Differences in Female and Male-to-Female Transgender Facial Skin Micro-Vessel Density.

Importance: The risk of hematoma formation after rhytidectomy is gender associated and can lead to postoperative complications. The literature to help explain and elucidate the mechanism behind this gender-associated risk is poorly developed and requires further investigation. Objective: The objective of this study was to compare facial skin micro-vessel density of female and male-to-female (MTF) transgender patients undergoing rhytidectomy to better understand the mechanism of gender-correlated hematoma risk factors. The authors hypothesized that transgender patients would have higher micro-vessel density compared with female patients. Design, Setting, and Participants: This was a prospective histopathological analysis of pre- and post-auricular facial skin samples from patients undergoing primary rhytidectomy. Patient clinical data and skin samples were collected. Histopathological slides were prepared and stained with CD-31, a marker of vessel endothelium, followed by image analysis allowing for micro-vessel stained pixel counts and calculated pixel density comparisons at a single academic hospital. Female, MTF transgender, and male patients >18 years of age were studied. Exposure: Patients undergoing primary rhytidectomy between 2015 and 2018. Main Outcomes: Gender-associated pre- and post-auricular micro-vessel pixel density. Results: Forty-one patients contributed skin samples for analysis. Post-auricular micro-vessel pixel density was greater than pre-auricular density (mean difference post-pre 0.359 percentage points [p.p.], standard error [SE] = 0.135, p = 0.009). The mean post-auricular micro-vessel pixel density was 1.60% (SE = 0.13 p.p.), 2.16% (SE = 0.19 p.p.), and 2.77% (SE = 0.34 p.p.) for female, transgender, and male patients, respectively (p = 0.016). Pre-auricular micro-vessel pixel density showed no difference among females, males, and transgender patients (p = 0.30). Gender was a strong predictor of increased post-auricular micro-vessel pixel density on stepwise linear regression, but it did not predict pre-auricular micro-vessel density. Both preoperative hair removal and a history of hypertension were associated with increased pre-auricular micro-vessel density. Conclusions and Relevance: Facial skin micro-vessel density differs by gender, in addition to pre- and post-auricular locations in patients undergoing rhytidectomy.

Circulating Tumor Cells In Advanced Cervical Cancer: NRG Oncology-Gynecologic Oncology Group Study 240 (NCT 00803062).

To isolate circulating tumor cells (CTC) from women with advanced cervical cancer and estimate the impact of CTCs and treatment on overall survival and progression-free survival (PFS). A total of 7.5 mL of whole blood was drawn pre-cycle 1 and 36 days post-cycle 1 from patients enrolled on Gynecologic Oncology Group 0240, the phase III randomized trial that led directly to regulatory approval of the antiangiogenesis drug, bevacizumab, in women with recurrent/metastatic cervical cancer. CTCs (defined as anti-cytokeratin+/anti-CD45- cells) were isolated from the buffy coat layer using an anti-EpCAM antibody-conjugated ferrofluid and rare earth magnet, and counted using a semiautomated fluorescence microscope. The median pre-cycle 1 CTC count was 7 CTCs/7.5 mL whole blood (range, 0-18) and, at 36 days posttreatment, was 4 (range, 0-17). The greater the declination in CTCs between time points studied, the lower the risk of death [HR, 0.87; 95% confidence interval (CI), 0.79-0.95)]. Among patients with high (≥ median) pretreatment CTCs, bevacizumab treatment was associated with a reduction in the hazard of death (HR, 0.57; 95% CI, 0.32-1.03) and PFS (HR, 0.59; 95% CI, 0.36-0.96). This effect was not observed with low (< median) CTCs. CTCs can be isolated from women with advanced cervical cancer and may have prognostic significance. A survival benefit conferred by bevacizumab among patients with high pretreatment CTCs may reflect increased tumor neovascularization and concomitant vulnerability to VEGF inhibition. These data support studying CTC capture as a potential predictive biomarker.

ThyroSeq v2 Testing: Impact on Cytologic Diagnosis, Management, and Cost of Care in Patients with Thyroid Nodule.

