Selection of Representative Histologic Slides in Interobserver Reproducibility Studies: Insights from Expert Review for Ovarian Carcinoma Subtype Classification.

BACKGROUND: Observer studies in pathology often utilize a limited number of representative slides per case, selected and reported in a nonstandardized manner. Reference diagnoses are commonly assumed to be generalizable to all slides of a case. We examined these issues in the context of pathologist concordance for histologic subtype classification of ovarian carcinomas (OCs). MATERIALS AND METHODS: A cohort of 114 OCs consisting of 72 cases with a single representative slide (Group 1) and 42 cases with multiple representative slides (148 slides, 2-6 sections per case, Group 2) was independently reviewed by three experts in gynecologic pathology (case-based review). In a follow-up study, each individual slide was independently reviewed in a randomized order by the same pathologists (section-based review). RESULTS: Average interobserver concordance varied from 100% for Group 1 to 64.3% for Group 2 (86.8% across all cases). Across Group 2, 19 cases (45.2%) had at least one slide classified as a different subtype than the subtype assigned from case-based review, demonstrating the impact of intratumoral heterogeneity. Section-based concordance across individual sections from Group 2 was comparable to case-based concordance for those cases indicating diagnostic challenges at the individual section level. Findings demonstrate the increased diagnostic complexity of heterogeneous tumors that require multiple section sampling and its impact on pathologist performance. CONCLUSIONS: The proportion of cases with multiple representative slides in cohorts used in validation studies, such as those conducted to evaluate artificial intelligence/machine learning tools, can influence diagnostic performance, and if not accounted for, can cause disparities between research and real-world observations and between research studies. Case selection in validation studies should account for tumor heterogeneity to create balanced datasets in terms of diagnostic complexity.

Pathologist Concordance for Ovarian Carcinoma Subtype Classification and Identification of Relevant Histologic Features Using Microscope and Whole Slide Imaging.

CONTEXT.­: Despite several studies focusing on the validation of whole slide imaging (WSI) across organ systems or subspecialties, the use of WSI for specific primary diagnosis tasks has been underexamined. OBJECTIVE.­: To assess pathologist performance for the histologic subtyping of individual sections of ovarian carcinomas using a light microscope and WSI. DESIGN.­: A panel of 3 experienced gynecologic pathologists provided reference subtype diagnoses for 212 histologic sections from 109 ovarian carcinomas based on optical microscopy review. Two additional attending pathologists provided diagnoses and also identified the presence of a set of 8 histologic features important for ovarian tumor subtyping. Two experienced gynecologic pathologists and 2 fellows reviewed the corresponding WSI images for subtype classification and feature identification. RESULTS.­: Across pathologists specialized in gynecologic pathology, concordance with the reference diagnosis for the 5 major ovarian carcinoma subtypes was significantly higher for a pathologist reading on a microscope than each of 2 pathologists reading on WSI. Differences were primarily due to more frequent classification of mucinous carcinomas as endometrioid with WSI. Pathologists had generally low agreement in identifying histologic features important to ovarian tumor subtype classification with either an optical microscopy or WSI. This result suggests the need for refined histologic criteria for identifying such features. Interobserver agreement was particularly low for identifying intracytoplasmic mucin with WSI. Inconsistencies in evaluating nuclear atypia and mitoses with WSI were also observed. CONCLUSIONS.­: Further research is needed to specify the reasons for these diagnostic challenges and to inform users and manufacturers of WSI technology.

Lymphatic Invasion in the Fallopian Tube is a Late Event in the Progression of Pelvic Serous Carcinoma and Correlates With Distant Metastasis.

