Publications by authors named "Brigitte M Ronnett"

121 Publications

Ovarian Metastasis from Pancreatic Ductal Adenocarcinoma.

World J Surg 2021 10 8;45(10):3157-3164. Epub 2021 Jul 8.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high propensity for systemic dissemination. Ovarian metastases are rare and poorly described.

Methods: We identified PDAC cases with ovarian metastasis from a prospectively maintained registry. We reported on the association between outcomes and clinicopathologic factors. Recurrence-free (RFS) and overall survival (OS) were calculated using Kaplan-Meier analysis.

Results: Twelve patients with PDAC and synchronous or metachronous ovarian metastases were identified. Nine patients (75%) underwent pancreatectomy for localized PDAC and developed metachronous ovarian recurrence. The median OS for all patients was 25.4 (IQR:15.4-82.9) months. For the nine patients with metachronous ovarian metastasis, the median RFS and OS were 14.2 (IQR:7.2-58.3) and 44.6 (IQR:18.6-82.9) months, respectively. Nodal disease, poor grade, vascular invasion in the pancreatic primary, and bilateral ovarian disease tended to confer worse outcomes.

Conclusion: Patients with resected PDAC and ovarian recurrence tend to have a comparable disease course to more common patterns of recurrence. Primaries with nodal disease, poorer grade, vascular invasion, and bilateral ovarian disease were indicative of more aggressive disease biology. The ideal management remains largely unknown, and future collaborative efforts should optimize therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00268-021-06209-xDOI Listing
October 2021

Loss of p57 Expression in Conceptions Other Than Complete Hydatidiform Mole: A Case Series With Emphasis on the Etiology, Genetics, and Clinical Significance.

Am J Surg Pathol 2021 Jun 2. Epub 2021 Jun 2.

Departments of Pathology Gynecology and Obstetrics Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Combined p57 immunohistochemistry and DNA genotyping refines classification of products of conception specimens into specific types of hydatidiform moles and various nonmolar entities that can simulate them. p57 expression is highly correlated with genotyping and in practice can reliably be used to identify virtually all complete hydatidiform moles (CHM), but aberrant retained or lost p57 expression in rare CHMs and partial hydatidiform moles (PHM), as well as loss in some nonmolar abortuses, has been reported. Among a series of 2329 products of conceptions, we identified 10 cases for which loss of p57 expression was inconsistent with genotyping results (none purely androgenetic). They displayed a spectrum of generally mild abnormal villous morphology but lacked better developed features of CHMs/early CHMs, although some did suggest subtle forms of the latter. For 5 cases, genotyping (4 cases) and/or ancillary testing (1 case) determined a mechanism for the aberrant p57 results. These included 3 PHMs-2 diandric triploid and 1 triandric tetraploid-and 1 nonmolar specimen with loss of p57 expression attributable to partial or complete loss of the maternal copy of chromosome 11 and 1 nonmolar specimen with Beckwith-Wiedemann syndrome. For 5 cases, including 2 diandric triploid PHMs and 3 biparental nonmolar specimens, genotyping did not identify a mechanism, likely due to other genetic alterations which are below the resolution of or not targeted by genotyping. While overdiagnosis of a PHM as a CHM may cause less harm since appropriate follow-up with serum β-human chorionic gonadotropin levels would take place for both diagnoses, this could cause longer than necessary follow-up due to the expectation of a much greater risk of persistent gestational trophoblastic disease for CHM compared with PHM, which would be unfounded for the correct diagnosis of PHM. Overdiagnosis of a nonmolar abortus with loss of p57 expression as a CHM would lead to unnecessary follow-up and restriction on pregnancy attempts for patients with infertility. Genotyping is valuable for addressing discordance between p57 expression and morphology but cannot elucidate certain mechanisms of lost p57 expression. Future studies are warranted to determine whether chromosomal losses or gains, particularly involving imprinted genes such as p57, might play a role in modifying the risk of persistent gestational trophoblastic disease for PHMs and nonmolar conceptions that are not purely androgenetic but have some abnormal paternal imprinting of the type seen in CHMs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001749DOI Listing
June 2021

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

J Pathol Inform 2021 22;12:15. Epub 2021 Mar 22.

Division of Molecular Genetics and Pathology, Office of In Vitro Diagnostics and Radiological Health, Office of Product Evaluation and Quality, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.

Background: Observer studies in pathology often utilize a limited number of representative slides per case, selected and reported in a nonstandardized manner. Reference diagnoses are commonly assumed to be generalizable to all slides of a case. We examined these issues in the context of pathologist concordance for histologic subtype classification of ovarian carcinomas (OCs).

Materials And Methods: A cohort of 114 OCs consisting of 72 cases with a single representative slide (Group 1) and 42 cases with multiple representative slides (148 slides, 2-6 sections per case, Group 2) was independently reviewed by three experts in gynecologic pathology (case-based review). In a follow-up study, each individual slide was independently reviewed in a randomized order by the same pathologists (section-based review).

Results: Average interobserver concordance varied from 100% for Group 1 to 64.3% for Group 2 (86.8% across all cases). Across Group 2, 19 cases (45.2%) had at least one slide classified as a different subtype than the subtype assigned from case-based review, demonstrating the impact of intratumoral heterogeneity. Section-based concordance across individual sections from Group 2 was comparable to case-based concordance for those cases indicating diagnostic challenges at the individual section level. Findings demonstrate the increased diagnostic complexity of heterogeneous tumors that require multiple section sampling and its impact on pathologist performance.

Conclusions: The proportion of cases with multiple representative slides in cohorts used in validation studies, such as those conducted to evaluate artificial intelligence/machine learning tools, can influence diagnostic performance, and if not accounted for, can cause disparities between research and real-world observations and between research studies. Case selection in validation studies should account for tumor heterogeneity to create balanced datasets in terms of diagnostic complexity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/jpi.jpi_56_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112350PMC
March 2021

Rare Complete Hydatidiform Mole With p57 Expression in Villous Mesenchyme: Case Report and Review of Discordant p57 Expression in Hydatidiform Moles.

Int J Gynecol Pathol 2021 Apr 23. Epub 2021 Apr 23.

ProPath (K.M.M.) Department of Obstetrics and Gynecology (V.R. and D.H.C.) Department of Pathology, Division of Cytogenetics (P.K.) Department of Pathology, Division of Gynecologic Pathology (K.C., K.G., and D.H.C.), UT Southwestern Medical Center, Dallas, Texas Departments of Pathology and Gynecology & Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, Maryland (B.M.R.).