Background: Novel molecular tests (MTs), such as ThyroSeq, may improve the management of thyroid nodules with indeterminate cytologic diagnoses; however, the impact of these tests on cost and outcome of management is unknown. Here, we evaluated the impact of ThyroSeq testing on the cytopathologic diagnosis, management, and cost of care in patients with thyroid nodules. Methods: In a retrospective study, using actual patient cohorts, the outcome and cost of management of patients with thyroid nodules seen before the introduction of ThyroSeq v2 at our institution (standard of care [StC] cohort) were compared with those seen after the introduction of this test (MT cohort). Results: A total of 773 consecutive patients entered the study (393 StC, 380 MT). The incidence of cytologically benign nodules decreased from 71.0% (StC) to 53.2% (MT) and those of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) increased from 8.9% (StC) to 21.3% (MT) and from 3.1% (StC) to 6.3% (MT), respectively. The overall rate of surgery did not change significantly (23.4% in StC vs. 23.2% in MT). Among patients who underwent surgery, the rate of overtreatment (surgeries performed on histologic benign nodules without clinical indication: compressive symptoms, hyperthyroidism resistant to medication, and nodule size >4 cm) slightly decreased from 18.8% (StC) to 16.7% (MT). The rate of malignancy decreased from 45.5% (StC) to 37.9% (MT) in AUS/FLUS and increased from 40.0% to 53.8% in FN/SFN. However, the overall rate of malignancy remained equal (47.8% in StC vs. 47.7% in MT). The average cost of care per patient in the AUS/FLUS and FN/SFN categories increased from $6,566 (StC) to $8,444 (MT) and from $9,313 (StC) to $10,253 (MT), respectively. Similarly, the overall average cost of care of a patient who underwent thyroid fine-needle aspiration increased from $3,088 (StC) to $4,282 (MT). Finally, the average cost per thyroid cancer detected increased from $26,312 (StC) to $38,746 (MT). Conclusions: Introduction of ThyroSeq v2 resulted in a shift toward indeterminate cytology results. The institutional rate of surgery, overtreatment, and malignancy did not change significantly. Lack of decrease in the rate of surgery along with the additional cost of ThyroSeq v2 increased the overall cost of care of patients including those with indeterminate cytology results.

A rare malignant thyroid carcinosarcoma with aggressive behavior and DICER1 gene mutation: a case report with literature review.

BACKGROUND: Malignant biphasic tumor also known as carcinosarcoma is an uncommon neoplasm that is composed of both malignant epithelial and mesenchymal components. Most reported cases of carcinosarcoma affect the female genital tract; however, other sites including head and neck, lung, and breast have been described. Carcinosarcoma of the thyroid is an extremely rare and aggressive malignancy with an ominous clinical course similar to anaplastic carcinoma. CASE PRESENTATION: We report a case of a 45-year-old female who was found to have a biphasic thyroid carcinosarcoma. Her clinical course declined significantly shortly after she underwent a total thyroidectomy and she developed distant metastases to the lungs. Histopathological features of the primary and metastatic tumor were identical. The tumor is composed of an intimately intermixed epithelial component of poorly differentiated follicular thyroid carcinoma and a spindle cell sarcoma with rhabdomyosarcoma differentiation. Molecular analysis using a next-generation sequencing based assay revealed a DICER1 (E1705K) point mutation in neoplastic cells. CONCLUSION: To our knowledge, the E1705K point mutation within the DICER1 gene is the first reported mutation in carcinosarcoma of the thyroid. A comprehensive review of the relevant literature is also included for discussion.

Differential expression of toll-like receptors in the human placenta across early gestation.

Toll-like receptors (TLRs) are an essential component of the innate immune system. While a number of studies have described TLR expression in the female reproductive tract, few have examined the temporal expression of TLRs within the human placenta. We hypothesized that the pattern of TLR expression in the placenta changes throughout the first and second trimester, coincident with physiological changes in placental function and the demands of innate immunity. We collected first and second trimester placental tissue and conducted quantitative PCR analysis for TLRs 1-10, followed by immunohistochemistry to define the cell specific expression pattern of a subset of these receptors. Except for the very earliest time points, RNA expression for TLRs 1-10 was stable out to 20 weeks gestation. However, the pattern of protein expression evolved over time. Early first trimester placenta demonstrated a strong, uniform pattern predominantly in the inner villous cytotrophoblast layer. As the placenta matured through the second trimester, both the villous cytotrophoblasts and the pattern of TLR expression within them became disorganized and patchy, with putative Hofbauer cells now identifiable in the tissue also staining positive. We conclude from this data that placental TLR expression changes over the course of gestation, with a tight barrier of TLRs forming a wall of defense along the cytotrophoblast layer in the early first trimester that breaks down as pregnancy progresses. These data are relevant to understanding placental immunity against pathogen exposure throughout pregnancy and may aid in our understanding of the vulnerable period for fetal exposure to pathogens.

Taxonomy of breast cancer based on normal cell phenotype predicts outcome.

Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0-HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.

The multidrug-resistance transporter ABCB5 is expressed in human placenta.

ATP-binding cassette (ABC) transporters in placenta protectively transport drugs and xenobiotics. ABCB5 [subfamily B (MDR/TAP)] is a novel ABC multidrug-resistance transporter that also mediates cell fusion, stem cell function, and vasculogenic plasticity. Immunohistochemistry and double-labeling immunofluorescence staining for ABCB5 and ABCB5/CD200, respectively, was performed on formalin-fixed, paraffin-embedded placental tissue from 5 first trimester, 5 second trimester, and 5 term pregnancies as well as 5 partial moles, and 5 complete moles. In addition, tumor cells from 5 choriocarcinoma and 5 placental site trophoblastic tumor cases were examined. ABCB5 staining was observed in villous trophoblasts in 100% (5/5) of first trimester placentas (with progressive decrease in term placentas); 100% of partial moles (5/5); and 100% of complete moles (5/5). Notably, reactivity was discretely restricted to the inner trophoblast layer, with no staining of overlying syncytiotrophoblast. Antibody specificity and localization was confirmed further by in situ hybridization. ABCB5 expression was retained in 20% of choriocarcinomas (1/5) and 40% of placental site trophoblastic tumors (2/5). Prior studies have localized expression of multidrug-resistance-1, also known as ABCB1, within the syncytiotrophoblast of early placentas, where it serves a protective function as an efflux transporter. Our results show that ABCB5 is preferentially expressed in the cytotrophoblast layer of placental villi. The expression of this novel biomarker at the maternal-fetal interface raises questions on its role in placental structure and function as well as on its potential contribution to the protective efflux provided by other P-glycoprotein transporters.

Predictive value of circulating tumor cells (CTCs) in newly-diagnosed and recurrent ovarian cancer patients.

OBJECTIVE: To determine whether circulating tumor cells (CTCs), as detected and enumerated by the Veridex CellSearch system, could predict for clinical outcomes in women with newly diagnosed or recurrent epithelial ovarian cancer. METHODS: Serial measurements of CTC s and paired serum CA125 were collected in a series of 78 women with newly diagnosed or recurrent ovarian cancer seen at our institution over a period of 15 months. Clinical data were abstracted from patient medical records. CTCs were detected and enumerated by the CellSearch protocol, and patients were divided into CTC negative (<2 CTCs) or positive (≥2 CTCs) groups. CTC groups were correlated with clinical characteristics and outcomes. A longitudinal analysis of CTC change and CA125 trends was also performed. RESULTS: At least one CTC was isolated from the peripheral blood of over 80% of the women participating in this study, with a range from 0 to 8. No correlations were observed between CTC numbers and clinical characteristics or outcomes. Although both serum CA125 and CTC number exhibited an overall significant decreasing trend over time, there was no correlation observed between change in CTCs and CA125. CONCLUSION: Using the FDA-approved CellSearch system, CTCs can be isolated from women with newly diagnosed or recurrent ovarian cancer. However, CTC numbers do not significantly correlate with clinical characteristics or patient outcomes. Future studies should focus on phenotypic characterization of CTCs and whether different isolation protocols yield a higher number of CTCs or add prognostic value.

Vascular endothelial growth factors and their receptors and regulators in gestational trophoblastic diseases and normal placenta.

OBJECTIVE: To study the expression of vascular endothelial growth factors (VEGFs), placental growth factor (PLGF) and their receptors (VEGFR-1, -2, -3) and their regulators (IL-6, CD147) in normal placenta and gestational trophoblastic disease (GTD) in order to evaluate their potential role in the biology of GTD. STUDY DESIGN: Paraffin sections of 10 normal, first-trimester placentas, 10 partial moles, 10 complete moles, 5 choriocarcinomas and 5 placental site trophoblastic tumors (PSTTs) were studied immunohistochemically for expression of VEGFR-1, VEGFR-2, VEGFR-3, IL-6, PLGF and CD147. Immunolocalization of VEGF, Angiopoietin-1 and Angiopoietin-2 was performed on 5 choriocarcinomas and 5 PSTTs. The levels of VEGF and VEGFR-2 were determined in supernatants and lysates of normal trophoblast, JEG-3 and JAR choriocarcinoma cells with electrochemiluminescence assays. RESULTS: The normal placenta had significantly stronger expression of VEGFR-2 than did those of partial and complete mole (p = 0.001, p = 0.003). VEGF, Angiopoietin-1 and Angiopoietin-2 expression in PSTT were significantly higher than those in choriocarcinoma (p = 0.002, p= 0.01, p = 0.038). Choriocarcinoma showed stronger intensity of staining for VEGFR-3 than did normal placenta, partial and complete mole (p = 0.036, p = 0.038, p = 0.05). Choriocarcinoma had significantly stronger staining of CD147 than did partial and complete mole (p<0.01, p<0.01). PSTT exhibited significantly stronger staining for IL-6 than did choriocarcinoma (p = 0.03). CONCLUSION: PSTTs exhibited strong staining for VEGF, and choriocarcinoma showed strong staining for VEGFR-3. Agents that inhibit the activity of VEGF and VEGF receptors may prove to be useful in the therapy of gestational trophoblastic neoplasia.

Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy.

PURPOSE: Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. PATIENTS AND METHODS: This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. RESULTS: Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. CONCLUSION: Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.

Matrix metalloproteinases and their inhibitors and inducer in gestational trophoblastic diseases and normal placenta.

OBJECTIVES: This study aimed to investigate the expression of recently identified matrix metalloproteinases (MMPs), their inhibitors (TIMPs), and inducer (CD147) in a wide range of gestational trophoblastic diseases (GTD) thereby expanding our understanding of the potential role of MMPs in GTD. METHODS: Paraffin sections of 10 normal first-trimester placentas (NP), 10 partial moles (PM), 10 complete moles (CM), 5 choriocarcinomas (CCA) and 5 placental site trophoblastic tumors (PSTT) were studied immunohistochemically for expression of MMP-7, MMP-14, MMP-21, MMP-28, TIMP-3, TIMP-4 and CD147. Immunolocalization of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13 and TIMP-1 was performed on 5 CCA and 5 PSTTs. RESULTS: CCA showed stronger intensity for MMP-14 and MMP-28 than PSTT (p<0.05, p<0.05). CCA and PSTT had stronger expression of MMP-21 than NP, PM and CM (p<0.05, p<0.05, p<0.01). PSTT (p<0.05, p<0.05), NP (p<0.01, p<0.01) and CM (p<0.01, p<0.05) showed stronger staining for TIMP-3 and TIMP-4 than CCA. CONCLUSION: Choriocarcinoma's high expression of MMPs and low expression of MMP inhibitors may contribute to its invasiveness and metastatic potential. Similarly, PSTT's lower expression of MMPs and high expression of MMP inhibitors may partly explain its lower invasiveness. Agents that inhibit MMP may prove useful in treating GTD.

High-grade and low-grade pelvic serous neoplasms demonstrate differential p53 immunoreactivity in peritoneal washings.

