Current concepts in the diagnosis and pathobiology of intraepithelial neoplasia: A review by organ system

open access
 6 JUN 2016

Ovary

There are many histologic types of primary ovarian carcinomas, and each of these is biologically unique with respect to histologic, immunohistochemical, and molecular features and pathogenesis. High-grade serous carcinoma is the most common ovarian malignancy and thus will be the focus of discussion for this section. Recent research has identified the precursor for this tumor as serous tubal intraepithelial carcinoma (STIC), which originates in the mucosa of the distal (fimbriated) end of the fallopian tube.

Terminology

STIC is the standardized designation for this form of intraepithelial neoplasia.[24, 25] Lesions related to STIC are serous tubal intraepithelial lesions (STILs) and “p53 signatures” (described below; see Molecular Underpinnings). It should be noted that these latter 2 lesions are not synonymous with STIC, and they are thought to precede the development of STIC as part of its pathogenesis. STIL, which is an atypical mucosal lesion intermediate between p53 signature and STIC, has also been referred to by a variety of other descriptive terms.[26] It also should be noted that the term p53 signature should be reserved only for research studies and should not be used in the pathology report.[21, 22]

Diagnostic Criteria

STIC is histologically characterized by significant nuclear atypia (Fig. 3). Several studies; however, have used different criteria for distinguishing STIC, atypical intermediate lesions, p53 signatures, and normal mucosa from one another. Consequently, there are no standardized criteria for these lesions, and the establishment of exact histologic diagnostic criteria for STIC has been difficult, because the morphologic spectrum of STIC is wide, and no 2 STICs appear to be exactly the same because of various degrees of histologic overlap between STICs. Variability of a diagnosis of STIC exists between pathologists, and several studies have shown that the interobserver agreement among pathologists based only on histologic features is inadequate.

For these reasons and to establish working criteria for standardization between pathologists for routine diagnosis and research, a diagnostic algorithm was developed that combines histologic features with coordinate immunohistochemical expression of p53 and Ki-67 (these markers are used to assess mutant tumor protein 53 [p53] and the proliferation index, respectively). Accordingly, STIC is diagnosed when significant atypia is present in combination with abnormal p53 expression and a high Ki-67 index. Interobserver reproducibility studies using this algorithmic approach have demonstrated that the agreement for STIC between pathologists was improved to a substantial level (from κ = 0.50 to κ = 0.67) compared with using only morphologic assessment and that this algorithm can be reproducibly applied.[26]

Risk Factors

A subset of STICs is associated with breast cancer (BRCA) germline mutations, whereas most STICs are sporadic. Other specific risk factors have not yet been identified, although a diagnosis of STIC before 40 years of age would be rare. The p53 signature, a putative precursor of STIC, is significantly associated with lower parity[27] (for additional information regarding the potential relation between the p53 signature and STIC/invasive high-grade serous carcinoma, see Vang et al).[25] However, the p53 signature does not appear to be associated with an increased risk of developing serous carcinoma.

Molecular Underpinnings

Abundant histologic and molecular evidence that has emerged over roughly the last 8 years strongly supports findings that the vast majority of ovarian and peritoneal high-grade serous carcinomas originate in the fallopian tube, specifically from an STIC, and thus implies that these ovarian/peritoneal tumors are metastases.[25, 28] It has been proposed that the p53 signature is the earliest step in the pathogenesis of STIC. The p53 signature consists of short stretches of tubal epithelium composed of cytologically benign, nonciliated (secretory) cells with overexpression of p53 and a low Ki-67 labeling index. However, the exact relation between p53 signatures and STIC is unclear (for additional information regarding the potential relation between the p53 signature and STIC/invasive high-grade serous carcinoma, see Vang et al).[26] It has been demonstrated that nearly all STICs harbor TP53 mutations, and short telomeres and aneusomy for multiple chromosomes have also been observed. In women with BRCA germline mutations, it has been suggested that loss of the wild-type BRCA allele is involved in tumor progression. STIL may represent a transitional step in pathogenesis between the p53 signature and STIC.

Management, Limitations, and Caveats

STIC may be recognized as an isolated finding in either 1) prophylactic specimens from women with an increased risk of ovarian/tubal carcinoma (ie, BRCA mutation carriers) or 2) routine specimens as part of a gynecologic surgical procedure performed for benign indications in women without a known history of breast/ovarian carcinoma or those not known to be BRCA mutation carriers (ie, sporadic cases). For such patients, the extent to which further clinical evaluation is needed is unclear. Using chemotherapy in this situation has not been preferred, but some patients in the literature have been treated in this fashion. Also, a proportion of patients with STIC as an isolated finding have had positive peritoneal cytology.

A significant limitation to the complete understanding of the natural history of STIC as an isolated finding is the availability of only a few studies with limited numbers of cases and short follow-up. While one study of isolated STIC observed no recurrences (median follow-up, 2.3 years),[29] a subset of patients in other studies subsequently developed recurrences as carcinoma from 3.6 to 4.0 years later.[30, 31] Furthermore, the outcome data on isolated STICs are based on BRCA germline mutation-associated cases. Because BRCA germline mutation-associated ovarian high-grade serous carcinomas have better survival than sporadic cases, it is possible that isolated sporadic STICs may have a greater propensity for progression compared with BRCA germline mutation-associated cases. Therefore, because 1) STIC is the histologic and immunohistochemical counterpart to endometrial serous intraepithelial carcinoma, 2) the latter can have extrauterine disease in the absence of myometrial invasion, and 3) STIC is typically located in the fimbriated end of the fallopian tube with direct access to the peritoneal cavity, the prognosis for patients with isolated sporadic STIC should be considered uncertain.

The opportunistic salpingectomy has been recognized as a potential means of preventing extrauterine high-grade serous carcinoma for women at average risk in whom the fallopian tubes have been removed before STIC can develop.[32] Thus, the entire fallopian tubes are removed in women undergoing pelvic surgery in instances in which an oophorectomy would not have been performed (eg, tubal ligation and hysterectomy in premenopausal women). Given that the ideal surgical candidate would be relatively young and that the mean age of women with sporadic STIC is the early 60s, it will likely be decades before future studies show the actual impact of the opportunistic salpingectomy on the general population. However, recent evidence suggests that this surgical procedure will be beneficial. In a Swedish population-based study in which women underwent bilateral salpingectomy, the risk for ovarian carcinoma was decreased by 65% (P = .004).[33] If additional large studies with lengthy follow-up can confirm these findings in women who undergo opportunistic salpingectomy, then this form of prevention will be of enormous value to women, because current screening modalities for detecting ovarian high-grade serous carcinoma have been unsuccessful.