Complete hydatidiform mole (CHM) is a premalignant proliferative disease of the placenta characterized by misexpression of imprinted gene products, most notably p57. The majority of CHM exhibit immunohistochemical absence of p57 protein in villous mesenchyme (VM) and cytotrophoblast (CT) and are thus p57 VM/CT concordant. However, some gestations show loss of p57 in only VM or CT, either in all chorionic villi or a subset thereof (VM/CT discordant). Here, we present a rare case of a p57 VM/CT-discordant CHM with diffuse retention of p57 expression in VM but complete absence in CT. Histologically, the case exhibited typical features of CHM including trophoblast hyperplasia and severe nuclear atypia, but was unusual in the presence of gestational membranes identified ultrasonographically and histologically. Ploidy determination by FISH and genotyping by short tandem repeat analyses showed that this was a diploid gestation with variable allelic ratios and with an androgenetic lineage, similar to previously reported p57 VM/CT-discordant cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000773DOI Listing
April 2021

Pathologist Concordance for Ovarian Carcinoma Subtype Classification and Identification of Relevant Histologic Features Using Microscope and Whole Slide Imaging: A Multisite Observer Study.

Arch Pathol Lab Med 2021 Feb 26. Epub 2021 Feb 26.

and the Division of Molecular Genetics and Pathology, Office of In Vitro Diagnostics and Radiological Health (Seidman), Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland.

Context.—: Despite several studies focusing on the validation of whole slide imaging (WSI) across organ systems or subspecialties, the use of WSI for specific primary diagnosis tasks has been underexamined.

Objective.—: To assess pathologist performance for the histologic subtyping of individual sections of ovarian carcinomas using the light microscope and WSI.

Design.—: A panel of 3 experienced gynecologic pathologists provided reference subtype diagnoses for 212 histologic sections from 109 ovarian carcinomas based on optical microscopy review. Two additional attending pathologists provided diagnoses and also identified the presence of a set of 8 histologic features important for ovarian tumor subtyping. Two experienced gynecologic pathologists and 2 fellows reviewed the corresponding WSI images for subtype classification and feature identification.

Results.—: Across pathologists specialized in gynecologic pathology, concordance with the reference diagnosis for the 5 major ovarian carcinoma subtypes was significantly higher for a pathologist reading on microscope than each of 2 pathologists reading on WSI. Differences were primarily due to more frequent classification of mucinous carcinomas as endometrioid with WSI. Pathologists had generally low agreement in identifying histologic features important to ovarian tumor subtype classification, with either optical microscopy or WSI. This result suggests the need for refined histologic criteria for identifying such features. Interobserver agreement was particularly low for identifying intracytoplasmic mucin with WSI. Inconsistencies in evaluating nuclear atypia and mitoses with WSI were also observed.

Conclusions.—: Further research is needed to specify the reasons for these diagnostic challenges and to inform users and manufacturers of WSI technology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2020-0579-OADOI Listing
February 2021

Refined diagnosis of hydatidiform moles with p57 immunohistochemistry and molecular genotyping: updated analysis of a prospective series of 2217 cases.

Mod Pathol 2021 05 6;34(5):961-982. Epub 2020 Oct 6.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Immunohistochemical analysis of p57 expression and molecular genotyping accurately subclassify molar specimens into complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM) and distinguish these from nonmolar specimens. Characteristics of a prospective series of potentially molar specimens analyzed in a large gynecologic pathology practice are summarized. Of 2217 cases (2160 uterine, 57 ectopic), 2080 (94%) were successfully classified: 571 CHMs (570 uterine, 1 ectopic), 498 PHMs (497 uterine, 1 ectopic), 900 nonmolar (including 147 trisomies, 19 digynic triploids, and 4 donor egg conceptions), and 56 androgenetic/biparental mosaics; 137 were complex or unsatisfactory and not definitively classified. CHMs dominated in patients aged < 21 and >45 years and were the only kind of molar conception found in the latter group. Of 564 successfully immunostained CHMs, 563 (99.8%) were p57-negative (1 p57-positive [retained maternal chromosome 11] androgenetic by genotyping). Of 153 genotyped CHMs, 148 (96.7%) were androgenetic (85% monospermic) and 5 were biparental, the latter likely familial biparental hydatidiform moles. Of 486 successfully immunostained PHMs, 481 (99%) were p57-positive (3 p57-negative [loss of maternal chromosome 11], 2 unknown mechanism). Of 497 genotyped PHMs, 484 (97%) were diandric triploid (99% dispermic) and 13 were triandric tetraploid (all at least dispermic). Of 56 androgenetic/biparental mosaics, 37 had a p57-negative complete molar component (16 confirmed as androgenetic by genotyping). p57 expression is highly correlated with genotyping, serving as a reliable marker for CHMs, and identifies molar components and androgenetic cell lines in mosaic conceptions. Correlation of morphology, p57 expression, genotyping data, and history are required to recognize familial biparental hydatidiform moles and donor egg conceptions, as the former can be misclassified as nonmolar and the latter can be misclassified as dispermic CHM on the basis of isolated genotyping results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-00691-9DOI Listing
May 2021

Coexistence of Conventional Leiomyoma, Fumarate Hydratase-deficient Atypical Leiomyoma, and Perivascular Epithelioid Cell Tumor in a Uterus: A Case Study.

Int J Gynecol Pathol 2021 Mar;40(2):134-140

A 44-yr-old woman with menorrhagia and uterine fibroids underwent total laparoscopic hysterectomy, revealing several submucosal, intramural, and subserosal tan-white nodules in the uterus. Microscopic examination revealed tumors displaying 3 distinct morphologies: 1 tumor with features of conventional leiomyoma; 1 tumor with increased cellularity, staghorn/hemangiopericytoma-like vasculature, and occasional atypical cells with prominent red nucleoli and some perinucleolar halos suggesting a fumarate hydratase (FH)-deficient atypical leiomyoma; and 1 tumor with an admixture of epithelioid and spindled cells with the former arranged around blood vessels suggesting a perivascular epithelioid cell tumor (PEComa). Immunohistochemical studies confirmed these diagnoses by demonstrating loss of FH expression in the atypical leiomyoma and diffuse expression of HMB45 and cathepsin K in the tumor with epithelioid features. Sanger sequencing analysis revealed that the FH-deficient atypical leiomyoma harbored a c.181A>G (p.Lys61Glu) mutation in exon 2 of the FH gene. As this mutation was not present in either the other tumors or peripheral blood, the mutation is somatic and hereditary leiomyomatosis and renal cell cancer syndrome is excluded. This case highlights the importance of thorough examination of uterine mesenchymal tumors with atypical and epithelioid features so that tumors with some potential for recurrence (PEComas) and those that might indicate a hereditary cancer syndrome (FH-deficient atypical leiomyoma) are identified and can trigger appropriate clinical investigation and follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000676DOI Listing
March 2021

A novel group of HPV-related adenocarcinomas of the lower anogenital tract (vagina, vulva, and anorectum) in women and men resembling HPV-related endocervical adenocarcinomas.

