对ATH与EC鉴别具有一定价值。另外，c-erbB-2与AX－Ⅰ的表达似乎存在一种平行的关系。     

Estrogen and endometrial carcinoma. An independent pathology review supporting original risk estimate.

Initial evidence suggested that estrogen therapy increases the risk of endometrial carcinoma. It was then suggested that some studies may have exaggerated the hazard of estrogen therapy by including patients with atypical endometrial hyperplasia among those having endometrial carcinoma. Three internationally recognized pathologists reviewed the histology slides available from the Ziel and Finkle study, which originally reported a risk ratio of 7.6 for estrogen users. At least one of the pathologists concurred with the original diagnosis in all but one case. Furthermore, all pathologists aggreed that 74 per cent (66/89) were correctly diagnosed. In the 66 patients with unanimous diagnosis, 61 per cent (40/66) had used conjugated estrogens, versus 57 per cent (54/94) in the original study. On the basis of 66 patients and 132 matched controls, the revised risk-ratio estimate is 8.1 (with a one-sided 95 per cent lower confidence limit of 4.5), validating the original estimate.     

Current concepts in the pathology and epigenetics of endometrial carcinoma

In the Western world, endometrial carcinoma is the most common malignant tumour of the female genital tract and is the fourth most common cancer in women. Two different clinicopathological subtypes are recognised: the oestrogen-related (type I, endometrioid) and the non-oestrogen related (type II, non-endometrioid). This article reviews the epidemiology, risk factors, genetic alterations during endometrial carcinogenesis, features of tumours and precursors and early detection of the disease. Insights into the epigenetic alterations, with emphasis on DNA methylation during endometrial carcinogenesis, and their diagnostic value are also provided.     

Mutational analysis of the PTEN gene in endometrial carcinoma and hyperplasia

To determine the potential role of PTEN in the process of endometrial carcinogenesis, we examined a series of endometrial carcinoma and hyperplasia of the uterine corpus for the presence of a PTEN mutation. The entire coding region of the gene was screened for the presence of mutations by single-strand conformation polymorphism analysis, and mutations were confirmed by sequencing. We detected mutations in 14 of 57 endometrial carcinomas (13 of 50 endometrioid adenocarcinomas and 1 of 7 nonendometrioid adenocarcinomas) and 7 of 73 endometrial hyperplasias (1 of 24 simple hyperplasias without atypia, none of 16 complex hyperplasias without atypia, and 6 of 33 complex hyperplasias with atypia). Most (88%) mutations were clustered in exons 5, 7, and 8. Of the 24 mutations detected in 21 cases, 12 were frameshifts, 9 were nonsense, 2 were missense, and 1 was a silent mutation. Patients with a PTEN mutation had a better prognosis than those with no PTEN mutation. The presence of PTEN mutations in hyperplasia suggests that PTEN inactivation may occur as an initiating event in endometrial carcinogenesis and is involved in the development of cytologic atypia in hyperplasia.     

Molecular pathogenesis and prognostic factors in endometrial carcinoma

Endometrial carcinoma is today among the most common gynecologic malignancies in industrialized countries. In order to improve the treatment and follow-up of these patients, various prognostic factors have been extensively studied. Patient age, stage of disease, histologic type and histologic grade have been shown to influence survival significantly, and the prognostic impact of these traditional clinicopathologic variables is well established. In addition, parity, hormone receptor concentration in the tumor, DNA ploidy and morphometric nuclear grade have all been found to influence prognosis. Information about DNA ploidy has especially been used in the clinical situation to determine individualized treatment. The prognostic significance of markers for tumor cell proliferation, cell cycle regulation (p53, p21 and p16) and angiogenesis is discussed as well as the molecular basis of endometrial carcinoma. In conclusion, several prognostic markers have been identified. It is likely that the information derived from these tumor biomarkers will reduce the need for extensive surgical staging and adjuvant treatment in endometrial carcinoma.     

原发性子宫内膜鳞状细胞癌伴子宫内膜不典型增生1例

原发性子宫内膜鳞状细胞癌(primary endometrial squamous cell carcinomas, PESCC)是一种罕见的子宫内膜癌。本文报道1例55岁患者, 刮宫标本及经腹腔镜筋膜外全子宫切除标本组织学形态均显示不同分化程度的鳞状上皮呈浸润性生长, 并见短梭形细胞, 胞质丰富、透亮。刮宫标本中未见正常子宫内膜腺体及异常腺性结构;全子宫切除标本中短梭形与鳞状上皮穿插生长, 侵犯浅肌层, 周围子宫内膜可见慢性子宫内膜炎, 局灶符合子宫内膜不典型增生;免疫表型:明确的鳞状上皮成分及短梭形细胞广谱细胞角蛋白、细胞角蛋白(CK)5/6、p63、β-catenin、CD10均阳性, CK7、CDX2阴性。患者随访8个月, 身体状况良好。PESCC需要严格掌握诊断标准, 除外子宫颈来源的鳞状细胞癌及子宫内膜样癌伴广泛鳞化。该文描述PESCC组织学特点、刮宫及全子宫标本诊断难点、阐述其诊断要点, 并复习和总结相关文献。