The majority of extrauterine high-grade serous carcinomas are believed to arise in the fallopian tube as serous tubal intraepithelial carcinomas. The primary mode of metastasis is intraperitoneal, and patients usually present with peritoneal carcinomatosis. Although the tubes have a rich lymphatic network, tubal lymphatic invasion is observed in only a minority of cases. Fallopian tube sections from 222 patients with advanced stage high-grade extrauterine serous carcinoma were reviewed and lymphatic invasion within the lamina propria and myosalpinx were assessed. Seventeen patients were FIGO stage II, 162 stage III, and 43 stage IV. Tubal lymphatic invasion was identified in 44 cases (19.7%). Among the cases with lymphatic invasion, nonfimbrial lamina propria, fimbrial lamina propria, and myosalpingeal lymphatic invasion were present in 23 (52%), 21 (48%), and 21 (48%), respectively. Among cases with lymphatic invasion, 16 (36%) were FIGO stage IV, while among cases without lymphatic invasion, 27 (15%) were stage IV (P=0.0014, χ). In summary, in women with advanced stage high-grade extrauterine serous carcinoma, lymphatic invasion in the fallopian tube is uncommon, and is more than twice as likely to be associated with distant metastases as compared with those without tubal lymphatic invasion.

Intratumoral Heterogeneity Accounts for Apparent Progression of Noninvasive Serous Tumors to Invasive Low-grade Serous Carcinoma: A Study of 30 Low-grade Serous Tumors of the Ovary in 18 Patients With Peritoneal Carcinomatosis.

Noninvasive ovarian low-grade serous tumors [atypical proliferative serous tumor (APST)/serous borderline tumor] appear to progress to invasive low-grade serous carcinoma (LGSC) at a low but regular rate. The underlying biology of this phenomenon is unknown. We studied 18 patients with 30 ovarian tumors (12 bilateral), including APST, noninvasive LGSC and invasive LGSC, who also had low-grade serous carcinomatosis. Tumors were evaluated for microinvasion (usual eosinophilic cell type), microinvasive carcinoma (<5 mm invasion of micropapillary nests), and overt carcinoma (≥5 mm invasion of micropapillary nests). Tumors were evaluated based on the original numerical order of sections under the hypothetical scenarios in which sampling was stopped at 1 section/cm and 2 sections/cm. Sampling based on 1 section/cm of greatest tumor dimension identified invasion of any type in 21 tumors (70%). Among these 21 tumors, 10 had microinvasive carcinoma, and 11 overt carcinoma. Sampling based on 2 sections/cm identified microinvasive carcinoma in 9 tumors and overt carcinoma in 14 tumors. With increased sampling from 1 to 2 sections/cm, the diagnosis in 3 tumors would have changed from microinvasive carcinoma to overt carcinoma, and in an additional 2 tumors from APST to APST with microinvasive carcinoma. Sampling based on >2 sections/cm changed the diagnosis in 1 additional case of APST with microinvasive carcinoma to overt carcinoma. These findings support that undetected (unsampled) occult invasion in the primary ovarian tumors is a likely explanation for some cases of apparent progression of noninvasive low-grade serous ovarian tumors to invasive LGSC. To minimize undetected occult invasion, consideration of sampling noninvasive low-grade ovarian serous tumors with at least 2 sections/cm of maximum tumor diameter may be warranted. The eosinophilic cell type of microinvasion, or microinvasive carcinoma, regardless of size, should prompt further sampling to identify overt carcinoma. The eosinophilic type of microinvasion was never seen alone in this cohort and by itself may be biologically insignificant.

Clinical Decision Support for Ovarian Carcinoma Subtype Classification: A Pilot Observer Study With Pathology Trainees.

CONTEXT.­: Clinical decision support (CDS) systems could assist less experienced pathologists with certain diagnostic tasks for which subspecialty training or extensive experience is typically needed. The effect of decision support on pathologist performance for such diagnostic tasks has not been examined. OBJECTIVE.­: To examine the impact of a CDS tool for the classification of ovarian carcinoma subtypes by pathology trainees in a pilot observer study using digital pathology. DESIGN.­: Histologic review on 90 whole slide images from 75 ovarian cancer patients was conducted by 6 pathology residents using: (1) unaided review of whole slide images, and (2) aided review, where in addition to whole slide images observers used a CDS tool that provided information about the presence of 8 histologic features important for subtype classification that were identified previously by an expert in gynecologic pathology. The reference standard of ovarian subtype consisted of majority consensus from a panel of 3 gynecologic pathology experts. RESULTS.­: Aided review improved pairwise concordance with the reference standard for 5 of 6 observers by 3.3% to 17.8% (for 2 observers, increase was statistically significant) and mean interobserver agreement by 9.2% (not statistically significant). Observers benefited the most when the CDS tool prompted them to look for missed histologic features that were definitive for a certain subtype. Observer performance varied widely across cases with unanimous and nonunanimous reference classification, supporting the need for balancing data sets in terms of case difficulty. CONCLUSIONS.­: Findings showed the potential of CDS systems to close the knowledge gap between pathologists for complex diagnostic tasks.