Mod Pathol 2020 05 19;33(5):944-952. Epub 2019 Dec 19.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Human papillomavirus (HPV) is an oncogenic virus associated with the development of several human cancers. Primary vaginal, vulvar, and anal adenocarcinomas are rare and, to date, have rarely been shown to be associated with HPV infection. We report a series of nine HPV-related adenocarcinomas of the lower anogenital tract distal to the cervix. The tumors involved the vagina (4), anorectum (3), and vulva (2). Two of the three anorectal cases involved men. Patients presented with a vulvar or vaginal mass/nodule, painless rectal bleeding, or during screening colonoscopy. Lesions ranged in size from 3.2 to 8.4 cm. The most salient morphologic characteristic was the presence of papillary or villiform/villoglandular architecture in all cases. Tumors displayed features similar to those of usual type high-risk HPV-related endocervical adenocarcinoma, namely, mucinous or mucin-poor (pseudoendometrioid) features or a hybrid of these, with columnar cells with crowded, cigar-shaped to ovoid irregular nuclei. Mitoses (mostly apical) and apoptotic bodies were easily identified. Adenosis was present in two vaginal cases. One anal tumor featured abundant intracytoplasmic mucin that was multivacuolated in some areas imparting a "clear cell"-like appearance. All tumors were diffusely and strongly positive for p16. Seven of seven tested cases were positive for high-risk HPV by in situ hybridization or polymerase chain reaction. Follow-up information, available in five patients, revealed two local recurrences but no tumor related deaths or distant metastases. We report the first well-documented series of HPV-associated primary adenocarcinomas of the vagina, vulva, and anorectum and broaden the spectrum of HPV-related neoplasia involving the lower anogenital tract in both women and men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0437-zDOI Listing
May 2020

Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes.

Mod Pathol 2020 05 19;33(5):880-892. Epub 2019 Dec 19.

Division of Experimental Medicine, McGill University, Montreal, QC, Canada.

Hydatidiform mole (HM) is an aberrant human pregnancy characterized by excessive trophoblastic proliferation and abnormal embryonic development. HM has two morphological types, complete (CHM) and partial (PHM), and non-recurrent ones have three genotypic types, androgenetic monospermic, androgenetic dispermic, and triploid dispermic. Most available studies on risk factors predisposing to different types of HM and their malignant transformation mainly suffer from the lack of comprehensive genotypic analysis of large cohorts of molar tissues combined with accurate postmolar hCG follow-up. Moreover, 10-20% of patients with one HM have at least one non-molar miscarriage, which is higher than the frequency of two pregnancy losses in the general population (2-5%), suggesting a common genetic susceptibility to HM and miscarriages. However, the underlying causes of the miscarriages in these patients are unknown. Here, we comprehensively analyzed 204 HM, mostly from patients referred to the Quebec Registry of Trophoblastic Diseases and for which postmolar hCG monitoring is available, and 30 of their non-molar miscarriages. We revisited the risk of maternal age and neoplastic transformation across the different HM genotypic categories and investigated the presence of chromosomal abnormalities in their non-molar miscarriages. We confirm that androgenetic CHM is more prone to gestational trophoblastic neoplasia (GTN) than triploid dispermic PHM, and androgenetic dispermic CHM is more prone to high-risk GTN and choriocarcinoma (CC) than androgenetic monospermic CHM. We also confirm the association between increased maternal age and androgenetic CHM and their malignancies. Most importantly, we demonstrate for the first time that patients with an HM and miscarriages are at higher risk for aneuploid miscarriages [83.3%, 95% confidence interval (CI): 0.653-0.944] than women with sporadic (51.5%, 95% CI: 50.3-52.7%, p value = 0.0003828) or recurrent miscarriages (43.8%, 95% CI: 40.7-47.0%, p value = 0.00002). Our data suggest common genetic female germline defects predisposing to HM and aneuploid non-molar miscarriages in some patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0432-4DOI Listing
May 2020

Characterization of an Adapted Murine Model of Intrauterine Inflammation-Induced Preterm Birth.

Am J Pathol 2020 02 16;190(2):295-305. Epub 2019 Dec 16.

The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland; Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Maternal Fetal Medicine, Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University, Baltimore, Maryland. Electronic address:

Preterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs, >25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. An in vivo imaging system revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI). Endotoxin concentrations in vaginal lavage fluid from SPI dams were significantly higher than from DDI dams. At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose-response, whereas SPI did not. Gene expression in myometrial tissue revealed increased levels of inflammatory markers in dams that received LPS DDI compared with LPS SPI. The SPI group showed more significant overexpression in cervical remodeling genes, likely due to the leakage of LPS from the uterine horns through the cervix. The more reliable PTB induction and uniform uterine exposure provided by this new model will be useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013271PMC
February 2020

Relationships of p16 Immunohistochemistry and Other Biomarkers With Diagnoses of Cervical Abnormalities: Implications for LAST Terminology.

Arch Pathol Lab Med 2020 06 13;144(6):725-734. Epub 2019 Nov 13.

From Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York (Dr Castle); Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom (Ms Adcock and Dr Cuzick); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland (Drs Wentzensen and Schiffman); the Department of Pathology, University of New Mexico Cancer Center, Albuquerque (Ms Torrez-Martinez, Dr Torres, Dr Joste, Dr Gravitt, Mr Hunt, and Dr Wheeler); the Department of Pathology, University of Virginia Health System, Charlottesville (Dr Stoler); the Department of Pathology, Johns Hopkins University, Baltimore, Maryland (Dr Ronnett); the Department of Pathology, University of California, San Francisco (Dr Darragh); and Sacramento, California (Dr Kinney).

Context.—: Lower Anogenital Squamous Terminology (LAST) standardization recommended p16 immunohistochemistry (p16 IHC) for biopsies diagnosed morphologically as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2) to classify them as low-grade or high-grade squamous intraepithelial lesions (HSILs).

Objective.—: To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses.

Design.—: A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available.

Results.—: Biopsies were more likely to test p16 IHC positive with increasing severity of CP diagnoses, overall ( ≤ .001) and within each HPV risk group ( ≤ .001 except for low-risk HPV [ < .010]). All abnormal grades of CP-diagnosed biopsies were more likely to test p16 IHC positive with a higher HPV risk group ( < .001), and testing p16 IHC positive was associated with higher HPV risk group than testing p16 IHC negative for each grade of CP-diagnosed biopsies ( < .001). p16 IHC-positive, CP-diagnosed CIN2 biopsies were less likely than CP-diagnosed CIN3 biopsies to test HPV16 positive, have an antecedent HSIL cytology, or to be diagnosed as CIN3 by the EP ( .001 for all). p16 IHC-positive, CP-diagnosed CIN1 biopsies had lower HPV risk groups than p16 IHC-negative, CP-diagnosed CIN2 biopsies ( < .001).

Conclusions.—: p16 IHC-positive, CP-diagnosed CIN2 appears to be lower cancer risk than CP-diagnosed CIN3. LAST classification of "HSIL" diagnosis, which includes p16 IHC-positive CIN2, should annotate the morphologic diagnosis (CIN2 or CIN3) to inform all management decisions, which is especially important for young (<30 years) women diagnosed with CIN2 for whom surveillance rather than treatment is recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2019-0241-OADOI Listing
June 2020

Ovarian Intermediate Trophoblastic Tumors: Genotyping Defines a Distinct Category of Nongestational Tumors of Germ Cell Type.

Am J Surg Pathol 2020 04;44(4):516-525

Departments of Pathology.

Trophoblastic neoplasms involving the ovary are uncommon and include gestational tumors, which are either metastatic from the uterus or ectopic and nongestational tumors, which include those of germ cell type/origin and somatic tumors with trophoblastic differentiation; in all these types, most are pure choriocarcinoma. Intermediate trophoblastic tumors, which include placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT), are rare in the ovary, with most assumed to be gestational; this is the only category formally recognized in 2014 World Health Organization (WHO) classification, likely due to few well-documented nongestational examples. We report the clinicopathologic features of 6 ovarian intermediate trophoblastic tumors, including 3 PSTTs, 2 ETTs, and 1 ETT with choriocarcinomatous differentiation. DNA-based short tandem repeat genotyping identified 4 of these as nongestational (3 PSTTs and 1 ETT), as evidenced by sharing of alleles between tumor and normal tissue at all informative loci. Interestingly, all 3 of the nongestational PSTTs coexisted with mature cystic teratoma. The remaining 2 tumors (1 ETT and 1 ETT with some choriocarcinomatous differentiation) were gestational (likely ectopic due to lack of evidence of a uterine tumor), as evidenced by the presence of both maternal and novel/nonmaternal alleles at informative loci in tumor compared with normal tissue. It is important to recognize a distinct category of primary ovarian nongestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, in classification systems to guide clinical management, as gestational and nongestational tumors have different genetic origins and may require different therapy. Genotyping is useful for classification as nongestational versus gestational, particularly as traditional clinicopathologic findings cannot always predict the nature of a trophoblastic tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373165PMC
April 2020

Tetraploid Partial Hydatidiform Moles: Molecular Genotyping and Determination of Parental Contributions.

J Mol Diagn 2020 01 24;22(1):90-100. Epub 2019 Oct 24.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

DNA genotyping studies have established that most partial hydatidiform moles (PHMs) are diandric dispermic triploid conceptions. Rare triandric tetraploid PHMs have been described, but genotyping cannot determine the manner in which three paternal chromosome complements are derived (one sperm with triplication, two sperm with one duplication, three different sperm, or one diploid and one haploid sperm). In a large prospective analysis of potentially molar products of conception, five tetraploid PHMs were encountered among 235 PHMs. Single-nucleotide polymorphism (SNP) arrays were used to define different paternal chromosomal contributions. Short tandem repeat analysis of the five tetraploid PHMs established that these contained three paternal and one maternal chromosome complements. In each case, the corresponding SNP array found five tracts with segmented absence of the central tract across approximately 25% of the genome. Meiotic crossovers could be observed directly in the chromosomes via the total number of starts and stops of regions of loss of heterozygosity. The findings are consistent with each conceptus having three different paternal contributions and one maternal contribution. These findings suggest that tetraploid PHMs arise when three different sperm fertilize a single, normal ovum. SNP array is useful to determine the parental contributions in triploid/tetraploid conceptuses. It also allows for direct visualization of meiotic crossover frequency and sites in these conceptions, providing insight into their biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2019.09.006DOI Listing
January 2020

Genetically Related Choriocarcinoma Developing 5 Yr After a Complete Hydatidiform Mole and Simulating a Cornual Ectopic Pregnancy.

Int J Gynecol Pathol 2020 Jul;39(4):367-372

Department of Gynecology and Obstetrics, The Kelly Gynecologic Oncology Service (D.B.C., A.L.B., A.N.F., R.S.) Department of Pathology (B.M.R., E.J., C.D.G.) Department of Gynecology and Obstetrics (B.M.R., J.A.) Department of Oncology (C.D.G.), Johns Hopkins Hospital, Baltimore, Maryland.

Persistent gestational trophoblastic disease can arise from any type of antecedent pregnancy, including molar and tubal pregnancies. While most cases of persistent gestational trophoblastic disease present within the first year following initial diagnosis, recurrence has rarely been reported many years after initial diagnosis. Distinguishing recurrence from a new independent lesion is clinically important. A 25-yr-old woman presented with a mass in the right uterine cornu that was discontiguous with the endometrial cavity and was associated with an elevated serum human chorionic gonadotropin level. She had a history of an invasive complete hydatidiform mole with lung involvement treated with chemotherapy 5 yr prior. Wedge resection of the right cornu was performed due to concern for a cornual ectopic pregnancy. Pathologic evaluation demonstrated a choriocarcinoma. Molecular genotyping confirmed the tumor as recurrent disease genetically related to the prior complete hydatidiform mole. She completed 4 cycles of EMA-CO therapy, and has been disease-free with undetectable serum human chorionic gonadotropin level for 2 yr.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000607DOI Listing
July 2020

Lineage-Specific Alterations in Gynecologic Neoplasms with Choriocarcinomatous Differentiation: Implications for Origin and Therapeutics.

Clin Cancer Res 2019 07 22;25(14):4516-4529. Epub 2019 Apr 22.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Purpose: Choriocarcinoma is most commonly gestational (androgenetic or biparental) but can be of germ cell origin or can develop as a component of a somatic neoplasm (genetically related to the patient). The latter type are aggressive neoplasms for which the underlying genetic alterations are not well characterized.

Experimental Design: To investigate the relationship between the different components of somatic neoplasms with choriocarcinomatous elements, the genetic differences between gestational and nongestational tumors, and identify potential targetable alterations, we analyzed 23 samples from 11 tumors, including five gynecologic-type somatic neoplasms with choriocarcinomatous differentiation (two to three different components each) and six pure choriocarcinomas, for somatic mutations, single-nucleotide polymorphisms, and PD-L1 expression.

Results: In mixed tumors, gynecologic-type carcinoma components demonstrated lineage-characteristic and lineage-specific alterations, with choriocarcinomatous components sharing some of these as well as demonstrating novel alterations, supporting a clonal relationship with divergent differentiation of the choriocarcinoma from the somatic carcinoma. mutation only occurred in nongestational tumors. Diffuse PD-L1 expression was characteristic of choriocarcinoma in both pure and mixed tumors but not seen in the gynecologic-type carcinoma components.

Conclusions: Given that the somatic carcinomatous and choriocarcinomatous components of mixed tumors have distinct genetic alterations and biomarker expression, separate analysis of these components is required to guide targeted therapy. High PD-L1 expression suggests a role for checkpoint inhibitor-based immunotherapy in tumors with a choriocarcinoma component. The underlying mechanisms by which cancer stem cells reprogram and initiate trophoblastic retrodifferentiation in some somatic tumors warrant further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-4278DOI Listing
July 2019

Nine-valent HPV vaccine efficacy against related diseases and definitive therapy: comparison with historic placebo population.

Gynecol Oncol 2019 07 11;154(1):110-117. Epub 2019 Apr 11.

Merck & Co., Inc., Kenilworth, NJ, United States. Electronic address:

Objective: Nine-valent human papillomavirus (9vHPV) vaccine efficacy against disease and cervical surgeries related to all nine vaccine components was assessed compared with a historic placebo population. This was not assessed in the 9vHPV vaccine efficacy trial since the trial was quadrivalent HPV (qHPV) vaccine-controlled, efficacy was measured for the five HPV types covered only by 9vHPV vaccine (HPV31/33/45/52/58), but not the four types covered by both vaccines (HPV6/11/16/18).

Methods: Three international, randomized, double-blind studies were conducted using the same methodology. In the 9vHPV vaccine study (NCT00543543), 7106 and 7109 women received 9vHPV or qHPV vaccine, respectively. In the historic qHPV vaccine studies (FUTURE I [NCT00092521] and II [NCT00092534]), 8810 and 8812 women received qHPV vaccine or placebo, respectively, based on the same eligibility criteria. Cervical cytological testing was performed regularly. Biopsy or definitive therapy specimens were assessed for HPV DNA.

Results: Among women negative for 14 HPV types prior to vaccination, incidence of high-grade cervical disease (9vHPV, n = 2 cases; placebo, n = 141 cases) and cervical surgery (9vHPV, n = 3 cases; placebo, n = 170 cases) related to the nine HPV types was reduced by 98.2% (95% confidence interval [CI], 93.6-99.7) and 97.8% (95% CI, 93.4-99.4), respectively. The 9vHPV vaccine did not prevent disease related to vaccine HPV types detected at baseline, but significantly reduced cervical, vulvar, and vaginal diseases related to other vaccine HPV types.

Conclusions: Effective implementation of the 9vHPV vaccine may substantially reduce the burden of HPV-related diseases and related medical procedures.

Trial Registrations: clinicaltrials.gov: NCT00543543, NCT00092521, NCT00092534.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ygyno.2019.03.253DOI Listing
July 2019

A Rare Case of Atypical Placental Site Nodule With an Emerging Intermediate Trophoblastic Tumor.

Int J Gynecol Pathol 2020 May;39(3):238-246

Department of Obstetrics/Gynecology (J.D.) Department of Obstetrics/Gynecology, Division of Gynecologic Oncology (D.M.O.), The Ohio State University College of Medicine Department of Pathology, The Ohio State University (W.C.), Columbus, Ohio Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland (B.M.R.).

Placental site nodule (PSN) is a benign lesion composed of chorionic-type intermediate trophoblastic cells and is typically an incidental finding in uterine or endocervical curettage specimens. Epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT) are intermediate trophoblastic neoplasms of chorionic and implantation site types, respectively. ETT is speculated to be the neoplastic counterpart of PSN. The term atypical placental site nodule (APSN) has been proposed for PSN-type lesions displaying one or more concerning features, including larger size/more abundant lesional tissue, more extensive plaque-like growth, increased cellularity with more cohesive nests and cords of cells, a greater extent/distribution of necrosis, increased atypia, mitotic activity, and/or a Ki-67 proliferation index greater than usually encountered in the typical PSN. It has been proposed that APSN is an intermediary lesion between PSN and intermediate trophoblastic tumors, more commonly ETT but also PSTT. We report a case of a 39-yr-old woman who developed abnormal uterine bleeding 44 mo after her last recognized pregnancy. An endometrial curettage specimen demonstrated an APSN with some features concerning for an intermediate trophoblastic tumor. A hysterectomy specimen demonstrated residual APSN with foci consistent with emerging PSTT and ETT. This case illustrates the earliest form of PSTT and ETT arising in association with an APSN and supports interpretation of APSN as an intermediary lesion between typical PSN and intermediate trophoblastic tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000598DOI Listing
May 2020

Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites.

Int J Gynecol Pathol 2019 Jan;38 Suppl 1:S75-S92

Department of Histopathology, King Edward Memorial Hospital and School for Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia (C.J.R.S.) Department of Pathology, Brigham and Women's Hospital (C.P.C.) Department of Pathology, Massachusetts General Hospital and Harvard Medical School (E.O.), Boston, Massachusetts Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK (W.G.M.) Department of Pathology, Memorial-Sloan Kettering Cancer Center, New York, New York (K.J.P.) Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California (J.K.R.) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.M.) Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (V.P.) Pathological Oncology Group and Pathology Department, Hospital Arnau de Vilanova, Lleida, Spain (X.M.-G.) Departments of Pathology and Gynecology and Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland (B.M.R.).

In most cases of suspected endometrial neoplasia tumor origin can be correctly assigned according to a combination of clinical, radiologic, and pathologic features, even when the latter are based upon the examination of relatively small biopsy samples. However there are well-recognized exceptions to this rule which continue to create diagnostic difficulty, and sometimes difficulties persist even after the detailed examination of resection specimens. Among the most common problems encountered in practice are the distinction of primary endometrial and primary endocervical adenocarcinomas, and the determination of tumor origin when there is synchronous, multifocal involvement of gynecologic tract sites, for example the endometrium and the ovary. However, accurate diagnosis in these cases is important because this has significant staging, management and prognostic implications. In this review we discuss the value and limitations of key morphologic, immunophenotypic and molecular findings in these diagnostic scenarios.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296834PMC
January 2019

Issues in the Differential Diagnosis of Uterine Low-grade Endometrioid Carcinoma, Including Mixed Endometrial Carcinomas: Recommendations from the International Society of Gynecological Pathologists.

Int J Gynecol Pathol 2019 Jan;38 Suppl 1:S25-S39

Pathology Department, University of California San Francisco, San Francisco, California (J.T.R.) Department of Pathology and Laboratory Medicine, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada (C.B.G.) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas (A.M.) Department of Pathology, University Hospital Arnau de Vilanova and Department of Pathology, University Hospital de Bellvitge, University of Lleida, IRBLLEIDA, IDIBELL, CIBERONC, Spain (X.M.G.) Department of Pathology, New York University Langone Medical Center, New York, New York (K.M.) Department of Pathology, Brigham and Women's Hospital (G.L.M.) Pathology Department, Massachusetts General Hospital (E.O.), Boston, Massachusetts Pathology Department, Yale New Haven Hospital, New Haven, Connecticut (V.P.) Department of Pathology, Johns Hopkins Medical Institutions (B.M.R.) Department of Pathology, University of Maryland School of Medicine (P.S.), Baltimore, Maryland Department of Histopathology, King Edward Memorial Hospital and School for Women's and Infants' Health, University of Western Australia, Perth, Australia (C.J.R.S.) Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland, UK (W.G.M.).

This article provides practical recommendations developed from the International Society of Gynecological Pathologists Endometrial Carcinoma Project to address 4 issues that may arise in the diagnosis of uterine corpus low-grade endometrioid carcinoma: (1) The distinction between atypical hyperplasia and low-grade endometrioid carcinoma. (2) The distinction between low-grade endometrioid carcinoma and serous carcinoma. (3) The distinction between corded and hyalinized or spindle cell variants of low-grade endometrioid carcinoma and carcinosarcoma. (4) The diagnostic criteria for mixed endometrial carcinomas, a rare entity that should be diagnosed only after exclusion of a spectrum of tumors including morphologic variants of endometrioid carcinoma, dedifferentiated endometrial carcinoma, carcinosarcoma, and endometrial carcinomas with ambiguous morphology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296831PMC
January 2019

Hydatidiform Moles: Ancillary Techniques to Refine Diagnosis.

Arch Pathol Lab Med 2018 12;142(12):1485-1502

From the Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland.

Context.—: Distinction of hydatidiform moles from nonmolar specimens and subclassification of hydatidiform moles as complete hydatidiform mole versus partial hydatidiform mole are important for clinical practice and investigational studies. Risk of persistent gestational trophoblastic disease and clinical management differ for these entities. Diagnosis based on morphology is subject to interobserver variability and remains problematic, even for experienced gynecologic pathologists.

Objectives.—: To explain how ancillary techniques target the unique genetic features of hydatidiform moles to establish diagnostic truth, highlight the issue of diagnostic reproducibility and importance of diagnostic accuracy, and illustrate use of p57 immunohistochemistry and polymerase chain reaction-based DNA genotyping for diagnosis.

Data Sources.—: Sources are the author's 10-year experience using ancillary techniques for the evaluation of potentially molar specimens in a large gynecologic pathology practice and the literature.

Conclusions.—: The unique genetics of complete hydatidiform moles (purely androgenetic), partial hydatidiform moles (diandric triploid), and nonmolar specimens (biparental, with allelic balance) allow for certain techniques, including immunohistochemical analysis of p57 expression (a paternally imprinted, maternally expressed gene) and genotyping, to refine diagnoses of hydatidiform moles. Although p57 immunostaining alone can identify complete hydatidiform moles, which lack p57 expression because of a lack of maternal DNA, this analysis does not distinguish partial hydatidiform moles from nonmolar specimens because both express p57 because of the presence of maternal DNA. Genotyping, which compares villous and decidual DNA patterns to determine the parental source and ratios of polymorphic alleles, distinguishes purely androgenetic complete hydatidiform moles from diandric triploid partial hydatidiform moles, and both of these from biparental nonmolar specimens. An algorithmic approach to diagnosis using these techniques is advocated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2018-0226-RADOI Listing
December 2018

Central Nervous System-type Neuroepithelial Tumors and Tumor-like Proliferations Developing in the Gynecologic Tract and Pelvis: Clinicopathologic Analysis of 23 Cases.

Am J Surg Pathol 2018 11;42(11):1429-1444

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Central nervous system (CNS)-type tumors and tumor-like proliferations arising in the gynecologic tract and pelvis are rare. Clinicopathologic features of 23 cases are reported using the current WHO classification system for CNS tumors, with selected relevant immunohistochemical and molecular genetic analyses when possible. There were 12 embryonal tumors, including 7 medulloepitheliomas, 2 embryonal tumors (not otherwise specified), 1 embryonal tumor with multilayered rosettes, 1 embryonal tumor with features of nodular desmoplastic medulloblastoma, and 1 medulloblastoma with extensive nodularity, with primary sites including ovary (7), uterus/endometrium (3), and pelvis (2). Six ovarian tumors had associated germ cell tumors (3 immature teratomas [1 also with yolk sac tumor], 2 mature cystic teratomas, and 1 yolk sac tumor). These tumors typically had some expression of synaptophysin (10/10), GFAP (5/9), S100 (3/6), and NeuN (3/3) and were negative for C19MC amplicon by fluorescence in situ hybridization (0/5). There were 6 glial tumors, including 3 ependymomas (1 anaplastic), 1 oligodendroglioma, not otherwise specified, 1 pilocytic astrocytoma, and 1 atypical glial proliferation after therapy of a high-grade high-stage immature teratoma, with primary sites including ovary (4), fallopian tube (1), and pelvic sidewall (1). Four ovarian tumors had associated teratomas (2 immature and 2 mature). These tumors expressed GFAP (5/6), OLIG2 (2/3), and S100 (1/1), and the pilocytic astrocytoma was negative for BRAF (V600E) mutant protein. There were 4 neuronal or mixed glioneuronal tumors, including 3 neurocytomas and 1 malignant (high-grade) glioneuronal neoplasm, all primary ovarian and associated with teratomas (3 mature, 1 immature). These tumors expressed synaptophysin (4/4), GFAP (1/3), NeuN (1/2), and OLIG2 (1/2). Single-nucleotide polymorphism microarray analysis of the malignant glioneuronal neoplasm demonstrated a partial deletion at location (1)(p36.23p35.2) on chromosome 1p, and 2 regions of deletion at locations (19)(q11q13.12) and (19)(q13.41qter) on 19q. One neurocytoma had no 1p and 19q co-deletions. There was 1 meningioma in the pelvis. For 10 patients with embryonal tumors and follow-up, 5 were alive with no evidence of disease (mean/median: 60/52 mo), 4 were alive with recurrent disease (mean/median: 32/31 mo), and 1 died of disease (13 mo). For 5 patients with other tumor types and follow-up, all were alive without evidence of disease (mean/median: 33/30 mo). Diagnostic evaluation and classification per systems used for primary CNS tumors are recommended for the wide spectrum of CNS-type neuroepithelial tumors that can occur in the female genital tract and pelvis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001131DOI Listing
November 2018

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

Obstet Gynecol 2018 08;132(2):261-270

Department of Microbiology Infectious Diseases, the Royal Women's Hospital, Department of Microbiology, the Royal Children's Hospital, Infection and Immunity, Murdoch Children's Research Institute, Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; the Department of Gynecology and Obstetrics, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; the Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas; Institut Catala d'Oncologia, IDIBELL, CIBER-ESP, RTICC, L'Hospitalet de Llobregat, Barcelona, Spain; the Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; the Department of Pathology, SMBD Jewish General Hospital and McGill University, Montréal, Québec, Canada; the Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia; the Center for Infection Research in Cancer, Moffitt Cancer Center, Tampa, Florida; the National Institute of Public Health, Cuernavaca, Morelos, Mexico; the Division of Gynecologic Oncology, University of Alabama, Birmingham, Alabama; the Department of Clinical Science, University of Bergen/Haukeland University Hospital, Bergen, Norway; the Danish Cancer Society Research Center, Copenhagen, Denmark and Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Johns Hopkins University School of Medicine, Baltimore, Maryland; the Department of Obstetrics and Gynecology, Clinica Colsanitas, Fundacion Universitaria Sanitas, Bogota, Colombia; Institut du col, Paris, France; the National Institute of Cancer, Bogotá, Colombia; the Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland; the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Direction des Risques Biologiques et de la Santé au Travail, Institut National de Santé Publique du Québec, Montréal, Québec, Canada; Robert E. Fechner Laboratory of Surgical Pathology, University of Virginia Health System, Charlottesville, Virginia; the Departments of Pathology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico; UCLA School of Nursing, Los Angeles, California; Merck & Co, Inc., Kenilworth, New Jersey; Universidad del Rosario, Bogota, Colombia; and Analytica LASÉR, Montréal, Québec, Canada.

Objective: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59).

Methods: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods.

Results: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs.

Conclusion: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs.

Clinical Trial Registration: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000002736DOI Listing
August 2018

An Epithelioid Smooth Muscle Neoplasm Mimicking a Signet Ring Cell Carcinoma in the Ovary.

Int J Gynecol Pathol 2019 Sep;38(5):464-469

Department of Pathology, The Johns Hopkins Medical Institute, Baltimore, Maryland (D.X., A.A.B., C.L., A.R., R.V., B.M.R.).

A 53-yr-old woman who presented with elevated renal indices was discovered to have a 4.5 cm right renal mass and an incidental 9.7 cm left ovarian mass on imaging studies. She underwent a partial nephrectomy and bilateral salpingo-oophorectomy, revealing a chromophobe renal cell carcinoma and an unusual ovarian neoplasm with epithelioid cells displaying prominent signet ring cell-like morphology. Immunohistochemical analysis of the ovarian neoplasm demonstrated that the tumor cells were diffusely immunoreactive for smooth muscle markers and negative for all tested cytokeratins and epithelial membrane antigen. On the basis of these results, the tumor was interpreted as an unusual epithelioid smooth muscle neoplasm with extensive signet ring cell-like features. Along with primary ovarian signet ring stromal tumors and sclerosing stromal tumors, this example adds epithelioid smooth muscle neoplasms with unusual cytologic alterations to the list of uncommon nonepithelial tumors that can simulate metastatic signet ring cell carcinoma (Krukenberg tumor) in the ovary.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000520DOI Listing
September 2019

Interpretation of P53 Immunohistochemistry in Endometrial Carcinomas: Toward Increased Reproducibility.

Int J Gynecol Pathol 2019 Jan;38 Suppl 1:S123-S131

Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta (M.K.) Department of Pathology, Vancouver General Hospital, Vancouver, British Columbia (C.B.G.), Canada Department of Pathology and Gynecology and Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, Maryland (B.M.R.) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (R.A.S.) Department of Cellular Pathology, Barts Health NHS Trust, London (N.S.) Department of Pathology, Belfast Health and Social Care Trust, Belfast (W.G.M.), UK.

P53 immunohistochemistry has evolved into an accurate surrogate reflecting the underlying TP53 mutation status of a tumor, and has utility in the diagnostic workup of endometrial carcinomas. Recent work predominantly carried out in tubo-ovarian high-grade serous carcinoma has revealed 4 main patterns of p53 staining (normal/wild-type, complete absence, overexpression, and cytoplasmic); the latter 3 patterns are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation. The aim of this review is to provide practical advice to pathologists regarding various aspects of p53 immunohistochemical staining. These include laboratory methods to optimize staining, a description of the different patterns of staining, advice regarding the interpretation, and reporting of p53 staining and practical uses of p53 staining in endometrial carcinoma diagnosis. Illustrations are provided to aid in the interpretational problems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PGP.0000000000000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127005PMC
January 2019

Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix.