OBJECTIVE: Serous neoplasms of the female pelvis share a müllerian phenotype. Unlike low-grade serous neoplasms (LGSNs), high-grade serous carcinomas (HGSCs) commonly display p53 mutations. The current study correlates p53 immunoreactivity in peritoneal washings with the cytologic interpretation and histology of the corresponding serous neoplasm. STUDY DESIGN: Peritoneal washings from consecutive cases of pelvic serous neoplasms were identified (n=45, 31 HGSCs and 14 LGSNs), with a control population selected from benign resections. Immunoreactivity for p53 was scored as a percentage of positive epithelioid cells by blinded manual cell count. RESULTS: Washings from LGSNs and HGSCs were cytomorphologically positive with similar frequency (57 vs. 77%, respectively, p=0.15, Fisher's exact test). Immunoreactivity for p53 was not predictive of morphologic positivity. The percentage of p53-positive cells was higher in HGSCs (47±42%), compared to LGSNs (9±9%) and negative controls (2±2%, n=10). The difference in p53 immunoreactivity was statistically significant (p<0.00009, ANOVA). CONCLUSIONS: The proportion of p53 immunoreactive cells was higher in cases of HGSCs, reflecting the importance of p53 mutations in high-grade serous tumorigenesis. The presence of p53 staining is not diagnostic for neoplastic cells; however, peritoneal washings are potential specimens in the investigation of serous neoplasia.

Utility of chromosomal chromogenic in situ hybridization as an alternative to flow cytometry and cytogenetics in the diagnosis of early partial hydatidiform moles: a validation study.

OBJECTIVE: The introduction of p57 immunohistochemistry has aided the distinction between early complete moles (CMs) and hydropic abortus (HA), but no single technique has emerged for the distinction between early partial moles (PMs) and HA. Flow cytometry and cytogenetics have been used, but these require specialized equipment/expertise. The goal of this study is validation of chromosome in situ hybridization (CrISH), focusing on comparing the results to those obtained by cytogenetic methods. STUDY DESIGN: Archival paraffin blocks from molar and nonmolar gestations were retrieved. Sections were labeled with a chromosome 10 probe. Hybridization and visualization were performed using standard protocols. One hundred nuclei per sample were scored for the number ofsignals. RESULTS: Of 50 hydatidiform moles, 22 were PMs and 28 were CMs. The CMs showed 2 signals in 25 cases and 4 signals in 3 cases. The PMs showed 3 signals in 21 cases and 2 signals in 1 case. For the HAs there were 2 signals in 24 cases, and 1 case had 3 signals. Concordance between CrISH and flow cytometry studies for molar gestations was 95%. CONCLUSION: CrlSH is a highly effective adjunct in differentiating between PM and CM and between PM and HA. CrlSH is a simple, cost effective adjunct in evaluating molar gestations.

Age related cellular immune response against complete molar pregnancy.

OBJECTIVE: Advanced maternal age may result in a weaker immune response against complete molar pregnancy, therefore increasing the risk of gestational trophoblastic neoplasia due to ineffective elimination of the trophoblastic cells after evacuation. The present study was undertaken to investigate the cellular immune response against complete molar pregnancy at the implantation site in younger and older patients. STUDY DESIGN: Immunolocalization of CD8, granzyme B (GrB), FoxP3 and CD56 was performed on histologic tissue sections prepared from 18 patients aged < or = 40 years and 10 patients aged > 40 years to characterize effector (GrB+CD8+) cytotoxic T cells, GrB positive and negative natural killer cells (CD56) and regulatory T cells (FoxP3+) at the implantation site in complete molar pregnancies. RESULTS: The number of the different immune cell types did not show significant differences in the implantation sites of complete molar pregnancies between the 2 age groups or between persistent and nonpersistent cases. CONCLUSION: Immunosenescence of the natural killer and T cells most likely does not play a role in the increased incidence of gestational trophoblastic neoplasia in older patients with complete moles.

Serous tubal intraepithelial carcinoma: diagnostic reproducibility and its implications.

Serous tubal intraepithelial carcinoma (STIC) is detected in between 5% and 7% of women undergoing risk-reduction salpingooophorectomy for mutations in the BRCA1 or 2 genes (BRCA+), and seems to play a role in the pathogenesis of many ovarian and "primary peritoneal" serous carcinomas. The recognition of STIC is germane to the management of BRCA+ women; however, the diagnostic reproducibility of STIC is unknown. Twenty-one cases were selected and classified as STIC or benign, using both hematoxylin and eosin and immunohistochemical stains for p53 and MIB-1. Digital images of 30 hematoxylin and eosin-stained STICs (n=14) or benign tubal epithelium (n=16) were photographed and randomized for blind digital review in a Powerpoint format by 6 experienced gynecologic pathologists and 6 pathology trainees. A generalized kappa statistic for multiple raters was calculated for all groups. For all reviewers, the kappa was 0.333, indicating poor reproducibility; kappa was 0.453 for the experienced gynecologic pathologists (fair-to-good reproducibility), and kappa=0.253 for the pathology residents (poor reproducibility). In the experienced group, 3 of 14 STICs were diagnosed by all 6 reviewers, and 9 of 14 by a majority of the reviewers. These results show that interobserver concordance in the recognition of STIC in high-quality digital images is at best fair-to-good for even experienced gynecologic pathologists, and a proportion cannot be consistently identified even among experienced observers. In view of these findings, a diagnosis of STIC should be corroborated by a second pathologist, if feasible.

Polymerase chain reaction detection of HPV in squamous carcinoma of the oropharynx.

Human papillomavirus (HPV) testing is routinely performed on oropharyngeal carcinomas. We compared the Access Genetics (Minneapolis, MN) polymerase chain reaction (PCR) assay (AGPCR), DNA-DNA in situ hybridization (ISH; Ventana, Tucson, AZ), and HPV-16 E7 PCR amplification in consecutively accessioned oropharyngeal cancers. We tested 126 cases by both PCR methods; 102 were positive by either for a maximum positive rate (MPR) of 81.0%. Relative to the MPR, the sensitivities of AGPCR and E7 PCR were 90.2% and 72.5%, respectively. Of 17 AGPCR+ cases tested by ISH, 14/14 unequivocally positive/negative were concordant. All cases (97/97) positive by either PCR assay were positive for p16. There was no relationship between level of histologic differentiation and HPV status. ISH and AGPCR have comparable performance for the detection of HPV in oropharyngeal carcinomas. PCR is a suitable and economical assay that is comparable to ISH in sensitivity and may provide logistical advantages relative to ISH for assessing HPV status in oropharyngeal malignancies. However, it is imperative that appropriate sensitivity controls be in place for such assays.

Coexisting intraepithelial serous carcinomas of the endometrium and fallopian tube: frequency and potential significance.

SUMMARY: Most serous adenocarcinomas involving both the endometrium and ovary are presumed to arise in the endometrium. Recently, serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. This study explored the potential relationship between STIC and uterine serous carcinoma. Twenty-two consecutive cases of serous carcinoma involving the endometrium were studied. In each case, fallopian tubes were submitted in toto according to the protocol for sectioning and extensive examination of the fimbriated end. Extent of the endometrial tumor and presence/absence of STIC were documented. Immunostaining for p53 and Wilms tumor-1 was performed on all cases with STIC. p53 mutation analysis was performed in a subset of matched STICs and endometrial tumors. Eleven cases showed concurrent endometrial and adnexal involvement, including 6 with endosalpingeal involvement; STIC was confirmed in 5. In all 5, the concurrent endometrial tumor was either noninvasive, or exhibited only superficial (<5%) myometrial invasion. In 2 cases, identical p53 mutations were shared by both tubal and endometrial lesions. This study shows that noninvasive, genetically related serous carcinomas may coexist in both tube and endometrium. As management of serous neoplasms is predicated on site of origin, we propose that the sectioning and extensively examining the fimbria protocol be applied to all endometrial serous carcinomas and that tumors with concurrent STIC be classified as a distinct subset of pelvic serous carcinomas pending a clearer understanding of tumor origin.

Serous tubal intraepithelial carcinoma and the dominant ovarian mass: clues to serous tumor origin?

Pelvic serous cancer is a diverse disease, and the assignment of primary site -- ovarian, tubal, or peritoneal -- is often problematic. Recent studies indicate that a proportion of these tumors arise from the distal fallopian tube, originating as serous tubal intraepithelial carcinoma (STIC). This study examined the relationship of 2 parameters for assigning origin -- endosalpingeal involvement and dominant ovarian mass -- in the context of STIC. Endometrioid carcinomas served as a reference. Eighty-seven consecutive pelvic serous cancers in which the tubes and ovaries were completely examined (SEE-FIM protocol) were analyzed. The presence of a dominant ovarian mass (DOM+), involvement of the fimbrial mucosa (FIM+), and STIC were correlated. In addition, tumor categories were compared with respect to PAX8, p73, p53, and p16 immunohistochemistry. Of the 27 DOM+ cases, 13 (48%) were FIM+ and a STIC was present in 3 (11%). Of the 60 DOM(-) cases, 48 (78%) were FIM+ and 28 (45%) harbored a STIC. In 92% of all cases, tumor distribution was extensive with bilateral ovarian and extraovarian peritoneal involvement. All tumor categories were immunophenotypically similar. In contrast, DOM+, FIM+, and STIC were found in 81%, 19%, and 0% of ovarian endometrioid carcinomas. In conclusion, there is a significant inverse relationship between DOM+ and STIC (P=0.001), indicating both parameters are of value in grouping pelvic serous carcinomas more likely to be ovarian [DOM+/FIM(-)] versus fimbrial [DOM(-)/STIC], and ovarian or peritoneal surface (DOM-/FIM-) in origin. Nevertheless, the shared immunophenotype suggests a common cell of origin for all categories, irrespective of site.

Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention.

PURPOSE: A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its clinical outcome in BRCA-positive women. PATIENTS AND METHODS: Presence or absence of STIC was recorded in consecutive cases meeting the 2001 WHO criteria for PPSC, including 26 patients with nonuniform sampling of the fallopian tubes (group 1) and 19 patients with complete tubal examination (group 2; sectioning and extensively examining the fimbriated end, or SEE-FIM protocol). In selected cases, STIC or its putative precursor and the peritoneal tumor were analyzed for p53 mutations (exons 1 to 11). Outcome of STIC was ascertained by literature review. RESULT: Thirteen (50%) of 26 PPSCs in group 1 involved the endosalpinx, with nine STICs (35%). Fifteen (79%) of 19 cases in group 2 contained endosalpingeal involvement, with nine STICs (47%). STIC was typically fimbrial and unifocal, with variable invasion of the tubal wall. In five of five cases, the peritoneal and tubal lesion shared an identical p53 mutation. Of 10 reported STICs in BRCA-positive women, all patients were without disease on follow-up. CONCLUSION: The fimbria is the source of nearly one half of PPSCs, suggesting serous malignancy originates in the tubal mucosa but grows preferentially at a remote peritoneal site. The generally low risk of recurrence in stage 0 (STIC) disease further underscores STIC as a possible target for early serous cancer detection and prevention.

Serous carcinogenesis in the fallopian tube: a descriptive classification.

The fimbria is the most common site of early serous cancer (tubal intraepithelial carcinoma or STIC) in women with BRCA mutations (BRCA+). A candidate serous cancer precursor--the p53 signature--has been found in nonneoplastic secretory cells of the fimbria, suggesting serous carcinogenesis in the tube (SCAT). This study surveyed fallopian tubes from 3 populations to characterize the morphological and immunohistochemical correlates of SCAT. The SCAT sequence was defined by strong nuclear p53 staining and DNA damage (gamma-H2AX+) in secretory cells and subdivided morphologically by (1) degree of nuclear stratification, (2) proliferative index, and (3) degree of disorganized growth. Fallopian tubes from women without a current ovarian cancer, women with BRCA mutations, and women with a coexisting pelvic serous cancer were completely examined. p53 signatures exhibited cuboidal to pseudostratified, polarized p53+ epithelial segments with variable nuclear enlargement and a MiB1 index of 0% to 30%. Tubal intraepithelial carcinomas contained from single (uncommon) to multilayered, poorly polarized, uninterrupted neoplastic cell populations that completely displaced the normal mucosa; MiB1 index exceeded 45% and was usually more than 70%. An uncommon third category, p53-positive foci with features intermediate between p53 signatures and STICs, exhibited preserved epithelial polarity, pseudostratification, incomplete replacement of the adjacent normal ciliated cells, and a MiB1 index between 40% and 75%. Transitions from 1 category to another were documented. Combined with recent reports associating STICs with pelvic serous cancer, this continuum of epithelial change validates the SCAT sequence and the fimbrial secretory cell as the site of origin for many serous carcinomas.