From morphology to methylome: epigenetic studies of Müllerian mesonephric-like adenocarcinoma reveal similarities to cervical mesonephric adenocarcinoma†.

Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix and are thought to arise from mesonephric remnants, MLAs occur in the endometrium and ovary and are believed to originate from transdifferentiation of Müllerian lesions. Both MAs and MLAs show a variety of architectural patterns, exhibit frequent expression of GATA3 by immunohistochemistry, and harbor KRAS mutations. In a recent article published in The Journal of Pathology, Kommoss and colleagues used DNA methylation profiling to extend these similarities and showed that MLAs and MAs cluster together based on their epigenetic signatures and are epigenetically distinct from other Müllerian adenocarcinomas. They also showed that MLAs and MAs harbor a high number of global copy number alterations. This study provides evidence that MLAs more closely resemble MAs than Müllerian carcinomas on an epigenetic level. As a result, the authors argue that MLA should be renamed 'mesonephric-type adenocarcinoma.' Further research is needed to establish the relationship between these two entities, their etiology, and pathogenesis. © 2024 The Pathological Society of Great Britain and Ireland.

Ultrasound Surveillance in Melanoma Management: Bridging Diagnostic Promise with Real-World Adherence: A Systematic Review and Meta-Analysis.

BACKGROUND: Ultrasound surveillance has become the new standard of care in stage III melanoma after the 2017 Multicenter Selective Lymphadenectomy Trial II (MSLT-II) demonstrated non-inferior 3-year survival compared with complete lymph node dissection. OBJECTIVE: We aimed to quantify diagnostic performance and adherence rates of ultrasound surveillance for melanoma locoregional metastasis, offering insights into real-world applicability. METHODS: Conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, we systematically searched the Medline, Embase, Cochrane Library, CINAHL, Scopus, and Web of Science databases from inception until 11 October 2023. All primary studies that reported data on the diagnostic performance or adherence rates to ultrasound surveillance in melanoma were included. R statistical software was used for data synthesis and analysis. Sensitivity and specificity were aggregated across studies using the meta-analytic method for diagnostic tests outlined by Rutter and Gatsonis. Adherence rates were calculated as the ratio of patients fully compliant to planned follow-up to those who were not. RESULTS: A total of 36 studies including 18,273 patients were analysed, with a mean age of 56.6 years and a male-to-female ratio of 1:1.11. The median follow-up duration and frequency was 36 and 4 months, respectively. The pooled sensitivity of ultrasound examination was 0.879 (95% confidence interval [CI] 0.878-0.879) and specificity was 0.969 (95% CI 0.968-0.970), representing a diagnostic odds ratio of 224.5 (95% CI 223.1-225.9). Ultrasound examination demonstrated a substantial improvement in absolute sensitivity over clinical examination alone, with a number needed to screen (NNS) of 2.95. The overall adherence rate was 77.0% (95% CI 76.0-78.1%), with significantly lower rates in the United States [US] (p <  0.001) and retrospective studies (p <  0.001). CONCLUSION: Ultrasound is a powerful diagnostic tool for locoregional melanoma metastasis. However, the real applicability to surveillance programmes is limited by low adherence rates, especially in the US. Further studies should seek to address this adherence gap.

Socioeconomic Disparities in Research Participation: Bias in Plastic Surgery Residency Match.

Background: Integrated plastic surgery residency applicants have increased at a rate disproportionate to available positions. Research productivity has become a surrogate marker for competitiveness, and many applicants pursue it to distinguish themselves. To date, no study has investigated socioeconomic disparities in extended research experience (ERE) participation. Methods: A 35-question cross-sectional survey was distributed to applicants to United States-based integrated plastic surgery residency programs during the 2019-2022 application cycles. Summary tables, student t test, and chi-square tests were used for statistical analysis. Results: A total of 161 responses (response rate: 20.9%) were recorded. Fifty-nine (40.7%) respondents participated in an ERE. The most common reason for ERE participation was strengthening one's application. The most common reason against participation was avoiding delays in career progression. A greater percentage of respondents from Northeastern medical schools participated in EREs (P = 0.019). There were no significant differences in debt burden between those who did or did not participate in an ERE. A greater percentage of applicants whose parents had advanced degrees participated in EREs (P = 0.053). Conclusions: There may be geographic and socioeconomic biases present in access to ERE for students interested in plastic surgery. The growing popularity of EREs may have unintended consequences for applicant diversity. As most plastic surgeons ultimately practice in nonacademic settings, applicants and plastic surgeons may consider the financial hardships and possible socioeconomic disparities in research opportunities before participating in or recommending them.

