Ovarian Cancer Is an Imported Disease : Fact or Fiction?

The cell of origin of ovarian cancer has been long debated. The current paradigm is that epithelial ovarian cancer (EOC) arises from the ovarian surface epithelium (OSE). OSE is composed of flat, nondescript cells more closely resembling the mesothelium lining the peritoneal cavity, with which it is continuous, rather than the various histologic types of ovarian carcinoma (serous, endometrioid, and clear cell carcinoma), which have a M\ufcllerian phenotype. Accordingly, it has been argued that the OSE undergoes a process termed "metaplasia" to account for this profound morphologic transformation. Recent molecular and clinicopathologic studies not only have failed to support this hypothesis but also have provided evidence that EOC stems from M\ufcllerian-derived extraovarian cells that involve the ovary secondarily, thereby calling into question the very existence of primary EOC. This new model of ovarian carcinogenesis proposes that fallopian tube epithelium (benign or malignant) implants on the ovary to give rise to both high-grade and low-grade serous carcinomas, and that endometrial tissue implants on the ovary and produces endometriosis, which can undergo malignant transformation into endometrioid and clear cell carcinoma. Thus, ultimately EOC is not ovarian in origin but rather is secondary, and it is logical to conclude that the only true primary ovarian neoplasms are germ cell and gonadal stromal tumors analogous to tumors in the testis. If this new model is confirmed, it has profound implications for the early detection and treatment of "ovarian cancer.

Serous tubal intraepithelial carcinoma upregulates markers associated with high-grade serous carcinomas including Rsf-1 (HBXAP), cyclin e and fatty acid synthase

Serous tubal intraepithelial carcinoma (STIC) has been proposed as a precursor for many pelvic high-grade serous carcinomas. Our previous analysis of the ovarian cancer genome identified several genes with oncogenic potential that are amplified and/or overexpressed in the majority of high-grade serous carcinomas. Determining whether these genes are upregulated in STICs is important in further elucidating the relationship of STICs to high-grade serous carcinomas and is fundamental in understanding the molecular pathogenesis of high-grade serous carcinomas. In this study, 37 morphologically defined STICs were obtained from 23 patients with stage IIIC/IV high-grade serous carcinomas. Both STICs and the high-grade serous carcinomas were analyzed for expression of Rsf-1 (HBXAP), cyclin E, fatty acid synthase (FASN) and mucin-4. In addition, they were examined for expression of established markers including p53, Ki-67 and p16. We found that diffuse nuclear p53 and p16 immunoreactivity was observed in 27 (75%) of 36 and 18 (55%) of 33 STICs, respectively, whereas an elevated Ki-67 labeling index ( 6510%) was detected in 29 (78%) of 37 STICs. Cyclin E nuclear staining was seen in 24 (77%) of 35 STICs, whereas normal tubal epithelial cells were all negative. Increased Rsf-1 and FASN immunoreactivity occurred in 63%, and 62% of STICs, respectively, compared with adjacent normal-appearing tubal epithelium. Interestingly, only one STIC showed increased mucin-4 immunoreactivity. Carcinomas, when compared with STICs, overexpressed p16, Rsf-1, cyclin E and FASN in a higher proportion of cases. In conclusion, STICs express several markers including Rsf-1, cyclin E and FASN in high-grade serous carcinomas. In contrast, mucin-4 immunoreactivity either did not change or was reduced in most STICs. These results suggest that overexpression of Rsf-1, cyclin E and FASN occurs early in tumor progression

The pathogenesis of atypical proliferative Brenner tumor : an immunohistochemical and molecular genetic analysis

Brenner tumors are ovarian tumors, usually benign, containing epithelium that resembles transitional epithelium. As with other epithelial tumors there exist frankly malignant tumors and tumors that display greater proliferation than the benign Brenner tumors but lack destructive infiltrative growth, and these have been designated 'atypical proliferative' (borderline) Brenner tumors. There have been no well-documented cases of atypical proliferative Brenner tumors that have exhibited malignant behavior. Based on shared morphologic features it is generally believed that atypical proliferative Brenner tumors develop from benign Brenner tumors. The aim of the present study was to confirm this impression by investigating the immunohistochemical and molecular genetic features of benign and atypical proliferative Brenner tumors. Immunohistochemical staining for p16, fluorescence in-situ hybridization (FISH) for CDKN2A (p16-encoding gene) and mutational analysis of the genes commonly mutated in ovarian tumors were performed. p16 immunostaining was positive in the epithelial component of 12 (92%) of 13 benign Brenner tumors, but completely negative in all 7 atypical proliferative Brenner tumors. FISH identified homozygous deletion of CDKN2A in the epithelial component of all atypical proliferative Brenner tumors, but CDKN2A was retained in all benign Brenner tumors. Two PIK3CA somatic mutations were detected in the stromal component in 1 (5%) of 20 Brenner tumors and 3 somatic mutations (1 in KRAS and 2 in PIK3CA) were identified in the atypical epithelial component of 2 (29%) of 7 atypical proliferative Brenner tumors. In summary, our findings suggest that loss of CDKN2A and, to a lesser extent, KRAS and PIK3CA somatic mutations have a role in the progression of a benign to an atypical proliferative Brenner tumor