High-grade Pelvic Serous Carcinoma Within the Fallopian Tube Lumen: Real or Artifact?

Tumor cells are occasionally observed in the lumen in histologic sections of the fallopian tube from women with gynecologic cancer. There is some evidence that this finding may be important in endometrial cancer, but its significance is unknown in women with extrauterine pelvic serous carcinomas (tubo-ovarian high-grade serous carcinoma). Fallopian tube sections from 213 women with extrauterine pelvic serous carcinoma were reviewed, and luminal tumor cells were correlated with clinical and pathologic features. Intraluminal tumor cells were found in 84 patients (39%). The presence or absence of luminal tumor cells correlated significantly with serous tubal intraepithelial carcinoma (52% and 33%, respectively, P=0.004), tubal lymphatic invasion (32% and 12%, respectively, P=0.0002), and number of tube sections reviewed (6.6 and 4.9 for lumen-positive and lumen-negative cases, respectively, P=0.0056). There was no correlation with the presence of ascites, peritoneal cytopathologic findings, lymph node metastases, or FIGO stage. In the setting of pelvic serous carcinoma, a substantial portion of fallopian tube tissue is often distorted, fibrotic, and difficult to identify. Since the identification of luminal tumor cells, serous tubal intraepithelial carcinoma and tubal lymphatic invasion all depend on identification of fallopian tube tissue, these correlates with luminal tumor cells could be a result of a higher likelihood of their observation when tubal tissue can be more readily identified and may not necessarily reflect a biologically important phenomenon. It remains unclear whether and in what proportion this finding reflects an artifact of specimen handling.

Early and consistent overexpression of ADRM1 in ovarian high-grade serous carcinoma.

BACKGROUND: Ovarian carcinoma is highly dependent on the ubiquitin proteasome system (UPS), but its clinical response to treatment with the proteasome inhibitor bortezomib has been disappointing. This has driven exploration of alternate approaches to target the UPS in ovarian cancer. Recently, proteasome inhibitors targeting the 19S regulatory particle-associated RPN13 protein have been described, such as RA190. RPN13, which is encoded by ADRM1, facilitates the recognition by the proteasome of its polyubiquinated substrates. Inhibition of RPN13 produces a rapid, toxic accumulation of polyubiquitinated proteins in ovarian and other cancer cells, triggering apoptosis. Here, we sought to determine if RPN13 is available as a target in precursors of ovarian/fallopian tube cancer as well as all advanced cases, and the impact of increased ADRM1 gene copy number on sensitivity of ovarian cancer to RA190. METHODS: ADRM1 mRNA was quantified by RNAscope in situ hybridization and RPN13 protein detected by immunohistochemistry in high grade serous carcinoma (HGSC) of the ovary and serous tubal intraepithelial carcinoma (STIC). Amplification of ADRM1 and sensitivity to RA190 were determined in ovarian cancer cell lines. RESULTS: Here, we demonstrate that expression of ADRM1mRNA is significantly elevated in STIC and HGSC as compared to normal fallopian tube epithelium. ADRM1 mRNA and RPN13 were ubiquitously and robustly expressed in ovarian carcinoma tissue and cell lines. No correlation was found between ADRM1 amplification and sensitivity of ovarian cancer cell lines to RA190, but all were susceptible. CONCLUSIONS: RPN13 can potentially be targeted by RA190 in both in situ and metastatic ovarian carcinoma. Ovarian cancer cell lines are sensitive to RA190 regardless of whether the ADRM1 gene is amplified.

Ovarian Epithelial Inclusions With Mucinous Differentiation: A Clinicopathologic Study of 42 Cases.

Ovarian epithelial inclusions lined by mucinous epithelium are rare and of uncertain origin. Ovaries containing such inclusions were studied in 42 women. The inclusions were divided into 3 groups: serous epithelial lined with typical ciliated morphology but with distinct basophilic cytoplasmic mucin in some or all of the lining cells, those lined by typical mucinous epithelium, and those lined by a combination of typical mucinous epithelium and serous epithelium. The mean patient age was 61.5 years. Pure mucinous inclusions were found in 27 patients, serous-type inclusions with cytoplasmic mucin in 20, and mixed type in 10. All 3 types of inclusions were found in 1 patient. Two types of inclusions were found in 13. Four patients had associated mucinous neoplasms (1 mucinous cystadenoma, 1 atypical proliferative seromucinous tumor, and 2 seromucinous cystadenomas), and 11 patients (26%) had endometriosis. The fallopian tubes in 4 patients (9.5%) also displayed mucinous metaplasia; this was not significantly different from the 3.1% we found in our previously reported series of unselected tubes from the same population. These findings suggest that mucinous inclusions may arise as a direct metaplastic change in serous-type inclusions. Other possible origins of mucinous inclusions in the ovarian cortex include endometriosis and Brenner (transitional cell) nests. Whether such inclusions can be a source of mucinous ovarian neoplasms as are Brenner tumors and mature cystic teratomas is unknown and may warrant further investigation.

Non-Neoplastic Conditions of the Ovaries in Grossly Normal Adnexa: A Clinicopathologic Study of 403 Completely Embedded Cases.

Most non-neoplastic lesions of the ovaries have not been comprehensively examined in the contemporary literature. We evaluated completely embedded ovaries from 403 unselected, consecutive patients who had grossly normal adnexa. These included prophylactic specimens in high-risk women with BRCA mutations (38 women) and women with a personal history of breast cancer or a family history of breast and/or ovarian cancer (79 women). Transitional cell (Brenner) nests were found in 9.1%; 31% of these lesions were smaller than 1 mm, and 8 were solitary nests. Cortical granulomas were found in 20.5%, fatty metaplasia in 5.3%, mucinous metaplasia of surface epithelial inclusions in 5.5%, and smooth muscle stromal metaplasia in 2%. One or more types of stromal hyperplasia were found in 24.3%. Endometriosis was found in 22% of adnexa. There were no significant differences in the findings in high-risk women compared with non-high-risk except those attributable to age differences between the groups. These findings establish baseline frequencies for non-neoplastic ovarian lesions, and suggest that transitional cell nests are so common that they can be regarded as a normal finding.

Incidental Serous Tubal Intraepithelial Carcinoma and Non-Neoplastic Conditions of the Fallopian Tubes in Grossly Normal Adnexa: A Clinicopathologic Study of 388 Completely Embedded Cases.

Serous tubal intraepithelial carcinoma (STIC), the putative precursor of the majority of extrauterine high-grade serous carcinomas, has been reported in both high-risk women (those with a germline BRCA mutation, a personal history of breast carcinoma, and/or family history of breast or ovarian carcinoma) and average risk women from the general population. We reviewed grossly normal adnexal specimens from 388 consecutive, unselected women undergoing surgery, including those with germline BRCA mutation (37 patients), personal history of breast cancer or family history of breast/ovarian cancer (74 patients), endometrial cancer (175 patients), and a variety of other conditions (102 patients). Among 111 high-risk cases and 277 non-high-risk cases, 3 STICs were identified (0.8%), all in non-high-risk women (high risk vs. non-high risk: P=not significant). STIC was found in 2 women with nonserous endometrial carcinoma and 1 with complex atypical endometrial hyperplasia. Salpingoliths (mucosal calcifications), found in 9% of high-risk cases, and fimbrial adenofibromas in 9.9% of high-risk cases, were significantly more common in high-risk as compared with non-high-risk women (1.8% and 2.5%, respectively; P<0.007). Mucinous metaplasia was found in 3.1%, salpingitis isthmica nodosa in 3.4%, hemosiderin or pseudoxanthoma cells in 4.9%, and fibrous luminal nodules in 4.1%. None of these latter features differed significantly in the high-risk versus non-high-risk groups. These findings suggest a possible association between STIC and endometrial hyperplasia and carcinoma, and clarify the frequency of non-neoplastic tubal findings in grossly normal fallopian tubes.