Increased PI3K pathway activity is associated with recurrent breast cancer in patients with low and intermediate 21-gene recurrence score.

AIMS: We investigated key signalling pathways' activity and mutational status of early-stage breast carcinomas with low and intermediate 21-gene recurrence score (RS) to identify molecular features that may predict recurrence. METHODS: This is a retrospective case-control study of 18 patients with recurrent breast carcinoma with low and intermediate 21-gene RS (<25) and control group of 15 non-recurrent breast cancer patients. DNA and mRNA were extracted from tumour tissue. mRNA expression of genes involved in oestrogen receptor (ER), androgen receptor (AR), PI3K and MAPK signalling pathways was measured by real-time quantitative reverse transcription-qPCR (OncoSIGNal G4 test, InnoSIGN). Tumour mutational landscape was assessed by targeted DNA sequencing (Oncomine Precision Assay). RESULTS: There were no statistical differences between the groups' demographic and clinicopathological characteristics. PI3K pathway showed significantly higher activity in cases compared with controls (p=0.0014). Receiver operating characteristic curve analysis showed an area under the curve of 0.79 for PI3K pathway activity in the prediction of recurrent disease in low and intermediate 21-gene RS breast cancer. There was no difference in ER, AR and MAPK pathway activity. PIK3CA alterations were the most common driver mutations, but no difference was found between the groups (p=0.46) and no association with PI3K pathway activity (p=0.86). Higher Ki67 gene expression was associated with recurrences (p=0.042) CONCLUSION: Increased PI3K pathway activity, independent of PIK3CA mutations, may play a role in the recurrence of early-stage breast cancer with low and intermediate 21-gene RS. Pathway analysis can help to identify high-risk patients in this setting.

Intermediate-Term Outcomes of Hip Arthroscopy for Femoroacetabular Impingement Syndrome in Patients With Global Versus Isolated Lateral Acetabular Overcoverage.

BACKGROUND: Previous studies evaluating the outcomes of hip arthroscopy for patients with global acetabular overcoverage and focal superolateral acetabular overcoverage suffer from short-term follow-up and inconsistent radiographic criteria when defining these subpopulations of patients with femoroacetabular impingement syndrome (FAIS). PURPOSE: To evaluate the intermediate-term postoperative outcomes for patients with FAIS in the setting of global acetabular overcoverage, lateral acetabular overcoverage, and normal acetabular coverage. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients undergoing hip arthroscopy for FAIS were enrolled in a prospective cohort study, and those with a minimum follow-up of 5 years were included in this analysis. Patients were grouped based on type of acetabular coverage: global overcoverage (lateral center-edge angle [LCEA] ≥40°, with coxa profunda), lateral overcoverage (LCEA ≥40°, without coxa profunda), and no overcoverage (LCEA <40°). Functional outcomes (modified Harris Hip Score and Nonarthritic Hip Score) and failure of primary hip arthroscopy were compared between groups. RESULTS: In total, 94 patients (mean age, 41.9 ± 14.2 years) were included with a mean follow-up duration of 6.1 ± 0.9 years. Of these patients, 40.4% had no acetabular overcoverage, 36.2% had lateral overcoverage, and 23.4% had global overcoverage. There was no difference between groups with respect to percentage of patients who underwent reoperation for either revision arthroscopy or conversion to total hip arthroplasty (28.9% for the normal acetabular coverage group, 29.4% for the lateral overcoverage group, and 31.8% for the global overcoverage group; P = .971). Among patients for whom primary hip arthroscopy did not fail, there was no difference in 5-year functional outcomes between groups. Postoperative LCEA >40° (ß = -13.3; 95% CI, -24.1 to -2.6; P = .016), female sex (ß = -14.5; 95% CI, -22.7 to -6.2; P = .001), and higher body mass index (ß = -1.9; 95% CI, -2.8 to -1.0; P < .001) were associated with worse intermediate-term hip function in terms of modified Harris Hip Score. CONCLUSION: There was no difference in functional outcomes or rate of reoperation at a minimum of 5 years postoperatively between those with global acetabular overcoverage, those with regional lateral overcoverage, and those with normal acetabular coverage. Provided that an appropriate acetabuloplasty is performed, there is no evidence to suggest that global acetabular overcoverage portends a worse prognosis than other FAIS subtypes.

