Cystic Walthard Nests of the Peritoneal Diaphragm: A Report of 3 Cases of a Common Process at an Unusual Site and Occurring in Patients With Endometriosis.

Nests of cells resembling urothelium, eponymously named "Walthard nests," are well-known incidental findings over the fallopian tube and occasionally undergo cystification resulting in clinical detection and surgical removal. Only rarely is this process noted outside the pelvic peritoneum. Herein we describe cystic Walthard nests occurring in the diaphragmatic peritoneum of three patients (aged 25, 36, and 39 yr) undergoing surgical evaluation for presumed endometriosis. In each case, small pearly white nodules on the diaphragmatic peritoneum were noted and biopsied. Microscopic examination revealed cystic spaces filled with pale eosinophilic secretion. The cysts were lined mostly by stratified transitional cells with pale eosinophilic to focally clear cytoplasm. Umbrella cells were focally present in all cases, and 1 showed focal glandular differentiation resembling cystitis glandularis. In areas, the epithelial cells became flattened and attenuated and nuclei were bland. By immunohistochemistry, all were positive for GATA3, cytokeratin 7, and BEREP4 and negative for cytokeratin 20, estrogen receptor, and WT-1. Walthard nests can rarely occur outside the pelvic peritoneum where they may be noted incidentally during surgery for other indications. This should be readily distinguished pathologically from other peritoneal lesions but lack of significant prior comment of them occurring on the diaphragm may result in diagnostic difficulty.

Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma.

Regional lymph node metastasis is a well-established negative predictive prognostic factor in endometrial carcinomas. Recently, our approach to the pathologic evaluation of lymph nodes in endometrial carcinomas has changed, mainly due to the utilization of immunohistochemical stains in the assessment of sentinel lymph nodes, which may result in the identification of previously unrecognized disease [particularly isolated tumor cells (ITCs)] on hematoxylin and eosin stained slides. However, the clinical significance of this finding is not entirely clear. Following the experience in other organs systems such as breast, the Eight Edition of the American Joint Committee on Cancer's Cancer Staging Manual has recommended utilizing the N0(i+) terminology for this finding, without impact in the final tumor stage. We performed a comparative retrospective multi-institutional survival analysis of 247 patients with endometrial carcinoma with regional lymph node metastasis of various sizes identified in nonsentinel lymphadenectomy, demonstrating that the cumulative survival of patients with isolated tumor cells in regional lymph nodes is not statistically different from patient with negative lymph nodes, and is statistically different from those with lymph nodes showing micrometastasis or larger metastatic deposits. In addition, we evaluated the prognostic implications of the number of involved regional lymph nodes, demonstrating a worsening prognosis as the number of involved lymph nodes increases from none to one, and from one to more than one. Our data suggests that regional lymph nodes with isolated tumor cells in patients with endometrial carcinoma should likely be considered, for staging purposes, as negative lymph nodes, simply indicating their presence with the (i+) terminology.

Preventing Ovarian Cancer through early Excision of Tubes and late Ovarian Removal (PROTECTOR): protocol for a prospective non-randomised multi-center trial.

BACKGROUND: Risk-reducing salpingo-oophorectomy is the 'gold standard' for preventing tubo-ovarian cancer in women at increased risk. However, when performed in pre-menopausal women, it results in premature menopause and associated detrimental health consequences. This, together with acceptance of the central role of the fallopian tube in etiopathogenesis of high-grade serous carcinoma, by far the most common type of tubo-ovarian cancer, has led to risk-reducing early salpingectomy with delayed oophorectomy being proposed as a two-step surgical alternative for pre-menopausal women declining/delaying oophorectomy. PRIMARY OBJECTIVE: To evaluate the impact on sexual function of risk-reducing early salpingectomy, within a two-step, risk-reducing, early salpingectomy with delayed oophorectomy tubo-ovarian cancer prevention strategy in pre-menopausal women at increased risk of tubo-ovarian cancer. STUDY HYPOTHESIS: Risk-reducing early salpingectomy is non-inferior for sexual and endocrine function compared with controls; risk-reducing early salpingectomy is superior for sexual/endocrine function, non-inferior for quality-of-life, and equivalent in satisfaction to the standard risk-reducing salpingo-oophorectomy. TRIAL DESIGN: Multi-center, observational cohort trial with three arms: risk-reducing early salpingectomy with delayed oophorectomy; risk-reducing salpingo-oophorectomy; controls (no surgery). Consenting individuals undergo an ultrasound, serum CA125, and follicle-stimulating hormone measurements and provide information on medical history, family history, quality-of-life, sexual function, cancer worry, psychological well-being, and satisfaction/regret. Follow-up by questionnaire takes place annually for 3 years. Women receiving risk-reducing early salpingectomy can undergo delayed oophorectomy at a later date of their choosing, or definitely by the menopause. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria: pre-menopausal; aged >30 years; at increased risk of tubo-ovarian cancer (mutation carriers or on the basis of a strong family history); completed their family (for surgical arms). EXCLUSION CRITERIA: post-menopausal; previous bilateral salpingectomy or bilateral oophorectomy; pregnancy; previous tubal/ovarian/peritoneal malignancy; <12 months after cancer treatment; clinical suspicion of tubal/ovarian cancer at baseline. PRIMARY ENDPOINT: Sexual function measured by validated questionnaires. SAMPLE SIZE: 1000 (333 per arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: It is estimated recruitment will be completed by 2023 and results published by 2027. TRIAL REGISTRATION NUMBER: ISRCTN registry: 25 173 360 (https://doi.org/10.1186/ISRCTN25173360).

