Progression of Peritoneal Mesothelioma In Situ to Invasive Mesothelioma Arising in the Setting of Endometriosis With Germline BAP1 Mutation: A Case Report.

Mesothelioma in situ has been proposed as a precursor to malignant mesothelioma arising in the pleura or peritoneum. We report a case of malignant peritoneal mesothelioma which progressed from mesothelioma in situ over a 10-mo period in a 24-yr-old woman with stage IV endometriosis. Initial surgery showed deeply infiltrative endometriosis with progestin effect. Postoperatively the patient had intractable pelvic pain and vaginal discharge. Imaging studies were negative. Repeat laparoscopy 10 mo later revealed vesicular lesions on the omentum and pinpoint white lesions studding the small bowel, appendix, and pelvic peritoneum. A diagnosis of epithelioid mesothelioma was established on biopsy of the omentum and confirmed by immunohistochemistry showing complete loss of BRCA1-associated protein-1 (BAP1) nuclear staining. Retrospectively, BAP1 loss was identified in the cytologically bland, single-layer surface mesothelium of the prior resection specimen, consistent with mesothelioma in situ . The patient underwent genetic testing and was found to have a pathogenic germline mutation in BAP1 .

Expanding the Morphologic, Immunohistochemical, and HPV Genotypic Features of High-grade Squamous Intraepithelial Lesions of the Vulva With Morphology Mimicking Differentiated Vulvar Intraepithelial Neoplasia and/or Lichen Sclerosus.

Squamous cell carcinoma of the vulva can arise through 2 pathways: human papillomavirus (HPV)-dependent high-grade squamous intraepithelial lesions (previously termed usual vulvar intraepithelial neoplasia) or HPV-independent (differentiated vulvar intraepithelial neoplasia, dVIN). Distinguishing between the 2 types can be clinically and histologically difficult. A subset of high-grade squamous intraepithelial lesions with superimposed chronic inflammation mimicking dVIN has recently been reported; p53 shows characteristic mid-epithelial staining (with basal sparing) in such cases. The pathology databases of 2 academic institutions were searched for vulva specimens with corresponding p53 and p16 immunohistochemical stains, yielding 38 specimens (from 27 patients). In situ hybridization and multiplex polymerase chain reaction-MassArray for high-risk HPV were performed on at least 1 block from each patient. All cases resembled dVIN or lichen sclerosus morphologically, but with a higher degree of atypia. All but 1 case demonstrated mid-epithelial p53 staining with basal sparing by immunohistochemistry. All cases showed block positivity for p16 and at least patchy positivity by HPV in situ hybridization. Of the 23 cases with valid HPV DNA polymerase chain reaction results, 15 were positive and 8 were negative. Of the positive cases, HPV16 was identified in 10 cases, with other high-risk types in the remaining 5. To our knowledge, this is the largest cohort of high-grade squamous intraepithelial lesions mimicking dVIN reported to date. Prior studies reported positivity for HPV16 in all cases tested, however, we found HPV16 in only 67% of HPV positive cases. This case series highlights the importance of immunohistochemistry, and occasionally HPV in situ hybridization, for accurate diagnosis, and expands the spectrum of associated HPV types.

Predictive Value of an Alternative Strategy for Measuring Depth and Size of Stage 1 Vulvar Squamous Cell Carcinoma.