Decreased Hip Labral Width Measured on Preoperative Magnetic Resonance Imaging Is Associated With Greater Revision Rate After Primary Arthroscopic Labral Repair for Femoroacetabular Impingement Syndrome at 5-Year Follow-Up.

PURPOSE: To examine the associations between hip labral width and patient-reported outcomes, clinical threshold achievement rates, and rate of reoperation among patients with femoroacetabular impingement syndrome (FAIS) who underwent hip arthroscopy and labral repair at minimum 5-year follow-up. METHODS: Patients were identified from a prospective database who underwent primary hip arthroscopy for treatment of labral tears and FAIS. Modified Harris Hip Score (mHHS) and Nonarthritic Hip Score (NAHS) were recorded preoperatively and at 5-year follow-up. Achievement of the minimal clinically important difference (MCID), substantial clinical benefit (SCB), and patient-acceptable symptom state (PASS) was determined using previously established values. Labral width magnetic resonance imaging measurements were performed by 2 independent readers at standardized "clockface" locations. Patients were stratified into 3 groups at each position: lower-width (<½ SD below mean), middle-width (within ½ SD of mean), and upper-width (>½ SD above mean). Multivariable regression was used to evaluate associations of labral width with patient-reported outcomes and reoperation rate. RESULTS: Seventy-three patients (age: 41.0 ± 12.0 years; 68.5% female) were included. Inter-rater reliability for labral width measurements was high at all positions (intraclass correlation coefficient 0.94-0.96). There were no significant intergroup differences in mHHS/NAHS improvement (P > .05) or in achievement rates of MCID/SCB/PASS at each clockface position (P > .05). Eleven patients (15.1%) underwent arthroscopic revision and 4 patients (5.5%) converted to total hip arthroplasty. Multivariable analysis found lower-width groups at 11:30 (odds ratio 1.75, P = .02) and 3:00 (odds ratio 1.59, P = .04) positions to have increased odds of revision within 5 years; however, labral width was not associated with 5-year improvement in mHHS/NAHS, achievement of MCID/PASS/SCB, or conversion to total hip arthroplasty (P > .05). CONCLUSIONS: Hip labral width <½ SD below the mean measured on preoperative magnetic resonance imaging at 11:30- and 3:00-clockface positions was associated with increased odds of reoperation after arthroscopic labral repair and treatment of FAIS. Labral width was not associated with 5-year improvement of mHHS, NAHS, achievement of clinical thresholds, or conversion to arthroplasty. LEVEL OF EVIDENCE: Level IV, case series.

Preoperative Symptom Severity Predicts 5-Year Hip Arthroscopy Outcomes.

PURPOSE: Thisstudy sought to assessthe prognostic effect of preoperative symptom severity on hip arthroscopy outcomes for femoroacetabular impingement syndrome (FAI). METHODS: Patients undergoing hip arthroscopy between September 2012 and July 2014 for FAI with a minimum of 5-year clinical outcomes were compiled. Patient reported outcomes (PROs) including modified Harris Hip Score (mHHS) and Nonarthritic Hip Score (NAHS) were collected. High and low preoperative function (PF) subgroups were created using baseline population median mHHS (43.3) as a threshold with PROs below the median score indicating low preoperative function and vice versa for scores above the median. Kaplan-Meier analysis, Cox proportional modeling, analysis of variance (ANOVA), and linear regressions were used for analysis. RESULTS: One hundred five of 131 eligible patients(80.2% inclusion; age: 42.6 ± 1.4 years; body mass index: 25.3 ± 0.4 kg/m2 ) met the study criteria. The 5-year survival-torevision rate (85% versus 61%, p = 0.013) and survivalto-arthroplasty rate (95% vs. 82%, p = 0.022) were greater in the high versus low PF group. ANOVA demonstrated the high versus low PF group had higher baseline (mHHS: 52.7 ± 1.4 vs. 36.1 ± 1.1, p < 0.001; NAHS: 57.4 ± 1.6 vs. 39.3 ± 1.2, p < 0.001) and 1-year (mHHS: 91.9 ± 1.8 vs. 79.5 ± 2.7, p < 0.001; NAHS: 91.7 ± 1.6 vs. 80.8 ± 2.5, p < 0.001) outcomes. High versus low PF achieved higher Minimal Clinically Important Difference (77% vs. 57%, p = 0.026) at 5-years. High versus low PF achieved higher Patient Acceptable Symptomatic State rates at 1 year (79% vs. 47%, p < 0.001) and 5 years (66% vs. 45%, p = 0.032). Linear regression demonstrated body mass index (mHHS: p = 0.002; NAHS: p = 0.005), pincer resection (mHHS: p = 0.046), and preoperative symptom severity (mHHS: p = 0.001; NAHS: p = 0.002) to be predictors of 5-year change in PROs. CONCLUSION: Preoperative symptom severity is a reliable prognostic indicator of clinical survival rates and PROs after hip arthroscopy for FAI. Subjects with high PF are likely to have increased longevity of the index procedure while maintaining excellent PASS and MCID rates mid-term as opposed to those with low PF.

DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features.

Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.

DNA Methylation Signature of Synchronous Endometrioid Endometrial and Ovarian Carcinomas.

Next-generation sequencing (NGS) studies have demonstrated that co-occurring sporadic endometrioid endometrial carcinoma (EEC) and endometrioid ovarian carcinoma (EOC) are clonally related, suggesting that they originate from a single primary tumor. Despite clonality, synchronous EEC and EOC when diagnosed at early stage behave indolently, similar to isolated primary EEC or isolated primary EOC. In the present study, we compared the DNA methylation signatures of co-occurring EEC and EOC with those of isolated primary EEC and isolated primary EOC. We also performed targeted NGS to assess the clonal relatedness of 7 co-occurring EEC and EOC (4 synchronous EEC and EOC and 3 metastatic EEC based on pathologic criteria). NGS confirmed a clonal relationship in all co-occurring EEC and EOC. DNA methylation profiling showed distinct epigenetic signatures of isolated primary EEC and isolated primary EOC. Endometrial tumors from co-occurring EEC and EOC clustered with isolated primary EEC while their ovarian counterparts clustered with isolated primary EOC. Three co-occurring EEC and EOC cases with peritoneal lesions showed a closer epigenetic signature and copy number variation profile between the peritoneal lesion and EOC than EEC. In conclusion, synchronous sporadic EEC and EOC are clonally related but demonstrate a shift in DNA methylation signatures between ovarian and endometrial tumors as well as epigenetic overlap between ovarian and peritoneal tumors. Our results suggest that tumor microenvironment in the ovary may play a role in epigenetic modulation of metastatic EEC.

Clinical Outcome and Morphology-Based Analysis of p53 Aberrant and Mismatch Repair Protein-Deficient Ovarian Clear Cell Carcinoma and Their Association With p16, HER2, and PD-L1 Expression.

OBJECTIVES: We studied the prevalence and prognostic significance of mismatch repair deficient (MMRD) and p53 aberrant ovarian clear cell carcinoma (CCO) and their association with other prognostic and theranostic biomarkers (p16, HER2, PD-L1). We also aimed to identify morphologic features to serve as screening tools for immunohistochemical testing for these biomarkers. METHODS: Tissue microarrays with 3-mm cores from 71 pure CCOs were immunostained with PMS2, MSH6, p53, p16, HER2, and PD-L1. Expression status was correlated with tumor recurrence/disease progression and survival. It was also correlated with morphologic features (tumor size, nuclear grade, tumor architecture, mitotic activity, presence of endometriosis, tumor budding, and tumor inflammation). RESULTS: p53 aberrant tumors were associated with shorter overall and recurrence-free survivals (P = .002 and P = .01, respectively). In multivariate analysis, p53 aberrant status and tumor stage were independently associated with recurrence/disease progression (hazard ratio [HR] = 3.31, P = .037 and HR = 1.465, P = .004, respectively). p53 aberrant status was associated with tumor budding (P = .037). MMRD, p16, HER2, and PD-L1 expression had no prognostic significance. HER2 and PD-L1 were expressed in 56% and 35% of tumors, respectively. MMRD was associated with tumor expression of PD-L1 (P > .05) but not with tumor inflammation. CONCLUSIONS: Aberrant p53 in CCO is infrequent but associated with poor prognosis independent of stage. Presence of tumor budding could be a screening tool for p53 testing. High prevalence of HER2 and PD-L1 expression indicates the eligibility of patients with CCO for ongoing clinical trials using these therapeutic targets.