Female Genital Tract Melanoma: 10 Years of Experience at a Single Tertiary Center.

OBJECTIVE: Malignant melanoma of the female genital tract is a rare disease with poor prognosis, with controversies remaining in its staging and management. In this study, we investigate clinical, pathological, and outcome data for patients referred to a tertiary cancer center with female genital tract melanoma over a decade. METHODS: Patients were retrospectively identified using a search of pathology reports to identify all cases of female genital tract melanoma from 2007 to 2019. Electronic patient records were used to record clinical information. Histopathology specimens were reviewed by a gynecological and dermatological pathology specialist. RESULTS: We identified 30 cases of genital tract melanoma, of which 19 were vulvar, 10 were vaginal, and 1 cervical. Overall survival at 1, 3, and 5 years was found to be 80%, 60%, and 57%. Patients who died were not significantly older at presentation than patients who survived (62 y vs 69 y, p = .215). No association was found between mortality and microscopic ulceration, lymphovascular invasion, pigmentation, resection margins, or radical versus local surgery.Nonvulvar lesions were significantly associated with mortality compared with vulvar lesions (p = .0018), despite similar age and Breslow thickness. Five patients were diagnosed at in situ stage, all of these were vulvar. Even after excluding these melanomas in situ, nonvulvar melanomas still had a significantly worse mortality rate (p = .048). A higher proportion of nonvulvar lesions than vulvar lesions displayed loss of pigmentation (p = .026). CONCLUSIONS: Nonvulvar genital tract melanomas carry a significantly worse prognosis. Survival was not related to resection margins, supporting the use of more conservative surgical margins.

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5-lipoxygenase expression in aggressive subtypes of endometrial cancer.

Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography-tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample-matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX-2-mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE2 /PGF2α inactivation via 15-hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5-lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5-hydroxyeicosatetraenoic acid (5-HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX-1 nor COX-2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression-free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor.

OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.

Disease Distribution in Low-stage Tubo-ovarian High-grade Serous Carcinoma (HGSC): Implications for Assigning Primary Site and FIGO Stage.

The latest FIGO and TNM (eighth edition) staging systems for ovarian, tubal, and peritoneal neoplasms require primary site assignment as tubal/ovarian/peritoneal, but provide no guidance or criteria. Fewer than 10% of extrauterine high-grade serous carcinoma (HGSC) cases present at low stage (stage I/II). Low-stage cases offer a unique opportunity to understand the pattern of disease early in its evolution prior to wide dissemination and provide valuable evidence for guiding specimen handling and tumor staging. This study aimed to examine disease distribution in low-stage tubo-ovarian HGSC. Anonymized pathology reports of 152 stage I/II extrauterine HGSCs from 6 teaching hospitals were analyzed: group 1 (n=67) comprised cases with complete tubal examination by Sectioning and Extensively Examining the FIMbriated end of the tube (SEE-FIM) and group 2 (n=85) consisted of cases without documentation of both tubes being fully examined by the SEE-FIM or a SEE-FIM-like protocol. The stage, site/pattern of involvement, site/size of largest tumor focus and laterality of tubal and ovarian involvement were recorded. Tubal mucosal involvement was present in 95% of optimally examined cases and many factors influenced detection of tubal disease. Bilateral involvement, suggestive of metastasis, was significantly more frequent in the ovaries (35%) than the tubes (9%) (P<0.0001, Fisher exact test). No case showed a complete absence of tubal/ovarian involvement, questioning the biological existence of primary peritoneal HGSC. Disease distribution in low-stage cases supports a tubal origin for most HGSCs. Detailed tubal sampling upstages some apparent stage I cases through detection of microscopic tubal involvement.

Characterization of Primary Cilia in Normal Fallopian Tube Epithelium and Serous Tubal Intraepithelial Carcinoma.

OBJECTIVES: The aim of this study was to investigate the distribution of primary cilia on secretory cells in normal fallopian tube (FT) and serous tubal intraepithelial carcinoma (STIC). METHODS: Fallopian tube tissue samples were obtained from 4 females undergoing prophylactic hysterectomies and 6 patients diagnosed with STIC. A mogp-TAg transgenic mouse STIC sample was also compared with a wild-type mouse FT sample. Serous tubal intraepithelial carcinoma was identified by hematoxylin and eosin staining and confirmed by positive Ki-67 and p53 immunohistochemical staining of tissue sections. We assessed the relative distribution of primary cilia on secretory cells and motile cilia on multiple ciliated cells by immunofluorescence and immunohistochemical staining. Ciliary function was assessed by immunofluorescence staining of specific ciliary marker proteins and responsiveness to Sonic Hedgehog signaling. RESULTS: Primary cilia are widespread on secretory cells in the ampulla, isthmus, and in particular, the fimbriae of human FT where they may appear to mediate ciliary-mediated Sonic Hedgehog signaling. A statistically significant reduction in the number of primary cilia on secretory cells was observed in human STIC samples compared with normal controls (P < 0.0002, Student t test), supported by similar findings in a mouse STIC sample. Immunohistochemical staining for dynein axonemal heavy chain 5 discriminated multiple motile cilia from primary cilia in human FT. CONCLUSIONS: Primary cilia are widespread on secretory cells in the ampulla, isthmus, and in particular, the fimbriae of the human FT but are significantly reduced in both human and mouse STIC samples. Immunohistochemical staining for ciliary proteins may have clinical utility for early detection of STIC.

The Fallopian Tube Origin and Primary Site Assignment in Extrauterine High-grade Serous Carcinoma: Findings of a Survey of Pathologists and Clinicians.

Accumulating recent evidence suggests that the majority of extrauterine high-grade serous carcinomas (HGSCs) do not arise from the ovary as historically accepted but from the distal, fimbrial end of the fallopian tube from a precursor known as serous tubal intraepithelial carcinoma. There has been variable acceptance of this evidence among pathologists and clinicians dealing with "ovarian" cancer and this has resulted in wide variation in the assignment of primary site between different institutions when HGSC involves >1 anatomic site. This has obvious implications for cancer epidemiology, registration, and entry into clinical trials. We undertook a survey of members of several national and international gynecologic pathology and clinical cancer societies with a view to ascertaining the degree of acceptance of the fallopian tube origin of extrauterine HGSC and to explore various aspects regarding site assignment, pathologic sampling, diagnosis, FIGO staging, and reporting of these neoplasms. The results indicate wide acceptance among both pathologists and clinicians of the fallopian tube theory of origin of HGSC (86% pathologists, 92% clinicians), although there is significant variation regarding the perceived importance of assigning a primary site given the limited prognostic and therapeutic significance. Interestingly, clinicians feel it is more important to assign a primary site than pathologists (71% vs. 49%). The survey also indicates widespread acceptance of recently proposed criteria for site assignment in extrauterine HGSC.

Adopting a Uniform Approach to Site Assignment in Tubo-Ovarian High-Grade Serous Carcinoma: The Time has Come.

There is currently sufficient evidence that nonuterine high-grade serous carcinoma (HGSC) originates in the fallopian tube in the majority of cases, but this is not uniformly reflected in our diagnostic terminology. This is because there remains wide variation in awareness and acceptance of this evidence, which conflicts with traditional views on origin. Accurate disease classification is fundamental to routine clinical practice and research, particularly at a time when exciting new approaches to therapy, early detection, and prevention are appearing on the horizon. We feel the time has come to minimize individual and institutional variations in practice, and agree on an evidence-based approach to uniform terminology and primary site assignment. In this paper we put forward a proposal for a unified approach based on published research evidence and discuss the reasons why it is vital to agree on a uniform protocol. We propose the term "Tubo-ovarian HGSC" in preference to "pelvic" or "Müllerian," as it accurately reflects the origin of this disease in the vast majority of cases, and is unambiguous, distinguishing it clearly from uterine serous carcinoma and ovarian low-grade serous carcinomas. A detailed protocol for primary site assignment is presented for different scenarios, which is easy to follow and has been developed with a view to promoting a uniform approach worldwide.

Assessment of a new system for primary site assignment in high-grade serous carcinoma of the fallopian tube, ovary, and peritoneum.

AIMS: The available evidence indicates that most non-uterine high-grade serous carcinomas (HGSCs) arise from the fallopian tube (FT), but approaches to primary site assignment have not evolved to reflect this. The aim of this study was to assess the application of recently proposed criteria for site assignment. METHODS AND RESULTS: One hundred and fifty-one HGSCs from four centres were reviewed retrospectively. Sixty-three of 80 (79%) chemonaive (CN) and 45 of 71 (68%) post-neoadjuvant chemotherapy (NACT) cases were assigned as FT primaries with the new criteria, whereas 58 of 80 (73%) and 45 of 71 (63%) were assigned as ovarian primaries with traditional criteria (P < 0.0001). Of 111 prospectively collected HGSCs, with consistent detailed fimbrial examination, 44 of 53 (83%) CN and 44 of 58 (76%) NACT cases were assigned as FT primaries. The reproducibility of site assignment was tested in a subset of 50 cases: all four reviewing pathologists agreed on the primary site in 48 of 50 (96%) cases, and three of four agreed in 49 of 50 (98%) cases. Of the 53 prospectively studied CN cases, bilateral ovarian involvement (62%) was significantly more frequent than bilateral tubal involvement (12%, P < 0.0001), further supporting a tubal origin and ovarian metastasis in most cases. CONCLUSIONS: With currently accepted protocols, the proposed guidelines are easy to apply and result in consistent site assignment in non-uterine HGSCs. Most cases of non-uterine HGSC were considered to be primary FT neoplasms.

Assignment of primary site in high-grade serous tubal, ovarian and peritoneal carcinoma: a proposal.

The revised FIGO 2013 staging for carcinomas of the ovary, fallopian tube and peritoneum has introduced a single system for tumours originating at these sites. The system requires pathologists to assign a primary site (ovary, tube or peritoneum), but does not provide guidance to aid this assignment. This is particularly problematic in cases of advanced-stage (stage II or greater) high-grade serous carcinoma (HGSC), where there is commonly involvement of two or more sites by tumour, and practice among pathologists in determining where a tumour has arisen varies widely. This has significant implications for recording of tumour incidence and mortality, data collection by cancer registries, and entry into clinical trials. We propose guidelines for assigning the primary site of HGSC based on careful macroscopic and histological assessment. The use of these guidelines, in conjunction with the new FIGO staging system, is intended to act as an impetus to promote debate and provide a uniform and consistent approach in assigning primary tumour site which will facilitate comparison of data between centres.

Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.

BACKGROUND: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3- CD56+ natural killer (NK) cells. METHODS: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5ß-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. RESULTS: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. CONCLUSIONS: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.

Data set for reporting of endometrial carcinomas: recommendations from the International Collaboration on Cancer Reporting (ICCR) between United Kingdom, United States, Canada, and Australasia.

The International Collaboration on Cancer Reporting is a quadripartite alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, and the Canadian Partnership Against Cancer. The International Collaboration on Cancer Reporting was formed with a view to reducing the global burden of cancer data set development and reduplication of the effort by different international institutions that commission, publish, and maintain standardized cancer-reporting data sets. The resultant standardization of cancer reporting would be expected to benefit not only those countries directly involved in the collaboration, but also others not in a position to develop their own data sets. The main objective of the International Collaboration on Cancer Reporting is to develop an evidence-based-reporting data set for each cancer site, and to this end, a project to develop data sets for prostate, endometrium, and lung cancers and malignant melanoma was piloted by the quadripartite group. This review describes the process of development of the endometrial cancer data set.

Comparison of Expectant and Excisional/Ablative Management of Cervical Intraepithelial Neoplasia Grade 2 (CIN2) in the Era of HPV Testing.

Objective: To investigate conservative and excisional/ablative treatment outcomes for cervical intraepithelial neoplasia grade 2 (CIN2) following introduction of virological test of cure. Methods: This was a retrospective study of prospectively collected data at a teaching hospital colposcopy unit. 331 sequential biopsy-proved CIN2 cases were involved. CIN2 cases diagnosed between 01/07/2014 and 31/12/2017 were either conservatively managed or treated with excision/ablation and then were followed up until discharge from colposcopy clinic and then using the national cervical cytology database. Outcomes were defined: cytological/histological regression was absence of high-grade CIN on biopsy and/or high-grade dysplasia; virological regression was cytological/histological regression and negative human papillomavirus testing; persistence was biopsy-proven CIN2 and/or moderate dyskaryosis; progression was biopsy-proven CIN3+ and/or severe dyskaryosis. Results: Median follow-up was 22.6 months (range: 1.9-65.1 months). Among 175 (52.9%) patients initially managed conservatively, 77.3% (133/172) regressed, 13.4% (23/172) persisted, 9.3% (16/172) progressed to CIN3+, and 97 (56.4%) patients achieved virological regression. 156 (47.1%) patients underwent initial excision/ablation, with an 89.4% (110/123) virological cure rate. After discharge, 7 (4.0%) and 3 (1.9%) patients redeveloped CIN in the conservative and treatment groups, respectively, during a median period of 17.2 months. Conclusion: Conservative management is a reasonable and effective management strategy in appropriately selected women with CIN2. High rates of histological and virological regression should be expected. The previously mentioned data provide useful information for deciding management options.

Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome.

PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.

A robust RNA integrity-preserving staining protocol for laser capture microdissection of endometrial cancer tissue.

Laser capture microdissection of frozen tissue sections allows homogeneous cell populations to be isolated for expression profiling. However, this requires striking a balance between retaining adequate morphology for accurate microdissection and maintaining RNA integrity. Various staining protocols were applied to frozen endometrial carcinoma tissue sections. Although alcohol-based methods were superior to aqueous stains for maintaining RNA integrity, they suffered from irreproducible staining intensity. We developed a modified alcohol-based, buffered cresyl violet staining protocol that provides reproducible staining with minimal RNA degradation suitable for tissues with moderate to high levels of intrinsic RNase activity.

Recurrent urachal mucinous adenocarcinoma presenting as bilateral ovarian tumors on cesarean delivery.

Secondary ovarian cancers, Krukenberg tumors, are a distinctive subset of metastatic tumors arising from the gastrointestinal tract (stomach, colon, and appendix), the biliary system, the breast, or other genital organs. These tumors account for 5% of all ovarian malignancies. Such metastases could mimic primary mucinous ovarian adenocarcinomas. Metastases from the urinary tract are uncommon. Primary adenocarcinoma of the bladder accounts for less than 1% of all bladder malignancies; one third of these tumors are urachal in origin. Urachal cancers are rare and tend to occur in older men (mean age, 50-60 years); however, it was described previously in a 15-year-old girl. Symptoms include hematuria, dysuria, frequency, urgency, and recurrent urinary tract infections. These tumors have a predilection to locally spread to the surrounding organs. Ovarian metastasis is a rare event and is infrequently reported in literature.

Proteomic profiling identifies afamin as a potential biomarker for ovarian cancer.

PURPOSE: To discover and validate serum glycoprotein biomarkers in ovarian cancer using proteomic-based approaches. EXPERIMENTAL DESIGN: Serum samples from a "discovery set" of 20 patients with ovarian cancer or benign ovarian cysts or healthy volunteers were compared by fluorescence two-dimensional differential in-gel electrophoresis and parallel lectin-based two-dimensional profiling. Validation of a candidate biomarker was carried out with Western blotting and immunoassay (n = 424). RESULTS: Twenty-six proteins that changed significantly were identified by mass spectrometric sequencing. One of these, confirmed by Western blotting, was afamin, a vitamin E binding protein, with two isoforms decreasing in patients with ovarian cancer. Validation using cross-sectional samples from 303 individuals (healthy controls and patients with benign, borderline, or malignant ovarian conditions and other cancers) assayed by ELISA showed significantly decreased total afamin concentrations in patients with ovarian cancer compared with healthy controls (P = 0.002) and patients with benign disease (P = 0.046). However, the receiver operating characteristic areas for total afamin for the comparison of ovarian cancer with healthy controls or benign controls were only 0.67 and 0.60, respectively, with comparable figures for CA-125 being 0.92 and 0.88 although corresponding figures for a subgroup of samples analyzed by isoelectric focusing for afamin isoform 2 were 0.85 and 0.79. Analysis of a further 121 samples collected prospectively from 9 patients pretreatment through to relapse indicated complementarity of afamin with CA-125, including two cases in whom CA-125 was noninformative. CONCLUSIONS: Afamin shows potential complementarity with CA-125 in longitudinal monitoring of patients with ovarian cancer, justifying prospective larger-scale investigation. Changes in specific isoforms may provide further information.