OBJECTIVES: Despite poor reproducibility for measuring vulvar cancer depth, 1-mm or greater invasion triggers lymphadenectomy for small tumors. Previous literature suggests that measuring depth from the nearest dysplastic rete peg (alternative method) rather than highest dermal papilla (conventional method) may be acceptable. METHODS: Pathologic staging and follow-up information were recorded for 100 pT1 vulvar squamous cell carcinoma (SCC) resected from 1990 to 2019. Conventional depth, alternative depth, gross/clinical size, and size of the invasive component were measured for each tumor. In this retrospective study, we evaluated which clinicopathologic factors were most predictive of lymph node involvement and recurrence. RESULTS: Depending on the measurements used (conventional vs alternative depth, clinical lesion size vs cumulative extent of invasive component), between 1 and 18 cases were downstaged to pT1a. All such cases were pN0, without lymphovascular or perineural invasion. Infiltrative cords (hazard ratio [HR] = 5.15; 95% CI = 1.63-16.2; p = .005) and perineural invasion (HR = 3.16; 1.18-8.45; p = .022) were most strongly associated with groin recurrence. Of staging criteria evaluated, only cumulative extent of the invasive component 2 cm or greater was significantly associated with groin recurrence (HR = 2.87; 1.01-8.17; p = .048). The Kaplan-Meier curves for local recurrence-free survival by stage did not show significant separation regardless of method. CONCLUSIONS: Patients downstaged using alternative measurement techniques lacked nodal disease/recurrence; one-third of those with nodal sampling experienced postoperative morbidity. Our data suggest that the use of alternative depth and cumulative extent of invasion could safely allow some conventional stage IB vulvar SCC patients to avoid groin surgery, thereby reducing treatment-related morbidity.

Rare Clinical Entity: Metastatic malignant struma ovarii diagnosed during pregnancy - Lessons for management.

BACKGROUND: Malignant struma ovarii is an ovarian teratoma containing at least 50% thyroid tissue which has the potential to metastasize and produce thyroid hormone. Given its rarity, management strategies are not well-established. We report a case of metastatic malignant struma ovarii discovered during pregnancy with lessons for evaluation and management. CASE PRESENTATION: A 30-year-old woman who was two months pregnant was discovered to have struma ovarii with over half of the struma comprised of papillary thyroid cancer. Following tumor resection, delivery, and thyroidectomy, she underwent evaluation with stimulated thyroglobulin testing and diagnostic staging sodium iodide-131 scan (I-131), which revealed the presence of skeletal metastases. Following administration of 320 mCi I-131, post-therapy scan also showed miliary pulmonary metastases with improved ability to localize the bony and pulmonary metastases with concurrent SPECT/CT imaging. A second dosimetry-guided I-131 therapy resulted in complete resolution of pulmonary metastases; however, small foci of residual bone disease persisted. Post-therapy scans demonstrated additional findings not shown on diagnostic I-131 scans obtained prior to both her initial and second I-131 therapy. CONCLUSIONS: SPECT/CT provides accurate anatomic correlation and localization of metastatic foci and can serve as a baseline study to assess interval response to treatment. Post-therapy scans should always be obtained when I-131 treatment is administered, as additional findings may be revealed versus low dose I-131 activity diagnostic scans. This patient had a high metastatic burden that would not have been discovered in a timely fashion with the conservative approach advocated by others. Thyroidectomy followed by a diagnostic staging radioiodine scan and a stimulated thyroglobulin level should be considered in patients with malignant struma ovarii for guiding therapeutic I-131 administration as metastatic risk is difficult to predict based on histopathologic examination.

High Variability in Lymph Node Counts Among an International Cohort of Pathologists: Questioning the Scientific Validity of Node Counts.

Background: The enumeration of lymph nodes (LNs) from surgical specimens plays a critical role in the staging of patients with cancer. LN count (LNC) can affect prognosis, staging, adequacy of resection, and/or eligibility for clinical trials. However, there is no standard method for counting LNs. Most studies in the literature site the pathology report as the source of LN data, without discussion of the counting criteria. Patients and Methods: Four microscopic slides from separate pelvic LN dissections were digitally scanned and uploaded with their gross descriptions to an online library and an online survey. Respondents were asked how many LNs they would count per slide as part of a staging procedure. The survey was distributed to an international cohort of pathologists. Results: A total of 122 surveys were returned: 79 from practicing pathologists and 43 from residents/fellows. There was no statistical difference between the groups. All slides showed significant individual variability. The LNC range for each slide was as follows: slide 1, 1-3; slide 2, 0-13; slide 3, 1-8; slide 4, 1-11. The intraclass correlation (ICC) for all responders was 0.26 (95% CI, 0.05

Struma Ovarii With Hyperthyroidism.