Pseudoxanthomatous salpingitis as an ex vivo model of fallopian tube serous carcinogenesis: a clinicopathologic study of 49 cases.

Iron is a well-documented carcinogen based on both animal models and observational studies in humans. There are limited published data on pseudoxanthomatous salpingitis, an uncommon condition characterized by the accumulation of histiocytes containing iron and iron-related compounds-lipofuscin and hemosiderin-in the lamina propria of the fallopian tube. The clinical and pathologic features of 49 consecutive cases were evaluated. The mean patient age was 53. A history of endometriosis was found in 20%, infertility in 17%, and tubal ligation in 7%. Thirteen (27%) had endometrial cancer and 2 patients had prior radiation therapy for cervical carcinoma. Histologic evidence of endometriosis other than tubal pigment deposition was identified in 65%, and in the fallopian tubes in 35%. Pigment deposition was unilateral in 65% and multifocal or diffuse in 80%. Plasma cells, eosinophils, and neutrophils were present in the tubal lamina propria in 57%, 18%, and 24%, respectively. Hydrosalpinx was present in 51%. An iron stain was positive in pseudoxanthoma cells lacking hemosiderin in 14 of 18 cases (78%). By immunohistochemistry, 2 of 22 cases displayed p53 signatures. The Ki67 proliferation index was elevated (>10%) in 11 of 22 cases, with a mean index of 32% in those cases. An elevated proliferation index did not correlate with inflammation. In summary, these findings characterize the clinical and pathologic features of pseudoxanthomatous salpingitis and confirm its close association with endometriosis, occasional association with radiation therapy, and the presence of iron in the histiocytes. In view of the evolving paradigm shift implicating the fallopian tubal epithelium as the site of origin of high-grade extrauterine serous carcinoma, the presence of iron and iron-related compounds in the fallopian tube provides an opportunity to study the early events in high-grade serous carcinogenesis in a setting characterized by a well-documented carcinogen in close anatomic proximity to the putative epithelium of origin.

Serous tubal intraepithelial carcinoma localizes to the tubal-peritoneal junction: a pivotal clue to the site of origin of extrauterine high-grade serous carcinoma (ovarian cancer).

Recent data suggest that intraepithelial carcinoma of the fallopian tube [serous tubal intraepithelial carcinoma (STIC)] is the precursor of high-grade extrauterine serous carcinoma. A more specific location for the origin of this lesion is suggested by the recently described junction between the fallopian tubal epithelium and the peritoneum [tubal-peritoneal junction (TPJ)]. Fallopian tubes from 202 patients with advanced-stage high-grade extrauterine serous carcinoma or carcinosarcoma were evaluated histologically as were 124 prophylactic salpingo-oophorectomy specimens. These included 54 patients with BRCA or other high-risk mutation or a family history of BRCA mutation and 70 with a personal or family history of breast carcinoma. STIC was found in 81 of 202 patients with serous carcinoma (40.1%). STIC was present in 73 of 141 (52%) cases in which the fimbriae were present and in 62 of 100 (62%) cases in which the TPJ was present (P not significant). In comparison with these groups, when fimbriae and TPJ were absent, STIC was found in 8 of 61 (13%) cases (P<0.0001). None of the prophylactic specimens contained STIC. The mean size of STIC was 1.7 mm. In 32 cases (39.5%), the lesion was flat and in 49 (60.5%), papillary. The mean size of flat STICs was 0.8 mm as compared with 2.3 mm for papillary STICs (P=0.00005). STIC was identified in the same tissue fragment as the junction in 48 cases. The mean distance of STIC to the junction was 1.8 mm. In 11 cases, STIC was flanked by peritoneal mesothelium on one side and tubal epithelium on the opposite side. In 51 patients, the mean distance of invasive carcinoma from the TPJ was 1.8 mm. This distance was 1.9 mm when STIC was present (37 cases) in comparison with 1.5 mm when STIC was absent (14 cases) (P not significant). In 27 of 42 cases (64%), STIC was contiguous with invasive carcinoma. Lamina propria invasion was present in 71% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P<0.0001). Myosalpingeal invasion was present in 40% of cases in which STIC was present as compared with 26% of cases in which STIC was absent (P not significant). It is concluded that serous tubal intraepithelial carcinoma occurs at and in the immediate vicinity of the TPJ. In combination with the findings that STICs are present in a majority of cases when the TPJ is present, that flat STICs are smaller than papillary STICs, and that lamina propria invasion is more frequent in the presence of STIC, these data support STIC as the precursor of extrauterine high-grade serous carcinoma, they provide important clues to the site of origin of high-grade serous carcinoma (ovarian cancer), and can guide further research.