HPV Cotesting of Unsatisfactory Papanicolaou Tests: Implications for Follow-up Intervals.

OBJECTIVES: The 2019 American Society of Colposcopy and Cervical Pathology management guidelines recommend that patients with an unsatisfactory Papanicolaou (Pap) test (UPT) and negative human papillomavirus (HPV) cotest undergo repeat age-based screening in 2 to 4 months. The rationale is that a negative HPV test in the setting of an UPT may reflect an inadequate sample and therefore should not be interpreted as truly "negative." For patients 25 years and older who are cotested, if HPV is positive for the 16 or 18 genotypes, direct referral for colposcopy is recommended. Our study aimed to determine if a negative HPV cotest result is predictive of the absence of a high-grade squamous intraepithelial lesion (HSIL) and whether these patients may be called back for repeat testing at an interval longer than 2 to 4 months. METHODS: Follow-up cervical cytology and biopsy results in women with UPT and HPV cotests from January 2017 to December 2021 were collected. Original UPT and HPV cotest results were correlated with the follow-up Pap and biopsy results. RESULTS: There were 1,496 (2.28%) UPT cases out of 65,641 total Pap tests. Among the 1,496 UPT cases, 1,010 (67.5%) had HPV cotesting; 676 (45.1%) were followed by repeat Pap or biopsy within 4 months and 850 (56.8%) within 12 months. The total follow-up rate was 81%, with a range of 3 days to 36 months. The HSIL rate in HPV-positive cases was 5.7% (3/53) vs 0.4% (2/539) (P = .006) in HPV-negative cases. In UPT, HPV cotesting showed negative predictive values for low-grade and high-grade squamous intraepithelial lesion detection of 98.5% and 99.6%, respectively, while positive predictive values were 19% and 5.7%. CONCLUSIONS: A negative HPV cotest in individuals with UPT predicted the lack of HSIL in our study. Compliance with the recommended follow-up time of 2 to 4 months for women with UPT was low (45.1%). Our study suggests that women with UPT and negative HPV cotest may be safely called back at an interval longer than 4 months.

Ovarian Clear Cell Carcinoma and Markers of Epithelial-Mesenchymal Transition (EMT): Immunohistochemical Characterization of Tumor Budding.

Tumor budding, largely considered a manifestation of epithelial-mesenchymal transition (EMT) is an established prognostic marker for several cancers. In a recent study, tumor budding was associated with poor clinical outcomes in early-stage ovarian clear cell carcinoma. Here, we evaluated the immune expression of 3 proteins shown to be associated with EMT (E-cadherin, ß-catenin, and glypican-3) in 72 primary tumors of ovarian clear cell carcinoma with median follow-up of 39.47 mo. E-cadherin and ß-catenin expression was further evaluated in tumor buds in 29 (40%) cases. In the tumor mass, diffuse membranous expression of E-cadherin and ß-catenin was seen in 83% (60/72) and 81% (58/72) cases, respectively. Nuclear accumulation of E-cadherin was seen in 7 (10%) cases, while none of the cases showed nuclear ß-catenin expression. Glypican-3 expression was diffuse in 33.3% (24/72), patchy in 29.2% (21/72), and absent in 37.5% (27/72) cases. Evaluation of tumor buds showed aberrant patterns of expression (complete loss/cytoplasmic accumulation/diminished, discontinuous incomplete membranous staining) of E-cadherin in 29/29 (100%) and of ß-catenin in 26/29 (90%) cases. E-cadherin, ß-catenin, and glypican-3 expression in the main tumor mass had no association with stage, lymph node status, recurrent/progressive disease, status at last follow-up, survival and histopathologic features ( P >0.05). Our finding of aberrant expression of both E-cadherin and ß-catenin in tumor buds indicates involvement of Wnt signaling pathway/EMT in tumor budding and outlines its significance as a prognostic marker especially for early-stage ovarian clear cell carcinoma.

Cervicovaginal cytology, HPV testing and vaginal flora in transmasculine persons receiving testosterone.