We report the case of a 61-year-old woman with persistent thyrotoxicosis for 7 years despite low thyroidal radioiodine uptake and methimazole treatment. Her initial I whole-body scan (WBS) was read as negative. Upon evaluation in our institution, she remained hyperthyroid after discontinuation of methimazole. Repeat WBS with SPECT/CT revealed low 24-hour thyroidal uptake (RAIU = 2%) and intensely focal radioiodine uptake in a large heterogeneous left pelvic mass, consistent with left adnexal struma ovarii. Resection of this mass confirmed benign struma ovarii. This case illustrates the advantage of fusion SPECT/CT imaging with planar I-WBS for diagnosis of extrathyroidal thyrotoxicosis.

Synuclein-γ in uterine serous carcinoma impacts survival: An NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Synuclein-γ (SNCG) is highly expressed in advanced solid tumors, including uterine serous carcinoma (USC). The objective of the current study was to determine whether SNCG protein was associated with survival and clinical covariates using the largest existing collection of USCs from the Gynecologic Oncology Group (GOG-8023). METHODS: High-density tissue microarrays (TMAs) of tumor tissues from 313 patients with USC were stained by immunohistochemistry for SNCG, p53, p16, FOLR1, pERK, pAKT, ER, PR, and HER2/neu. Associations of SNCG and other tumor markers with overall and progression-free survival were assessed using log-rank tests and Cox proportional-hazards models, which also were adjusted for age, race, and stage. RESULTS: The overall survival at 5 years was 46% for women with high SNCG expression and 62% for those with low SNCG expression (log-rank P = .021; hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.91-1.9 in adjusted Cox model). The progression-free survival rate at 5 years was worse for women who had high SNCG expression, at 40%, compared with 56% for those who had low SNCG expression (log-rank P = .0081; HR, 1.36; 95% CI, 0.96-1.92 in adjusted Cox model). High levels of both p53 and p16 were significantly associated with worse overall survival (p53: HR, 4.20 [95% CI, 1.54-11.45]; p16: HR, 1.95 [95% CI, 1.01-3.75]) and progression-free survival (p53: HR, 2.16 [95% CI, 1.09-4.27]; p16: HR, 1.53 [95% CI, 0.87-2.69]) compared with low levels. CONCLUSIONS: This largest collection of USCs to date demonstrates that SNCG was associated with poor survival in univariate analyses. SNCG does not predict survival outcome independent of p53 and p16 in models that jointly consider multiple markers. Cancer 2017;123:1144-1155. © 2016 American Cancer Society.

Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies.

OBJECTIVE: Systemic lupus erythematosus (SLE) is associated with increased risk of adverse pregnancy outcomes, including pre-eclampsia, particularly in association with antiphospholipid antibody syndrome (APS). While significant placental abnormalities are expected in pre-eclampsia, less is known about how lupus activity and APS in pregnancy affect the placenta. We describe placental pathology from a population of lupus pregnancies, several of which were complicated by APS-related thromboses, in which pre-eclampsia and other complications developed. We performed standard histopathological placental review and quantified neutrophils and neutrophil extracellular traps (NETs) in the intervillous space, given the recognised association of NETs with lupus, APS and pre-eclampsia. METHODS: Pre-eclampsia, SLE and control placentas were scored for histological features, and neutrophils were quantified on H&E and immunohistochemical staining for the granular protein myeloperoxidase. NETs were identified by extracellular myeloperoxidase staining in the setting of decondensed nuclei. Non-parametric analysis was used to evaluate differences in netting and intact neutrophils between groups, with Kruskal-Wallis testing for associations between histological findings and neutrophils. RESULTS: Placentas were evaluated from 35 pregnancies: 10 controls, 11 pre-eclampsia, 4 SLE+pre-eclampsia and 10 SLE, including one complicated by catastrophic APS and one complicated by hepatic and splenic vein thromboses during pregnancy. Intrauterine growth restriction and oligohydramnios were observed in lupus cases but not controls. Significantly more NETs were found infiltrating placental intervillous spaces in pre-eclampsia, SLE+pre-eclampsia and all 10 SLE non-pre-eclampsia cases. The ratio of NETs to total neutrophils was significantly increased in all case groups compared with controls. When present, NETs were associated with maternal vasculitis, laminar decidual necrosis, maternal-fetal interface haemorrhage and non-occlusive fetal thrombotic vasculopathy. CONCLUSIONS: In this pilot study of placental tissue from lupus pregnancies, outcomes were more complicated, particularly if associated with APS. Placental tissue revealed marked inflammatory and vascular changes that were essentially indistinguishable from placental tissue of pre-eclampsia pregnancies.

