Molecular abnormalities in ovarian carcinoma: clinical,morphological and therapeutic correlates

The histopathological classification of ovarian surface epithelial carcinomas (referred to hereafter as ‘ovarian carcinoma’) has shifted over the past 10 years to reflect more clearly our understanding of molecular events during carcinogenesis. Ovarian carcinoma is no longer viewed as a single entity but as multiple disease processes, with each having different molecular pathways altered during oncogenesis, resulting in differences in clinical and pathological features, such as biomarker expression, pattern of spread and response to chemotherapy. There are five subtypes of ovarian carcinoma that are sufficiently distinct and well‐characterized that they should be considered to be different diseases, i.e. high‐grade serous, clear cell, endometrioid, mucinous and low‐grade serous, from most to least common, respectively. This review summarizes the molecular abnormalities of these five ovarian carcinoma subtypes, relating them to clinical and pathological features.     

子宫内膜样腺癌组织中PRRX1蛋白的表达及临床意义

目的探讨配对相关同源框1(paired related homoeobox 1,PRRX1)蛋白在子宫内膜样腺癌组织中的表达及临床意义。方法选取安徽医科大学第一附属医院以及安徽医科大学附属巢湖医院267例子宫内膜组织标本,其中正常子宫内膜86例,子宫内膜上皮内瘤变90例,子宫内膜样腺癌91例,均行免疫组化EliVision法检测,观察不同子宫内膜组织中PRRX1表达及子宫内膜样腺癌临床病理特征与PRRX1的关系。结果PRRX1蛋白表达主要定位于子宫内膜样腺癌组织的细胞核中,91例子宫内膜样腺癌组织中PRRX1阳性率为79.1%,高于正常子宫内膜组织(0)、子宫内膜上皮内瘤变组织(10.0%),差异有统计学意义(P<0.05)。子宫内膜样腺癌患者按FIGO分级分类,FIGO1级的PRRX1阳性率低于FIGO 2、3级,差异有统计学意义(P<0.05);按患者年龄、临床分期、有无淋巴结转移分组,PRRX1阳性率差异均无统计学意义(P>0.05)。结论子宫内膜样腺癌组织中的PRRX1表达量高,且与FIGO分级相关。     

Genome‐wide mutation analysis in precancerous lesions of endometrial carcinoma

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole‐exome sequencing to identify somatic mutations and copy number changes in micro‐dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co‐developing with distinct genetic trajectories. Our genome‐wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

子宫内膜癌前病变及子宫内膜样腺癌组织中P73和Ki-67蛋白的表达

目的 :用P73和Ki 6 7蛋白对子宫内膜癌前病变及内膜样腺癌组织中的表达进行检测 ,探讨其与子宫内膜病变的关系及作为早期癌变生物学标志的可能性。方法 :用免疫组化SP法 ,对 13例子宫内膜增生期 ,2 0例简单型增生过长、2 2例复杂型增生过长 (含 11例不典型增生 )及 38例内膜样腺癌组织中的P73、Ki 6 7蛋白的表达进行检测。结果 :在子宫内膜增生期、简单型增生过长、复杂型增生过长及内膜样腺癌中 ,P73蛋白阳性检出率分别为15 .38% (4 / 13) ,2 5 .0 0 % (5 / 2 0 ) ,4 0 .91% (9/ 2 2 ) ,76 .32 % (2 9/ 38) ;Ki 6 7蛋白阳性检出率分别为 2 3.0 8% (6 / 13) ,30 .0 0 % (6 / 2 0 ) ,4 5 .4 5 % (10 / 2 2 ) ,71.0 5 % (2 7/ 38)。随着子宫内膜病变的增生演进 ,P73和Ki 6 7蛋白的阳性表达率上调且呈显著正相关 (P <0 .0 1) ,Pearson列联系数为 0 .5 6 0 8。结论 :P73和Ki 6 7协同调控子宫内膜腺上皮细胞的生长、增殖 ,并促进癌变。P73和Ki 6 7表达上调 ,有可能成为在子宫内膜癌癌前确定高危个体和选择重点预防个体的分子生物学标记。     

Molecular genetic evidence that endometriosis is a precursor of ovarian cancer

Histopathology and epidemiology studies have consistently demonstrated a strong link between endometriosis and endometriosis-associated ovarian cancers (EAOCs)--in particular, the endometrioid and clear cell subtypes. However, it is still unclear whether endometriosis is a precursor to EAOCs, or whether there is an indirect link because similar factors predispose to both diseases. In order to search for evidence of clonal progression, we analyzed 10 EAOCs (endometrioid=4; clear cell=6) with coexisting endometriosis for common molecular genetic alterations in both the carcinoma and corresponding endometriosis. We used 82 microsatellite markers spanning the genome to examine loss of heterozygosity (LOH) in the coexisting carcinoma and endometriosis samples. A total of 63 LOH events were detected in the carcinoma samples; twenty two of these were also detected in the corresponding endometriosis samples. In each case, the same allele was lost in the endometriosis and cancer samples. Interestingly, no marker showed LOH in the endometriosis alone. These data provide evidence that endometriosis is a precursor to EAOCs.     