Am J Surg Pathol 2018 06;42(6):750-760

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943084PMC
June 2018

Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study.

Hum Pathol 2018 02 11;72:160-166. Epub 2017 Dec 11.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21231; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, 21231. Electronic address:

Serous ovarian neoplasms can overlap morphologically with peritoneal mesothelial proliferations, including well-differentiated papillary mesothelioma (WDPM) and malignant epithelioid mesothelioma (MM). Accurate histologic classification of these neoplasms is important for clinical management. The Pax-8 protein is commonly used for differentiating peritoneal MM from serous carcinoma, but the diagnostic value of Pax-8 for distinguishing WDPM from borderline or low-grade serous tumors is unknown. We used immunohistochemistry staining to assess Pax-8 expression in 33 WDPMs, 34 peritoneal MMs, 48 pleural MMs, 11 adenomatoid tumors, 5 peritoneal inclusion cysts, and 51 benign/reactive mesothelium specimens. Staining was noted in 20 WDPMs (61%), with 17 showing strong and diffuse nuclear staining and 3 patchy/focal staining. Calretinin was expressed in 33 cases (100%), whereas focal BerEP4 staining was noted in 2 of 29 cases (7%). In contrast, 4 peritoneal MM (12%) were Pax-8 positive (3 diffuse and 1 focal staining). All adenomatoid tumors and peritoneal inclusion cysts were negative for Pax-8. Of the 48 pleural MM cases, 2 (4%) showed focal weak to moderate nuclear labeling for Pax-8, and 2 cases (4%) of reactive mesothelium demonstrated focal and scattered Pax-8 staining. Pax-8 appears to be a useful marker for distinguishing MM from gynecologic malignancies but is not reliable for distinguishing WDPM from borderline or low-grade gynecologic lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2017.10.036DOI Listing
February 2018

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.

Lancet 2017 Nov 5;390(10108):2143-2159. Epub 2017 Sep 5.

Merck & Co, Inc, Kenilworth, NJ, USA.

Background: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.

Methods: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543.

Findings: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.

Interpretation: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.

Funding: Merck & Co, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(17)31821-4DOI Listing
November 2017

Choriocarcinoma in Women: Analysis of a Case Series With Genotyping.

Am J Surg Pathol 2017 Dec;41(12):1593-1606

Departments of *Pathology ‡Gynecology & Obstetrics, The Johns Hopkins Medical Institutions, Baltimore, MD †ProPath, Dallas, TX.

Choriocarcinoma is an uncommon malignant neoplasm, which can be either gestational or nongestational in origin. Distinction of these subtypes has prognostic and therapeutic implications. Twenty-two tumors were genotyped using polymerase chain reaction amplification of 15 short tandem repeat loci and the amelogenin locus (XY determination). DNA patterns from tumor and maternal tissue, as well as villous tissue from any available prior or concurrent gestation, were compared, to determine gestational versus nongestational nature (containing vs. lacking a paternal chromosome complement, respectively) and the relationship between the tumor and any prior or concurrent gestation. Nineteen tumors were gestational. Of these, 14 were purely androgenetic/homozygous XX: 6 uterine tumors with a concurrent or prior genetically related complete hydatidiform mole (CHM), 4 uterine tumors without an accompanying villous component, 1 uterine cornual tumor separate from a genetically distinct second trimester intrauterine placenta, 1 ectopic ovarian tumor separate from a genetically distinct third trimester intrauterine placenta, and 2 ectopic fallopian tube tumors. Five gestational tumors were biparental: 3 (2 XX, 1 XY) intraplacental choriocarcinomas genetically related to the placenta and 2 uterine tumors without accompanying placental tissue after term deliveries (1 XX 4 weeks postpartum and 1 XYY with allelic imbalances 1 year postpartum; prior placentas not available for analysis). Three tumors were nongestational: all XX with allelic imbalances; 2 ovarian, 1 pelvic. Gestational choriocarcinoma can be androgenetic or biparental. Most are androgenetic/homozygous XX, often associated with a genetically related concurrent or prior CHM, and thus of molar-associated type. These findings support that homozygous XX CHMs are associated with some risk of significant gestational trophoblastic disease. Intraplacental choriocarcinomas are biparental and genetically related to the placenta. Biparental choriocarcinoma detected in a postpartum uterine sample is consistent with undetected intraplacental choriocarcinoma. Eutopic or ectopic androgenetic choriocarcinoma separate from a concurrent intrauterine placenta is not derived from intraplacental tumor and is consistent with either a form of dispermic twin gestation (molar-type choriocarcinoma and coexistent nonmolar fetus) or origin from an antecedent molar pregnancy. While fallopian tube tumors are usually gestational, tumors in other sites (ovary, pelvis) can be nongestational and should not be assumed to be metastatic from a regressed or occult intrauterine or intraplacental gestational tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000000937DOI Listing
December 2017

Hydatidiform Moles: Genetic Basis and Precision Diagnosis.

Annu Rev Pathol 2017 Jan;12:449-485

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231.

Hydatidiform moles are intriguing pathologic entities representing abnormal placental villous tissue with unique genetic profiles and a wide spectrum of morphologic features, which makes accurate diagnosis challenging. Overrepresentation of the paternal genome in sporadic hydatidiform moles (purely androgenetic in complete hydatidiform moles and diandric triploid in partial hydatidiform moles) is a fundamental genetic event leading to global alteration of imprinting gene expression in the molar trophoblast. Rare familial biparental hydatidiform moles (due to NLRP7 or KHDC3L mutations) share such global imprinting alterations, implying a common end point of pathogenesis. Despite being the cornerstone of diagnosis, routine morphologic assessment of hydatidiform moles continues to suffer from interobserver diagnostic variability, emphasizing the need for new diagnostic modalities. Analyses of p57 expression by immunohistochemistry and polymerase chain reaction-based DNA genotyping have emerged as powerful diagnostic methods for accurate classification of hydatidiform moles. Algorithmic approaches combining histology and these ancillary techniques provide the best diagnostic practice currently available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1146/annurev-pathol-052016-100237DOI Listing
January 2017
-->