"Equivocal" high-risk HPV DNA tests performed on ThinPrep specimens after ASC-US diagnoses are associated with an increased incidence of CIN3: a cytologic/histologic review of 315 cases.

OBJECTIVE: The Hybrid Capture II high-risk HPV test (HC II hrHPVT) improves early detection of cervical neoplasia in Pap tests. However, weakly positive HC II results may be reported as indeterminate or "equivocal," for which there is little clinical guidance. This study is designed to evaluate the clinical outcome of equivocal HC II hrHPVTs and concurrent atypical squamous cells of undetermined significance (ASC-US) on ThinPrep Pap specimens through correlation with 2-year follow-up cervical biopsies. MATERIALS AND METHODS: Over a 5-year period, ThinPrep Pap tests diagnosed as ASC-US were grouped according to their hrHPVT results (i.e., positive, negative, or equivocal) and correlated with histologic follow-up. All equivocal and representative positive and negative hrHPVTs were included. Biopsies showing high-grade dysplasia were reviewed by two pathologists. RESULTS: Of 9,012 ASCUS Pap tests, 945 had corresponding hrHPVTs and follow-up cervical biopsies. High-grade squamous intraepithelial lesion (HSIL-cervical intraepithelial neoplasia grades 2/3, CIN2/3) was identified in 20.3% (14/69) of biopsies after equivocal hrHPVTs (CIN2-5.8%, CIN3-14.5% (p=.0261); 16.7% (25/150) after positive hrHPVT (CIN2-12%, CIN3-4.7%); and 5.4% (5/93) of biopsies after negative hrHPVT (CIN2-4.3%, CIN3-1.1%). CONCLUSION: ASC-US in association with equivocal and positive HC II results respectively shows similar incidences of CIN2/3 on 2-year follow-up cervical biopsy. Additionally, a significant proportion of CIN3 biopsies are in the equivocal HC II cohort. As clinical decision making would be impacted by this finding, laboratories should consider evaluating the clinical performance of their HC II assay via correlation with subsequent cervical biopsies.

Assessment of "fresh" versus "macerated" as accurate markers of time since intrauterine fetal demise in low-income countries.

OBJECTIVE: To compare provider assessment of fetal maceration with death-to-delivery interval to evaluate the reliability of appearance as a proxy for time of death. METHODS: Cohort chart abstraction was performed for all stillbirth deliveries at or above 28 weeks of gestation during a 1-year period in a teaching hospital in Ghana. RESULTS: Of 470 stillborn infants, 337 had adequate data for analysis. Of 47 fetuses alive on admission with death-to-delivery intervals estimated to be less than 8 hours (expected to be reported as fresh), 14 (30%) were actually reported as macerated. Of 94 cases in which the fetus was deceased on admission with death-to-delivery interval of more than 8 hours (expected to be macerated), 17 (18%) were described as fresh. CONCLUSION: Provider description of fetal appearance may be an unreliable indicator for time since fetal death. The findings have significant implications for stillbirth prevention and assessment.

Seasonal influenza A (H1N1) infection in early pregnancy and second trimester fetal demise.

A second trimester fetal demise followed influenza-like illness in early pregnancy. Influenza A virus (H1N1) was identified in maternal and fetal tissue, confirming transplacental passage. These findings suggested a causal relationship between early exposure and fetal demise. Management of future influenza outbreaks should include evaluation of products of conception associated with fetal loss.