Ovarian endometrioid adenocarcinoma associated with steroidogenic foamy stromal cells

A case of a 69-year-old woman with endometriold adenocarcinoma of the ovary with functioning stromal cells is presented. The patient complained of genital bleeding. Endometrial curettage revealed endometrial hyperplasia. Preoperative levels of serum estradiol and progesterone were elevated, and serum gonadotropin levels were suppressed. The surgical specimen contained fist-sired, bilateral, solid, ovarian tumors and a mildly enlarged uterus. Histologically, the proliferating, atypical, columnar cancer cells resembled early secretory, endometrial epithelial cells with subnuclear vacuolation, and there were clusters of fat-laden foamy cells in the stroma. immunohistochemically, the cancer cells were positive for cytokeratin and progesterone receptor but negative for estrogen receptor. The stromal foamy cells were immunoreactive for vimentin, progesterone receptor, P450 side chain-cleavage, 3β-hydroxysteroid dehydrogenase, and adrenal 4-binding protein. immunoreactivities of P450c-17α hydroxylase and aromatase were only focally observed. These findings indicated that the stromal cells were steroldogenic and mainly produced progesterone. The cancer cells that expressed progesterone receptors showed morphologic changes in response to hormonal stimulation.     

Fallopian tube cytology: A histocorrelative study of 150 washings

The aim of the study was to assess the relationship between fallopian tube lavage cytology and recognized microscopic prognostic features in cancer of the uterine corpus. Tubal (TW) and peritoneal washing cytology (PW), endometrial tumor grade, and tumor involvement of the cervix, myometrium, myometrial vessels, and peritoneum were assessed in 150 patients. Endometrioid adenocarcinoma grade 1 was considered a low-grade tumor, while endometrioid carcinoma grades 2/3, serous/clear cell carcinoma, carcinosarcoma, and high-grade stromal sarcoma were considered high grade. The overall concordance rate for paired TWs and PWs was 72% (108/150). Forward stepwise logistic regression analysis of the 150 tumors revealed that only PWs and cervical involvement were independently predictive of TWs. No relationship was evident between TWs and depth of myometrial invasion, myometrial vascular involvement, or peritoneal metastases. It is concluded that retrograde transtubal spread by malignant endometrial cells occurs independently of myometrial histoprognostic features. TWs provide supporting evidence for diagnostically difficult PWs, and malignant TWs may be detected in the presence of minimally invasive serous/clear cell carcinoma and carcinosarcoma of the endometrium. Diagn. Cytopathol. 16:483–488, 1997. © 1997 Wiley-Liss, Inc.     

Matrix metalloproteinases 2 and 9, E-cadherin, and beta-catenin expression in endometriosis, low-grade endometrial carcinoma and non-neoplastic eutopic endometrium

OBJECTIVES: Endometriosis and endometrial endometrioid carcinoma are both capable of invasion and metastasis, but their biological behavior is strikingly different. Matrix metalloproteinases (MMPs) and changes in adhesion molecules have a role in the pathogenesis of various physiological and pathological processes, as well as in the development of endometriosis and endometrioid endometrial carcinoma. We hypothesized that endometriosis, being a benign process, will show different MMPs and adhesion molecules expressions, compared to endometrioid endometrial carcinoma, a disease with potential of malignant behavior. STUDY DESIGN: We performed an immunohistochemical study to investigate expression of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), E-cadherin and beta-catenin in endometriosis, low-grade endometrial endometrioid carcinoma, and eutopic proliferative endometrium. Endometriotic tissues (n=15), low-grade endometrial endometrioid carcinomas (n=15), and unremarkable proliferative endometrium from women without endometriosis or carcinoma (n=10) were examined. RESULTS: Endometriotic tissues showed statistically significantly stronger staining for MMP-9 and reduced beta-catenin expression when compared with proliferative endometrium. Endometrial endometrioid carcinoma showed decreased E-cadherin expression in comparison with proliferative endometrium. MMP-2 and MMP-9, and E-cadherin expressions were significantly higher and beta-catenin expression was significantly lower in endometriosis as compared to endometrioid carcinoma. CONCLUSIONS: We suggest that increased MMPs and altered beta-catenin may play a role in the pathogenesis of endometriosis. Decreased E-cadherin may be important in the development of endometrial endometrioid carcinoma. The changes in MMPs, E-cadherin and beta-catenin differ in endometriosis from those in endometrioid carcinoma, an interesting finding in view of the fact that both these diseases are capable of invasion and metastasis, but have different biological behavior.