BACKGROUND: Testosterone is one of the strategies that transmasculine persons can elect in order to align physical traits to their gender identity. Previous studies have shown morphologic changes in the genital tract associated with testosterone. Here, we aim to evaluate cervicovaginal cytology specimens (Pap tests) and high-risk HPV (HR-HPV) testing from transmasculine individuals receiving testosterone. METHODS: This is a retrospective cohort of 61 transmasculine individuals receiving testosterone from 2013 to 2021. Cytologic diagnoses from 65 Pap tests were correlated with HPV status and histologic follow-up and compared with the institutional data and a cohort of cisgender women with atrophic changes. RESULTS: The median age was 28 years and median time of testosterone use was 3 years. Transmasculine persons showed significantly higher rates of HSIL (2%) and unsatisfactory (16%) when compared with the institutional data and atrophic cohort of cisgender women. After reviewing slides of 46 cases, additional findings were noted: atrophy was present in 87%, glycogenated cells were seen in 30%, and Lactobacilli were substantially decreased in 89%. Among 32 available HPV tests, 19% were positive for HR-HPV and 81% were negative. On histologic follow-up, all HR-HPV-positive cases with abnormal cytology showed HSIL, while none of the HPV-negative cases revealed HSIL. CONCLUSION: Our study cohort demonstrated a high percentage of abnormal Pap tests in transmasculine persons receiving testosterone. Testosterone seems to induce changes in squamous cells and shifts in vaginal flora. HR-HPV testing can be a useful adjunct in the workup of abnormal Pap tests from transmasculine individuals.

Role of High-Risk HPV Testing in Papanicolaou Tests With Atypical Glandular Cells With and Without Concurrent Squamous Cell Abnormalities.

OBJECTIVES: Data on Papanicolaou (Pap) tests with atypical glandular cells (AGCs) with concurrent squamous cell abnormalities (AGC + Sq) are limited. We evaluated histologic outcomes and the role of high-risk human papillomavirus (HR-HPV) testing in this setting compared with AGCs without concurrent squamous cell abnormalities (AGC-alone). METHODS: This study used a retrospective cohort of patients with Pap test diagnoses of AGC + Sq and AGC-alone between October 2013 and August 2021. RESULTS: We included 287 Pap tests from 278 patients. The HR-HPV test was positive in 55% of AGC + Sq cases and 14% of AGC-alone cases (P < .0001). Most AGC + Sq cases displayed squamous lesions (41.5%) or were benign (41.5%) on histology, whereas AGC-alone cases were predominantly benign (72%) or extracervical neoplasms (18%). AGC + Sq cases showed higher rates of significant histologic lesions (P = .0001), which were associated with positive HR-HPV status (P = .0012). In AGC-alone cases, HR-HPV status was associated with significant histology only in patients 50 years of age or younger. In both groups, 20% or more of HR-HPV-negative patients harbored significant lesions. CONCLUSIONS: AGC + Sq represents a distinct group of patients. HR-HPV testing and patient age provide useful information in the evaluation of AGC, but triage based on HR-HPV testing is not recommended because of the potential for missing significant lesions.

A Primer for Success as an Early Career Academic Plastic Surgeon.

The early career academic plastic surgeon strives to be an expert surgeon, an innovative researcher, and an impactful educator. Navigating these challenges is difficult in a healthcare landscape with diminishing public research funding, increasing demand from institutions for clinical productivity, and decreased value of surgical education. To help the junior academic plastic surgeon, this article discusses the fundamental aspects of developing an early academic plastic surgery practice, rooted in clinical care, research, and education. METHODS: Using published literature, expert opinion, and faculty interviews, the authors prepared this primer for education and guidance of plastic surgery residents considering a career in academic plastic surgery and early career academic plastic surgeons. RESULTS: This primer highlights elements important to succeeding as a junior academic plastic surgeon including defining goals and priorities, institutional and financial support, mentorship, education of students and residents, developing a practice niche, promotion and tenure, and social support and burnout. CONCLUSION: The early career academic plastic surgeon can create an environment for academic success with appropriate institutional support, mentorship, personal, and social support, to progress toward promotion while minimizing burnout and professional exhaustion.

Histologic Findings in Gynecologic Tissue From Transmasculine Individuals Undergoing Gender-Affirming Surgery.