Enhancing colposcopy with polarized light.

OBJECTIVE: To determine the potential utility of polarized light used during colposcopic examinations. MATERIALS AND METHODS: Matched, polarized, and unpolarized colposcopic images and diagnostic annotations from 31 subjects receiving excisional treatment of cervical neoplasia were compared. Sensitivity, specificity, and mean Euclidean distances between the centroids of the gaussian ellipsoids for the different epithelial types were calculated for unpolarized and polarized images. RESULTS: The sensitivities of polarized colposcopic annotations for discriminating cervical intraepithelial neoplasia (CIN) 2 or higher were greater for all 3 acetowhite categories when compared with unpolarized annotations (58% [44/76] vs 45% [34/76], 68% [50/74] vs 59% [45/76], and 68% [49/72] vs 66% [50/76], respectively). The average percent differences in Euclidean distances between the epithelial types for unpolarized and polarized cervical images were as follows: CIN 2/3 versus CIN 1 = 33% (10/30, p =.03), CIN 2/3 versus columnar epithelium = 22% (p =.004), CIN 2/3 versus immature metaplasia = 29% (14/47, p =.11), and CIN 1 versus immature metaplasia = 27% (4.4/16, p =.16). CONCLUSIONS: Because of its ability to interrogate at a deeper plane and eliminate obscuring glare, polarized light colposcopy may enhance the evaluation and detection of cervical neoplasias.

Home study course: spring 2009.

GLOBAL OBJECTIVE: The Home Study Course is intended for the practicing colposcopist or practitioner who is seeking to develop or enhance his/her colposcopic skills. The goal of the course is to present colposcopic cases that are unusual or instructive in terms of appearance, presentation, or management or that demonstrates new and important knowledge in the area of colposcopy or pathology. Participants may benefit from reading and studying the material or from testing their knowledge by answering the questions. TARGET AUDIENCE: Target learners for Home Study Courses are colposcopists in clinical practice and may include gynecologists, family physicians, pathologists, residents in training in any one of these specialties, gynecologic oncologists, and midlevel providers such as nurse practitioners, physician's assistants, and certified nurse midwives. ACCME ACCREDITATION: The ASCCP is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ASCCP designates this education activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity.The Home Study Course is planned and produced in accordance with the ACCME's Essential Areas and Elements and Updated Criteria. DISCLOSURE AND MANAGEMENT OF CONFLICTS OF INTEREST: As an accredited provider of CME credit, ASCCP is required to comply with the ACCME's Standards of Commercial Support and has implemented a process to manage potential conflicts of interest. We have a process to ensure that anyone who is in a position to affect the content of the educational activity (e.g., faculty, planners, etc.) has disclosed to us all relevant financial relationships with any commercial interest. The ASCCP then discloses to learners any relevant financial relationship(s) to include the following information: (1) the name of the individual; (2) the name of the commercial interest; and (3) the nature of the relationship the person has with each commercial interest. Slides are reviewed for possible bias before the course by the Editor, and concerns are resolved before publication. Any discussion of off-label use of products is noted. Disclosures of these commitments and/or relationships will be published in the enduring materials, so those learners in the activity may formulate their own judgments regarding the presentation(s). Under ASCCP policy, anyone declining either to disclose or amend material to eliminate potential bias identified by the Editor will be replaced. DISCLOSURES: : R. Kevin Reynolds, MD (author); L. Stewart Massad, MD (Accreditation and Enduring Materials Chair); Deborah L. McClain (Home Study Course Staff Administrator); Thomas M. Julian, MD (Journal of Lower Genital Tract Disease Executive Editor); and Sandra Smith (Journal of Lower Genital Tract Disease Administrative Assistant to the Editor) have no such financial relationship or conflict of interest to report.Richard W. Lieberman, MD (author): Science and Technology International (consultant).Mark Spitzer, MD (Home Study Course Editor): Merck (advisory board, honorarium); Elsevier (book author or CD author, royalty); Quest Laboratories (speaker's bureau, honorarium); SABK (book author or CD author, royalty)Kathleen G. Poole (ASCCP, Executive Director): Pfizer (stockholder); Eli Lilly & Co. (stockholder). DISCLAIMER: : The clinical history and images in the Home Study Course may represent an actual case, but not always. To improve educational quality, some gross, cytological, or histological images may come from photographic libraries. Good teaching cases are often difficult to obtain, and we encourage our readers to submit cases with high-quality images to the Home Study Course Editor or Executive Editor to consider for publication. ACKNOWLEDGMENT: All images courtesy of Richard W. Lieberman, MD.

Examining the relationship between positive mid-gestational fetal fibronectin assays and histological evidence of acute placental inflammation.

AIMS: Both acute placental inflammation and positive mid-gestational cervico-vaginal fetal fibronectin assays have been independently correlated with preterm delivery. We conducted this study to examine the relationship between positive mid-gestational fetal fibronectin (fFN) assays and histological evidence of acute placental inflammation at delivery among women presenting with symptomatic preterm labor. METHODS: This retrospective chart review included women who underwent cervico-vaginal fFN testing for preterm contractions between 24-34 weeks gestation and also had placental histological analysis after delivery. Women with a multiple gestation, cerclage, preterm premature rupture of membranes, intercourse or vaginal bleeding within 24 h before the assay were excluded. The primary outcome was histological evidence of acute placental inflammation defined as acute chorioamnionitis, acute deciduitis, funisitis, or microabscess formation. RESULTS: Of 82 women who met all study inclusion criteria, 45% were fFN positive. Women with positive assays were no more likely to have histological evidence of acute inflammation noted at birth than women with negative assays (45% vs. 26%, P=0.07). The assay had a sensitivity of 58.6%, specificity of 62.3%, positive predictive value of 46.0%, and negative predictive value of 73.3% for predicting acute inflammation at delivery. CONCLUSIONS: No association exists between positive fetal fibronectin assays and acute histologic placental inflammation at birth.

Pediatric sex cord-stromal tumor with composite morphology: a case report.

A 12-year-old female with developmental delay/mental retardation and a family history of gynecologic cancers presented with nonspecific abdominal complaints and was found to have a 4.5-kg, 25- x 23- x 15-cm pelvic mass with solid and cystic components and associated retroperitoneal and mesenteric lymphadenopathy. Laboratory studies revealed increased serum levels of CA-125 and inhibin B. Histologically, the tumor exhibited several different morphologic appearances including adult granulosa cell tumor, juvenile granulosa cell tumor (with areas of marked atypia), and Sertoli cell tumor. Immunohistochemically, the tumor was positive for calretinin, MIC-2 (CD99), S100 protein, PGP 9.5, and neuron-specific enolase. Electron microscopy of the Sertoli cell tumor-like areas showed Charcot-Bottcher filaments, a distinguishing feature of Sertoli cells. Together, these findings supported a diagnosis of mixed sex cord-stromal tumor including granulosa cell tumor of adult and juvenile types and intermediate- to high-grade Sertoli cell tumor, with large areas of markedly atypical sex cord-stromal tumor.

Polarizable placental particles: a case study and brief review of the literature.

Two otherwise healthy pregnant women presented with intrauterine fetal demise and underwent unremarkable induction of labor. Histopathologic examination of both placentas revealed polarizable foreign material with minimal associated tissue reaction in the membranes and adjacent maternal decidua. No overt foreign body giant cell reaction or inflammation was seen, suggesting recent introduction of the material. Further review of the histories showed that both women had undergone cervical ripening with laminaria. These are strips of collagenous seaweed placed in a closed cervix, where they absorb moisture and swell, dilating the cervix and hastening the onset of labor. Microscopic examination and polarization of known laminaria fragments identified this substance as the likely source of the polarizable material within the placental membranes. Laminaria fragments should be distinguished from other polarizable materials such as talc, suture, and retained foreign bodies on the basis of their histologic appearance and the acute nature of the accompanying tissue reaction.