Ovarian Brenner tumour : a morphologic and immunohistochemical analysis suggesting an origin from fallopian tube epithelium

Background Brenner tumours (BTs), like other epithelial ovarian tumours, are thought to develop from the ovarian surface epithelium. Aim and Methods We hypothesised that BTs arise from transitional metaplasia near the tuboperitoneal junction which, when embedded in the ovary as Walthard cell nests, may progress to BTs. The aim of this study was to validate this hypothesis by a morphologic and immunohistochemical (IHC) analysis. Results The IHC analysis revealed that fallopian tube secretory cells, transitional metaplasia, Walthard cell nests and the epithelial component of BTs shared a similar IHC profile, consistently expressing AKR1C3 (an enzyme involved in androgen biosynthesis) and androgen receptor, but not calretinin. The tumour stromal cells that immediately surrounded the epithelial nests showed strong expression of calretinin, inhibin and steroidogenic factor 1 (markers of steroidogenic cells) in the majority of BTs. Using a highly sensitive immunofluorescent staining method, we detected small groups of cilia in transitional metaplasia and Walthard cell nests, multifocal stretches of cilia and/or ciliated vacuoles in benign BTs and well-developed cilia in atypical proliferative BTs. Conclusions Our findings suggest a tubal origin of BTs through transitional metaplasia and Walthard cell nests, based on their anatomic proximity, similar IHC profile and the presence of cilia. In addition, we hypothesise a role of androgenic stimulation in the pathogenesis of BT, based on the IHC staining pattern of calretinin, inhibin and steroidogenic factor 1 expressed in the luteinised stromal cells surrounding the epithelial nests of the tumours, and AKR1C3 and androgen receptor expressed in both the epithelial and stromal components

Steroid hormone synthesis by the ovarian stroma surrounding epithelial ovarian tumors : a potential mechanism in ovarian tumorigenesis

Epithelial ovarian tumors are responsive to steroid hormone stimulation and the ovarian stroma may have a direct role in this process. We evaluated immunohistochemical markers of sex-steroid differentiation and steroidogenesis (calretinin, inhibin, steroidogenic factor 1), steroid enzymes involved in hormone biosynthesis (CYP17, CYP19, HSD17\u3b21, AKR1C3), and hormone receptors (estrogen receptor, progesterone receptor, and androgen receptor) in 101 epithelial ovarian tumors and in normal structures implicated in ovarian carcinogenesis (ovarian surface epithelium and cortical inclusion cysts) in an attempt to elucidate this process. We hypothesized that ovarian stroma immediately adjacent to tumors express markers of sex-steroid differentiation and steroidogenesis and steroid enzymes whereas the epithelium contains corresponding hormone receptors. As the findings in seromucinous, endometrioid, and clear cell neoplasms, tumors closely associated with endometriosis, were very similar, these were combined into a group designated 'endometriosis-related tumors.' Significantly increased expression of markers of sex-steroid differentiation and steroidogenesis was found in stroma immediately adjacent to endometriosis-related tumors (P=0.003) and mucinous tumors (primary and metastatic mucinous tumors were combined because of similar findings) (P<0.0001) compared with more remote ovarian stroma. In addition, sex-steroid enzymes were increased in stroma adjacent to endometriosis-related tumors (P=0.02) and mucinous tumors (P=0.02) compared with more distant stroma. Steroid hormone receptors showed greater expression in epithelium compared with stroma in the endometriosis-related tumors (P=0.0009), low-grade serous tumors (P<0.0001), and high-grade serous carcinoma (P=0.0036). In contrast, there was greater expression in stroma compared with epithelium (P<0.0001) in mucinous tumors, which may be due to the fact that they are not derived from m\ufcllerian epithelium. In conclusion, our findings strongly support the view that the stroma surrounding epithelial tumors in the ovary is activated to elaborate steroid hormones which may stimulate further neoplastic growth. The precise mechanisms by which this process might occur are complex and require further investigation

TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma-evidence supporting the clonal relationship of the two lesions

Serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of ovarian, tubal and 'primary peritoneal' (pelvic) high-grade serous carcinoma (HGSC). As somatic mutation of TP53 is the most common molecular genetic change of ovarian HGSC, occurring in more than 95% of cases, we undertook a mutational analysis of 29 pelvic HGSCs that had concurrent STICs to demonstrate the clonal relationship of STICs and HGSCs. In addition, we correlated the mutational data with p53 immunostaining to determine the role of p53 immunoreactivity as a surrogate for TP53 mutations in histological diagnosis. Somatic TP53 mutations were detected in all 29 HGSCs analysed and the identical mutations were detected in 27 of 29 pairs of STICs and concurrent HGSCs. Missense mutations were observed in 61% of STICs and frameshift/splicing junction/nonsense mutations in 39%. Interestingly, there were two HGSCs with two distinctly different TP53 mutations each, but only one of the mutations was detected in the concurrent STICs. Missense mutations were associated with intense and diffuse ( 65 60%) p53 nuclear immunoreactivity, while most of the null mutations were associated with complete loss of p53 staining (p < 0.0001). Overall, this p53 staining pattern yielded a sensitivity of 87% and a specificity of 100% in detecting TP53 missense mutations. In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations