Pelvic Serous Carcinoma Research Articles

Breast cancer following ovarian cancer in BRCA mutation carriers.

BRCA mutation carriers are at increased risk of developing breast cancer. However, the incidence of breast cancer after a diagnosis of epithelial ovarian cancer (EOC), one of the tubal/peritoneal cancers collectively referred to as pelvic serous carcinomas, is not well known. Optimal breast cancer surveillance and detection for these patients have also not been well characterized. To determine the incidence of breast cancer after a diagnosis of EOC and to evaluate the need for breast cancer surveillance for these patients. A retrospective database review of 364 patients who underwent BRCA mutation testing for EOC (stages I-IV) between 1998 and 2012 at an academic medical center with gynecologic and breast cancer centers. Incidence of breast cancer and methods of surveillance. Of 364 patients, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 mutation. The mean age of patients at diagnosis of EOC was 49.5 years (range, 28-89 years). Of the 135 patients, 12 (8.9%) developed breast cancer. The median time from diagnosis of EOC to diagnosis of breast cancer was 50.5 months. Annual mammography was performed for 80 patients (59.3%), with annual magnetic resonance imaging of the breasts performed for 60 patients (44.4%). Thirteen patients (9.6%) underwent a bilateral prophylactic mastectomy at a median of 23 months following EOC diagnosis. Breast cancer was most commonly diagnosed by mammography for 7 of the 12 patients (58.3%), 3 (25.0%) of whom had a palpable mass and 2 (16.7%) of whom had incidental breast cancer detected during a prophylactic mastectomy. Seven patients with breast cancer (58.3%) underwent a bilateral mastectomy. All patients had early-stage breast cancer (stages 0-II). Four patients (33.3%) received adjuvant chemotherapy. At a median follow-up of 6.3 years, 4 of the 12 patients (33.3%) died of recurrent EOC after a diagnosis of breast cancer. The overall 10-year survival rate for the entire cohort of 135 patients was 17.0%. The risk of metachronous breast cancer is low in patients with known BRCA mutations and EOC. A majority of these cases of breast cancer at an early stage are detected by use of mammography. Despite the small number of patients in our study, these results suggest that optimal breast cancer surveillance for patients with BRCA-associated EOC needs to be reevaluated given the low incidence of breast cancer among these high-risk patients. Confirmation of our findings from larger studies seems to be indicated.

Evaluation of the fallopian tubes after neoadjuvant chemotherapy: persistence of serous tubal intraepithelial carcinoma.

The origin of pelvic serous carcinoma continues to be controversial. Recent studies of patients undergoing primary surgery for ovarian, primary peritoneal, and uterine serous carcinomas have indicated the value of complete fimbrial sampling for detecting occult serous tubal intraepithelial carcinoma (STIC). Evidence suggests that a significant proportion of pelvic serous carcinomas may arise from in situ lesions on the distal fallopian tube. In this study, 14 consecutive cases of interval debulking surgery after neoadjuvant chemotherapy were reviewed, using both hematoxylin and eosin staining and, as needed, immunohistochemistry for p53 and MIB-1. The degree of fimbrial sampling was evaluated, and cases were examined for tumor involvement in the endosalpinx and the presence of STIC. Tumor treatment response was classified using a semiquantitative 4-tier scale. The results indicate that STIC can persist despite chemotherapy and can be readily identified during microscopic examination. These results are expected to improve the quality of the pathology evaluation by providing data-driven recommendations for sampling in interval surgery cases and showing the value of a systematic approach to evaluating the fallopian tube (sectioning and extensively examining the fimbria protocol). These results demonstrate that a tubal primary can still be assigned in these situations. Finally, this study raises interesting biologic questions about the sensitivity of cells originating from serous cancer tumor to chemotherapy. The presence or absence of STIC in specimens from interval surgery after neoadjuvant treatment has not previously, to our knowledge, been addressed.

The association of serous tubal intraepithelial carcinoma with gynecologic pathologies and its role in pelvic serous cancer

ObjectivesPossible primary sites of pelvic serous cancers are, fallopian tubes, ovaries or peritoneum. Recent studies have revealed that a portion of these tumors originates from serous tubal intraepithelial carcinoma (STIC) at the distal end of fallopian tubes. In this study, the association of STIC with pelvic serous carcinomas and the pathologic parameters that indicate the tubes as the primary site were assessed. MethodsIn total, 495 pairs of fallopian tubes obtained via total abdominal hysterectomy and bilateral salpingo-oophorectomy between 2011 and 2013 were examined according to SEE-FIM protocol. Hematoxylin and eosin-stained slides were examined by pathologists. Suspicious areas were immunostained with p53 and Ki-67 to diagnose STIC precisely. ResultsOf the 495 cases, 110 cases were malignant. Among 34 cases of non-uterine serous carcinomas, 13 were diagnosed with STIC. STIC was located at the fimbrial end of the fallopian tubes in 12 cases. No STIC was identified in the gynecologic malignancies other than non-uterine serous pelvic carcinomas and benign gynecologic pathologies. Comparison of the ovarian and tubal cancer cases with and without STIC did not reveal a factor that helps to define the primary site. STIC was an important factor associated in a higher portion of the cases with bilateral ovarian cancer. ConclusionThe role of STIC in carcinogenesis continues to be discussed as it is unknown whether STIC is the precursor lesion or just associates with the malignancies. Discovering the accurate precursor lesions and tumor carcinogenesis is essential to prevent these malignancies and to develop early diagnostic methods.

IMP3 signatures of fallopian tube: a risk for pelvic serous cancers.

BackgroundRecent advances suggest fallopian tube as the main cellular source for women’s pelvic serous carcinoma (PSC). In addition to TP53 mutations, many other genetic changes are involved in pelvic serous carcinogenesis. IMP3 is an oncofetal protein which has recently been observed to be overexpressed in benign-looking tubal epithelia. Such findings prompted us to examine the relationship between IMP3 over-expression, patient age and the likelihood of development of PSC.MethodsFallopian tubes from three groups (low-risk, high-risk, and PSC) of patients with matched ages were studied. Age was recorded in 10 years intervals ranging from age 20 to older than 80. The number of IMP3 signatures (defined by 10 or more tubal secretory cells stained positively and continuously in benign appearing tubal mucosa) from both tubal fimbria and ampulla segments was measured. The data was analyzed by standard contingency table and Poisson distribution methods after age adjustment. IMP3 overexpression was also examined in serous tubal intraepithelial carcinoma and PSC.ResultsThe positive IMP3-stained cells are mainly tubal secretory cells. The absolute number of tubal IMP3 signatures increased significantly within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. IMP3 signatures were more frequent in the patients of both high-risk and PSC groups. The presence of IMP3 signatures in tubal mucosa was significantly associated with tubal or pelvic serous carcinogenesis (p < 0.001).ConclusionsThe findings suggest that tubal secretory cells with IMP3 signatures showing growth advantage could potentially serve as a latent precancer biomarker for tubal or pelvic serous carcinomas in women.

Early detection of high-grade tubal serous carcinoma in women at low risk for hereditary breast and ovarian cancer syndrome by systematic examination of fallopian tubes incidentally removed during benign surgery.

Early detection of sporadic pelvic serous carcinoma remains an elusive goal. In women at high risk for hereditary breast and ovarian cancer syndrome who undergo prophylactic salpingectomy, systematic pathologic examination of the fallopian tubes will detect occult tubal cancer, mostly in the fimbriae, of a minority of women. Such tubal cancers are the putative precursor to advanced-stage pelvic cancer. We hypothesized that early tubal cancer detection can also be accomplished in women at low risk using a similar approach. In this study, we performed complete and systematic examination of the fallopian tubes removed during surgery performed for benign indications. Among 522 women, 4 cases of serous tubal intraepithelial carcinoma (STIC) were identified. Three of these cases would have gone undetected using the current standard of care of sampling only a single random section of the tube. The fourth case was accompanied by occult ovarian carcinoma. The fimbriae contained STIC in 3 of the 4 cases and atypical mucosa in 1 case in which the STIC was in the nonfimbriated portion of the tube. The morphologic and immunohistochemical features (aberrant p53 and MIB-1) of these STICs were similar to those expected in high-risk women. All 4 patients with STIC underwent BRCA1 and BRCA2 gene testing; no germline mutations were identified in any patient. An additional 11 specimens contained atypical mucosal proliferations that fell short of morphologic and immunohistochemical criteria for STIC. Two of these 11 fulfilled criteria for a serous tubal intraepithelial lesion, and the remaining atypical proliferations exhibited normal p53 and MIB-1. For most specimens, the fimbriae could be completely submitted in 1 or 2 cassettes per tube. These results demonstrate that systematic examination of the tubal fimbriae can serve as a form of early detection of sporadic tubal cancer without incurring significant labor or cost. We propose that the tubal fimbriae should be completely examined in all patients undergoing benign surgery even if there are no clinical features to suggest risk for hereditary breast and ovarian cancer syndrome.

Clinical Outcome of Isolated Serous Tubal Intraepithelial Carcinomas (STIC)

Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women with BRCA mutation due to increased risk of pelvic serous carcinoma. Serous tubal intraepithelial carcinoma (STIC) is a pathologic finding of unknown clinical significance. This study evaluates the clinical outcome of patients with isolated STIC. We retrospectively reviewed the medical records of consecutive patients with a germline BRCA1/2 mutation or a high-risk personal or family history of ovarian cancer who underwent RRSO between January 2006 and June 2011. All patients had peritoneal washings collected. All surgical specimens were assessed using the sectioning and extensively examining the fimbria protocol, with immunohistochemistry when indicated. p53 signature lesions and secretory cell outgrowths were excluded. Of 593 patients who underwent RRSO, isolated STIC was diagnosed in 12 patients (2%). Five patients (42%) were BRCA1 positive, 5 patients (42%) were BRCA2 positive, and 2 patients (17%) had high-risk family history. Preoperatively, all patients with STIC had normal CA-125 levels and/or pelvic imaging results. Seven patients underwent hysterectomy and omentectomy, 6 patients (46%) had pelvic node dissections, and 5 patients (39%) had para-aortic node dissections. With the exception of positive peritoneal washings in 1 patient, no invasive or metastatic disease was identified. No patient received adjuvant chemotherapy. At median follow-up of 28 months (range, 16-44 months), no recurrences have been identified. Among the cases of isolated STIC after RRSO reported in the literature, the yield of surgical staging is low, and short-term clinical outcomes are favorable. Peritoneal washings are the most common site of disease spread. Individualized management is warranted until additional data become available.

Secretory cell expansion with aging: Risk for pelvic serous carcinogenesis

ObjectiveRecent advances suggest that precancerous lesions of pelvic serous carcinoma (PSC) originate from tubal secretory cells. The purpose of our study was to determine if increased number of secretory cells shows difference in age and location and to examine their association with serous neoplasia. Materials and methodsThree groups (benign control, high-risk, and PSC) of patients with matched ages were studied. The age data was stratified into 10-year intervals ranging from age 20 to older than 80. The number of secretory and ciliated cells from both tubal fimbria and ampulla segments was counted by microscopy and immunohistochemical staining methods. The data was analyzed by standard contingency table and Poisson distribution methods after age justification. ResultsWe found that the absolute number of tubal secretory cells increased significantly with age within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. In addition, a dramatic increase of secretory cells was observed in high-risk and PSC patients. Further, secretory cell expansion (SCE) was more prevalent than secretory cell outgrowth in both fimbria and ampulla tubal segments and was significantly associated with serous neoplasia (p<0.001). ConclusionsThese findings suggest that SCE could potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube. Findings support a relationship between serous neoplasia and increased secretory to ciliated cell ratios. Findings also support a relationship between frequency of SCE and increasing age, presence of high-risk factors and co-existing serous cancers.

The Presence of Mucosal Iron in the Fallopian Tube Supports the “Incessant Menstruation Hypothesis” for Ovarian Carcinoma

The incessant ovulation hypothesis for the etiology of ovarian carcinoma has been accepted for decades, but recent evidence strongly implicates the fallopian tube mucosa as the source of most high-grade "ovarian serous carcinomas." Menstrual reflux through the tubes, a normal phenomenon, is a putative source of tubal mucosal exposure to carcinogens. We searched for histologic evidence of deposition of iron, a well-recognized carcinogen, in the fallopian tubes in 196 women with advanced-stage high-grade pelvic serous carcinomas in comparison with 370 controls. Tubal hemosiderin and/or pseudoxanthoma cells were found in 20% of the serous carcinoma cases, and an iron stain was positive in 30% of a sample of pigment-negative cases. Controls displayed pigment in 5% (P<0.001). In both cases and controls, pigment was significantly more frequently present in women with endometriosis as compared with those without. We conclude that tubal mucosal iron is present in a significant proportion of women with advanced-stage high-grade pelvic serous carcinoma. As a carcinogen, iron may play a role in the pathogenesis of these tumors. As compared with the incessant ovulation hypothesis, the recently proposed "incessant menstruation hypothesis" may be a better explanation of the well-recognized association of ovarian carcinoma with the length of the reproductive life uninterrupted by pregnancy.

Origin and Pathogenesis of Pelvic (Ovarian, Tubal, and Primary Peritoneal) Serous Carcinoma

A new paradigm for the pathogenesis of female pelvic cancer helps explain persistent problems in describing the development and diverse morphology of these neoplasms. This paradigm incorporates recent advances in the molecular pathogenesis of epithelial ovarian cancer (EOC) with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies gave rise to a dualistic model that divides the various histologic types of EOCs into two broad categories designated type I and type II. Because serous carcinomas are the most common EOC and account for the vast majority of deaths, they form the subject of this review. Recent studies indicate that the precursor of ovarian high-grade serous carcinoma appears to develop from an occult intraepithelial carcinoma in the fimbria of the fallopian tube and involves the ovary secondarily. Another possible mechanism is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs, causing the development of cortical inclusion cysts. The dualistic model serves as a framework for the study of ovarian cancer and can help investigators organize this complex group of neoplasms. It also facilitates the development of novel approaches to prevention, screening, and treatment of this devastating disease.

Fallopian Tube Intraluminal Tumor Spread From Noninvasive Precursor Lesions

Pelvic serous carcinoma is usually advanced stage at diagnosis, indicating that abdominal spread occurs early in carcinogenesis. Recent discovery of a precursor sequence in the fallopian tube, culminating in serous tubal intraepithelial carcinoma (STIC), provides an opportunity to study early disease events. This study aims to explore novel metastatic routes in STICs. A BRCA1 mutation carrier (patient A) who presented with a STIC and tubal intraluminal shedding of tumor cells upon prophylactic bilateral salpingo-oophorectomy (PBSO) instigated scrutiny of an additional 23 women who underwent a PBSO and 40 patients with pelvic serous carcinoma involving the tubes. Complete serial sectioning of tubes and ovaries of patient A did not reveal invasive carcinoma, but subsequent staging surgery showed disseminated abdominal disease. STIC, intraluminal tumor cells, and abdominal metastases displayed an identical immunohistochemical profile (p53/WT1/PAX8/PAX2) and TP53 mutation. In 16 serous carcinoma patients (40%) tubal intraluminal tumor cells were found, compared with none in the PBSO group. This is the first description of a STIC, which plausibly metastasized without the presence of invasion through intraluminal shedding of malignant surface epithelial cells in the tube and subsequently spread throughout the peritoneal cavity. These findings warrant a reconsideration of the malignant potential of STICs and indicate that intraluminal shedding could be a risk factor for early intraperitoneal metastasis. Although rare in the absence of invasive cancer, we show that intraluminal shedding of tumor cells in the fallopian tubes from serous carcinoma cases are common and a likely route of abdominal spread.

Do Deeper Sections Increase the Frequency of Detection of Serous Tubal Intraepithelial Carcinoma (STIC) in the “Sectioning and Extensively Examining the FIMbriated End” (SEE-FIM) Protocol?

Studies have suggested serous tubal intraepithelial carcinoma (STIC) of the fallopian tube to be a putative precursor to ovarian and peritoneal serous carcinoma. It has been recommended that resected fallopian tube specimens should be rigorously examined for STIC, especially in women at high risk of serous carcinoma, such as those with BRCA mutations or with a strong family history. The SEE-FIM protocol allows for the greatest surface area of the tube to be histologically assessed. There have been suggestions that multiple deeper sections should be examined if the initial hematoxylin and eosin (H&E) sections are negative; however, whether this identifies more cases of STIC has not rigorously examined. We examined deeper sections from 56 cases of pelvic carcinoma in which the initial H&E sections of the fallopian tubes were negative for STIC. All initial and deeper sections underwent consensus review by panel of experts in gynecologic pathology. These cases are part of a larger study in which we had examined 300 consecutive bilateral salpingectomies using the SEE-FIM protocol and a single-H&E section per block and had identified 68 cases of pelvic serous carcinoma, of which 12 were associated with STIC. We calculated the sensitivity of a single-H&E section to detect STIC, as compared with examination of multiple deeper sections, and reevaluated the clinicopathologic data of the parent study in light of the additional cases of STIC. In the 56 cases initially negative for STIC, 4 cases of STIC were identified after examination of multiple deeper sections of the fallopian tubes. The single-H&E section SEE-FIM approach therefore detected only 75% (95% confidence interval, 51%-90%) of STIC that was present. Three of these new cases were associated with primary ovarian serous carcinoma and 1 with primary peritoneal serous carcinoma. All 3 new cases associated with ovarian carcinoma were noted in women without neoadjuvant chemotherapy. In considering the data from the parent study, we calculated a statistically significant lower incidence of STIC in women with ovarian serous carcinoma who received neoadjuvant chemotherapy as compared with those who did not (P=0.042). Our study demonstrated that additional cases of STIC can be detected if deeper sections are examined. These additional cases also highlighted a statistically significant difference in the incidence of STIC associated with ovarian serous carcinoma who received neoadjuvant chemotherapy relative to those who did not. Consideration to this should be given in future studies of the prevalence of STIC and to routine examination of salpingectomy specimens from women at high risk for pelvic serous carcinoma.

Gynäkopathologie-Update

Recent years have witnessed significant achievements in light microscopic, immunohistochemical and molecular diagnostics in gynecopathology. In this article four topics will be discussed as examples. The squamous precancerous and carcinomatous lesions of the female anogenital tract and the cervix are caused by a transforming high risk human papillomavirus (HPV) infection. No differences in morphological findings can be found between the different locations. In contrast to the current WHO classification a new categorization into low grade and high grade precancerous lesions is suggested. Only some cervical adenocarcinomas are related to high risk HPV infection. Nevertheless, some of these unusual variants demonstrate p16 overexpression. Uterine leiomyosarcomas are clinically aggressive neoplasms independent of the histological grade and in most cases curative treatment is not feasible. It is most important to distinguish leiomyosarcoma from those leiomyoma variants which mimic uterine leiomyosarcoma. Pelvic and ovarian serous carcinomas can be separated into low grade and high grade types which differ significantly in formal pathogenesis, molecular features and pathomorphological findings. Significant differences are also obvious in clinical behavior and response to chemotherapy regimens.

Mucinous adenocarcinoma developed from human fallopian tube epithelial cells through defined genetic modifications

Recent studies have suggested that some ovarian and pelvic serous carcinomas could originate from the fimbriated end of the distal fallopian tube. To test this hypothesis, we immortalized a normal human fallopian tube epithelial (FTE) cell line by using retrovirus-mediated overexpression of the early region of the SV40 T/t antigens and the human telomerase reverse transcriptase subunit (hTERT). These immortalized FTEs were then transformed by ectopic expression of oncogenic human HRASV12. Tumorigenicity of the immortalized and/or transformed cells was subsequently tested by anchorage-independence growth assay and inoculation into nude mice via subcutaneous and intraperitoneal injection. As expected, the HRASV12-transformed FTEs produced tumors through both subcutaneous and intraperitoneal injections, whereas no tumor growth was observed in immortalized FTEs. Unexpectedly, histopathological examination of tumors resulting from subcutaneous as well as intraperitoneal injections revealed largely poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma. The tumor implants invaded extensively to the liver, colon, spleen, omentum, adrenal gland and renal capsule. Immunohistochemical staining of tumor cells showed positive staining for the epithelial cell markers cytokeratin AE1/AE3 and Müllerian lineage marker PAX8. Our study demonstrates that FTEs can generate poorly differentiated mucinous adenocarcinoma mixed with undifferentiated carcinoma through genetic modifications. Thus, we provide the first experimental evidence that fimbrial epithelial cells of the fallopian tube could be a potential source of ovarian mucinous adenocarcinoma.

Abstract 3292: A genetically engineered mouse model for high grade serous “ovarian” carcinoma arising in the fallopian tube

Abstract Ovarian cancer is the most lethal gynecologic malignancy because the vast majority of cases are detected in late stage, a finding that has thwarted attempts to understand the pathogenesis and cell-of-origin of this disease. The traditional view of epithelial ovarian pathogenesis asserts that all tumor subtypes share a common origin in the ovarian surface epithelium (OSE). There is robust data to support the OSE as the site of origin for many ovarian tumors, including low-grade carcinomas and borderline tumors. However, the pathogenesis of high-grade serous ovarian carcinoma, the most common type of ovarian cancer, continued to defy explanation by the OSE model. More recent studies suggested that the fallopian tube epithelium (FTE), rather than the OSE, may be the site-of-origin for a majority of pelvic serous carcinomas (PSC, defined as ovarian, peritoneal and tubal high grade serous carcinomas). We show here that the FTE can be site of origin for PSC by genetically engineering a mouse model that specifically targets the FT secretory cell with defined genetic alterations that are characteristic of human PSC. These mice develop tubal intraepithelial serous carcinomas, a precursor to PSC, that are morphologically and immunophenotypically similar to the lesions described in human patients. Furthermore, these intraepithelial lesions progress to widespread peritoneal disease that recapitulates the presentation of high-grade PSC in women. The tumors express common serous markers such as P53, αH2A.X, PAX8 and CA-125. Taken together our model is the first fully genetically engineered mouse model that truly recapitulates human serous carcinoma pathogenesis. Our model serves as proof-of-concept that the FTE can be site-of-origin to PSC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3292. doi:1538-7445.AM2012-3292

Ovarian serous carcinoma: recent concepts on its origin and carcinogenesis

Recent morphologic and molecular genetic studies have led to a paradigm shift in our conceptualization of the carcinogenesis and histogenesis of pelvic (non-uterine) serous carcinomas. It appears that both low-grade and high-grade pelvic serous carcinomas that have traditionally been classified as ovarian in origin, actually originate, at least in a significant subset, from the distal fallopian tube. Clonal expansions of the tubal secretory cell probably give rise to serous carcinomas, and the degree of ciliated conversion is a function of the degree to which the genetic hits deregulate normal differentiation. In this article, the authors review the evidentiary basis for aforementioned paradigm shift, as well as its potential clinical implications.

Fallopian tube metastases of non‐gynaecological origin: a series of 20 cases emphasizing patterns of involvement including intra‐epithelial spread

To determine the frequency and distribution of Fallopian tube involvement in patients with ovarian metastases of non-gynaecological origin. All Fallopian tube tissue was processed for histological examination in a consecutive series of 31 patients with ovarian metastases of non-gynaecological origin. The most common primary sites were appendix (n = 10) colon (n = 7), stomach (n = 6) and breast (n = 4). Twenty cases (65%) showed at least one type of tubal spread. Mural involvement was most common (14 cases) but serosal, intra-vascular, intra-epithelial and intra-lumenal spread were also identified in 12, 9, 8 and 11 cases respectively. Intra-epithelial involvement was restricted to the fimbrial epithelium and mimicked tubal carcinoma in situ (CIS) architecturally. Pagetoid invasion was noted in two of the cases. The Fallopian tubes are commonly involved in patients who have neoplasms metastatic to the ovaries. Metastases may show a CIS-like pattern of intra-epithelial spread and therefore small serous CIS-type lesions may not represent proof of tubal tumour origin in patients who have high-stage pelvic serous carcinomas. The frequency of intra-lumenal tumour cells supports transtubal spread as a likely mechanism for mucosal involvement by metastatic tumours involving the lower genital tract.

Frequency of Serous Tubal Intraepithelial Carcinoma in Various Gynecologic Malignancies

Serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. We hypothesized that, if this is the case, the frequency of STIC should be substantially lower in endometrial serous carcinomas, in nonserous gynecologic malignancies, and in benign gynecologic neoplasms than in ovarian or peritoneal serous carcinomas. From 2007 to 2009 the fallopian tubes of 342 consecutive gynecologic cases were entirely submitted for histology using the Sectioning and Extensively Examining the FIMbriated end protocol. This study included 300 of these cases (277 TAH-BSO, 23 BSO) after exclusion. The hematoxylin and eosin-stained slides from the fallopian tubes were independently reviewed by 2 gynecologic pathologists who were blinded to all other findings; disagreements were resolved by a third pathologist. Among 46 cases of ovarian malignancies, STIC was identified in 6 (18.8%) of 32 cases of serous carcinoma, but not in any other subtype. Similarly, STIC coexisted in 4 (14.3%) of 28 cases of endometrial serous carcinoma; however, no STIC was identified in any of the 74 cases of nonserous endometrial malignancies. STIC was identified in 2 (28.6%) of 7 cases of peritoneal serous carcinoma. No STIC was identified among 15 nongynecologic malignancies, 90 cases of benign conditions, and 27 cases of other conditions including 4 cases of cervical adenocarcinoma in situ and high-grade cervical intraepithelial lesions, 8 cases of endometrial atypical complex hyperplasias, and 15 cases of ovarian borderline tumors. In conclusion, the fallopian tube may be the origin of some pelvic serous carcinomas. Other possibilities that may explain the origin of pelvic high-grade serous carcinoma are discussed. Given that STIC coexisted with 14% of endometrial serous carcinomas, a more unifying theory may be that gynecologic serous carcinomas and STIC are multifocal lesions.

Fallopian Tube as Main Source for Ovarian and Pelvic (Non-Endometrial)Serous Carcinomas

Fallopian Tube as Main Source for Ovarian and Pelvic (Non-Endometrial)Serous Carcinomas

Trompe de Fallope : le côté obscur de la carcinogenèse pelvienne

Ovarian carcinomas are a heterogeneous group of lesions, among which serous histologic subtype is the most frequent. Ovarian and peritoneal serous carcinomas are subdivided into low- and high-grade tumors. Low-grade carcinomas derive from serous tumors of low malignant potentiel, while high-grade carcinomas were thought to derive de novo from ovarian surface epithelium. Studies from prophylactic salpingo-oophorectomy in women with BRCA mutations revealed a precursor to pelvic serous carcinomas that originates in the distal fallopian tube, called STIC (serous tubal intraepithelial carcinoma). This review reports new findings on serous carcinogenesis in the tube (SCAT). It brings an explanation in French on different terminologies used in the English literature these last years such as SCOUT (secretory cell outgrowth), p53 signature, TILT (tubal intraepithelial lesion in transition), STIC and SCAT and on the macroscopic protocol of Brigham and Women's Hospital of annexectomies specially in the setting of BRCA mutation, the SEE-FIM (sectioning and extensively examining the fimbriated end of the fallopian tube).

Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas

Background Most high-grade pelvic serous carcinomas (HGPSCs) arise from fallopian tube epithelium (FTE). To date, few markers have been shown to characterize FTE transformation. Stathmin 1 (STMN1) is a candidate oncogene whose activity is influenced by p53, p27Kip1 (p27), and PI3K/Akt pathway activation. As a microtubule destabilizing protein, STMN1 regulates cytoskeletal dynamics, cell cycle progression, mitosis, and cell migration. This study examines the expression of STMN1 and its negative regulator p27 along the morphologic continuum from normal FTE to invasive carcinoma. Methods STMN1 and p27 expression were examined by immunohistochemistry (IHC) in benign ( n = 12) and malignant ( n = 13) fallopian tubes containing normal epithelium, morphologically benign putative precursor lesions (“p53 signatures”), potential transitional precursor lesions (“proliferative p53 signatures”), tubal intraepithelial carcinoma (TIC), and/or invasive serous carcinoma. STMN1 expression was further assessed in 131 late-stage HGPSCs diagnosed as primary ovarian and in 6 ovarian cancer cell lines by IHC and Western blot, respectively. Results STMN1 expression was absent in benign FTE and infrequently detected in p53 signatures. However, it was weakly expressed in proliferative p53 signatures and robustly induced upon progression to TIC and invasive carcinoma, typically accompanied by decreased p27 levels. STMN1 was expressed in > 80% of high-grade serous ovarian carcinomas and cell lines. Conclusions STMN1 is a novel marker of early serous carcinoma that may play a role in FTE tumor initiation. Our data are consistent with a model by which STMN1 overexpression, resulting from loss of p27-mediated regulation, may potentiate aberrant cell proliferation, migration, and/or loss of polarity during early tumorigenesis.