Distribution and case-fatality ratios by cell-type for ovarian carcinomas: a 22-year series of 562 patients with uniform current histological classification.

BACKGROUND: Ovarian carcinoma is comprised of several different cell types reflecting different clinicopathologic features. Pathologic criteria for distinguishing cell types have evolved, and therefore non-contemporary literature on ovarian cancer may have limited current relevance. A new dualistic model of pathogenesis that distinguishes type I (endometrioid, mucinous, clear cell and low grade serous carcinomas) from type II (high grade serous carcinomas and carcinosarcomas) tumors has become widely accepted. METHODS: A cohort of 562 patients with invasive ovarian carcinoma from a large community hospital practice was reviewed. Cell type, FIGO stage, mortality and interpathologist diagnostic reproducibility were analyzed. RESULTS: Advanced stage ovarian carcinomas were type II in 86% of cases while low stage tumors were most often type I. Only 1.7% of type II tumors were confirmed to be stage I with comprehensive surgical staging. Type II tumors accounted for 85% of deaths, and clear cell carcinomas, 5% of deaths. Cell type-specific case-fatality ratios for type II tumors were 62% and 79% for high grade serous carcinoma and carcinosarcoma, respectively. For type I tumors, case-fatality ratios were 38%, 36%, 27% and 13% for low grade serous, clear cell, endometrioid and mucinous carcinomas, respectively. The kappa value for diagnostic reproducibility among 3 gynecologic pathologists was 0.83. CONCLUSIONS: Current diagnostic criteria confirm that high grade serous carcinoma and carcinosarcoma account for the vast majority (85%) of ovarian cancer deaths. Cell type designation is highly reproducible among gynecologic pathologists. Type II tumors are rarely stage I (<2%) when comprehensively staged by a gynecologic oncologist.

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.

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.

Transitional cell carcinoma of the ovary is related to high-grade serous carcinoma and is distinct from malignant brenner tumor.

Transitional cell tumors of the ovary include benign, borderline (atypically proliferating), and malignant Brenner tumors (BT), as well as transitional cell carcinoma (TCC). Some TCCs could conceivably be examples of malignant BT where the benign component has been overgrown. Our objectives were: (A) compare the immunophenotypes of BT and TCC and (B) examine a large cohort of ovarian carcinomas for cases with the immunophenotype of BT and transitional features but lacking a benign BT component. Seven BTs (3 benign, 3 borderline/atypically proliferating, 1 malignant) and 7 TCCs were stained for WT1, ER, p53, and p16(INK4a). The BTs were negative for WT1, p53 overexpression, ER (except for weak positivity in 1), and negative or weakly positive for p16(INK4a). In contrast, the TCCs stained as follows: 4/6 positive for WT1, 5/7 positive for ER, 2/7 strongly positive for p16(INK4a), and 6/7 showed abnormal p53, an immunophenotype resembling that of high-grade serous carcinoma. A database of 500 cases of ovarian carcinoma was searched and 116 showed an immunoprofile characteristic of BT: WT1 negative, ER negative, p16(INK4a) or weak positive, p53 negative (77 clear cell carcinoma, 14 endometrioid carcinoma, 12 mucinous carcinoma, 8 high-grade serous carcinoma). None of these tumors showed transitional features on review, indicating that if examples of malignant BT where there has been overgrowth of benign BT components exist, they are rare. Our results suggest that BT and TCC are unrelated, and should not be combined for classification purposes.

Validation of an algorithm for the diagnosis of serous tubal intraepithelial carcinoma.

It has been reported that the diagnosis of serous tubal intraepithelial carcinoma (STIC) is not optimally reproducible on the basis of only histologic assessment. Recently, we reported that the use of a diagnostic algorithm that combines histologic features and coordinate immunohistochemical expression of p53 and Ki-67 substantially improves reproducibility of the diagnosis. The goal of the current study was to validate this algorithm by testing a group of 6 gynecologic pathologists who had not participated in the development of the algorithm (3 faculty and 3 fellows) but who were trained in its use by referring to a website designed for the purpose. They then reviewed a set of microscopic slides, which contained 41 mucosal lesions of the fallopian tube. Overall consensus (≥4 of 6 pathologists) for the 4 categories of STIC, serous tubal intraepithelial lesion (our atypical intermediate category), p53 signature, and normal/reactive was achieved in 76% of the lesions, with no consensus in 24%. Combining diagnoses into 2 categories (STIC versus non-STIC) resulted in an overall consensus of 93% and no consensus in 7%. The κ value for STIC versus non-STIC among all 6 observers was also high at 0.67 and did not significantly differ, whether for faculty (κ=0.66) or fellows (κ=0.60). These findings confirm the reproducibility of this algorithm by a group of gynecologic pathologists who were trained on a website for that purpose. Accordingly, we recommend its use in research studies. Before applying it to routine clinical practice, the algorithm should be evaluated by general surgical pathologists in a community setting.

Survival rates for international federation of gynecology and obstetrics stage III ovarian carcinoma by cell type: a study of 262 unselected patients with uniform pathologic review.

OBJECTIVE: Published data are conflicting on the influence of cell type on prognosis in ovarian cancer. The recent separation of low-grade serous carcinoma as a distinctive cell type of ovarian cancer with an indolent behavior, in retrospect, suggests that survival in studies that have not separated this group may be inaccurate. METHODS: An unselected series of 262 International Federation of Gynecology and Obstetrics stage III ovarian carcinomas was studied. Diagnostic classification of each tumor was made with particular attention to recent refinements in cell-type classification. Survival curves were constructed according to Kaplan-Meier and compared with the log-rank test. RESULTS: The 5-year survival for 207 high-grade serous carcinomas was 40%, as compared with 71% for 18 patients with low-grade serous carcinoma (P = 0.0113). Low-grade serous carcinoma was significantly more likely to be optimally debulked (P = 0.0039) and significantly less likely to be substage IIIC (P < 0.0001). The survival for carcinosarcoma was significantly inferior to all serous carcinomas (P = 0.0322). The significance of this latter comparison was lost when carcinosarcomas were compared with only high-grade serous carcinoma (P > 0.05). CONCLUSIONS: Low-grade serous carcinoma has a significantly better prognosis than high-grade serous carcinoma and also differs with regard to substage distribution and proportion of patients optimally debulked. Because of its excellent prognosis, failure to separate low-grade serous carcinomas, notwithstanding its infrequent occurrence, can change the results of survival analyses that do not make this separation.

Mucinous metaplasia of the fallopian tube: a diagnostic pitfall mimicking metastasis.

Interpretation of the mucinous change in the fallopian tubes has been difficult because several reports consider this mucinous change as a metastasis from a mucinous tumor. To clarify this issue, we decided to retrospectively review salpingectomies from 3 institutions looking for mucinous change in the fallopian tubes and documented the clinical history of these patients. Twenty-three cases of fallopian tubes with mucinous changes were found, including 11 patients without evidence of malignancy, 4 patients with mucinous ovarian tumors, 5 patients with nonmucinous gynecologic tumors, 2 patients with mucinous appendiceal neoplasm, and 1 patient with colon carcinoma. As mucinous changes are seen in several patients who do not have a malignant tumor, we believe that these changes represent a metaplastic process. The mucinous changes are frequently seen with chronic inflammation and/or other metaplastic changes and without cytologic evidence of malignancy.