CONTEXT.­: Gender-affirming surgery is part of a multidisciplinary approach in gender transitioning. Deeper histologic examination may strengthen care for transmasculine individuals and increase the understanding of the influence of hormonal therapy in specific organs. OBJECTIVE.­: To evaluate and catalogue histologic findings of tissue obtained from gender-affirming gynecologic surgery and cervical cytology specimens. DESIGN.­: This is an institutional review board-approved retrospective study that included transmasculine individuals who underwent gender-affirming gynecologic surgery from January 2015 to June 2020. All surgical gynecologic pathology and cervical cytology slides were reviewed by 2 pathologists. RESULTS.­: Fifty-five patients were included, which represented 40 uteri, 35 bilateral ovaries, 15 vaginectomy specimens, and 24 cervical cytology results. The median age was 27 years (range, 18-56), and 94% (50 of 53) of patients were receiving testosterone for at least 1 year. Seventy-five percent (30 of 40) of endometria were inactive, while 25% (10 of 40) showed evidence of cycling. Transitional cell metaplasia was the most common finding in the cervix (17 of 40) and vagina (15 of 15), reflecting a high percentage (4 of 24) of unsatisfactory or ASC-US (atypical squamous cells of undetermined significance) cervical cytologies. Prostatic-type glands were identified in 20% (8 of 40) of cervices and 67% (10 of 15) of vaginectomy specimens. Multiple bilateral cystic follicles and evidence of follicular maturation were present in 57% (20 of 35) of cases. Four cases showed paratubal epididymis-like mesonephric remnant hypertrophy. CONCLUSIONS.­: A comprehensive evaluation of tissue from gender-affirming surgery increases knowledge of the changes following androgen therapy in transmasculine individuals and may contribute to optimal patient care by raising awareness of normal histologic variations in this population.

Histological validation of prostate tissue composition measurement using hybrid multi-dimensional MRI: agreement with pathologists' measures.

PURPOSE: To validate prostate tissue composition measured using hybrid multi-dimensional MRI (HM-MRI) by comparing with reference standard (ground truth) results from pathologists' interpretation of clinical histopathology slides following whole mount prostatectomy. MATERIALS AND METHODS: 36 prospective participants with biopsy-confirmed prostate cancer underwent 3 T MRI prior to radical prostatectomy. Axial HM-MRI was acquired with all combinations of echo times of 57, 70, 150, 200 ms and b-values of 0, 150, 750, 1500 s/mm2 and data were fitted using a 3-compartment signal model using custom software to generate volumes for each tissue component (stroma, epithelium, lumen). Three experienced genitourinary pathologists independently as well as in consensus reviewed each histology image and provide an estimate of percentage of epithelium and lumen for regions-of-interest corresponding to MRI (n = 165; 64 prostate cancers and 101 benign tissue). Agreement statistics using total deviation index (TDI0.9) was performed for tissue composition measured using HM-MRI and reference standard results from pathologists' consensus. RESULTS: Based on the initial results showing typical variation among pathologists TDI0.9 = 25%, we determined we will declare acceptable agreement if the 95% one-sided upper confident limit of TDI0.9 is less than 30%. The results of tissue composition measurement from HM-MRI compared to ground truth results from the consensus of 3 pathologists, reveal that ninety percent of absolute paired differences (TDI0.9) were within 18.8% and 22.4% in measuring epithelium and lumen, respectively. We are 95% confident that 90% of absolute paired differences were within 20.6% and 24.2% in measuring epithelium and lumen, respectively. These were less than our criterion of 30% and inter-pathologists' agreement (22.3% for epithelium and 24.2% for lumen) and therefore we accept the agreement performance of HM-MRI. The results revealed excellent area under the ROC curve for differentiating cancer from benign tissue based on epithelium (HM-MRI: 0.87, pathologists: 0.97) and lumen volume (HM-MRI: 0.85, pathologists: 0.77). CONCLUSION: The agreement in tissue composition measurement using hybrid multidimensional MRI and consensus of pathologists is on par with the inter-raters (pathologists) agreement.

Effusion fluid cytology and COVID-19 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus disease 2019 (COVID-19), is known to cause severe respiratory infections with occasional accompanying pleural effusion (PE), pericardial effusion (PCE), or peritoneal effusion (PTE). The effect of COVID-19 on effusion cytology is not yet known. This study aimed to examine the cytomorphologic features and workup of effusion fluids in patients with active COVID-19 infection versus those in recovery. METHODS: PE (n = 15), PCE (n = 1), and PTE samples (n = 20) from hospitalized patients with a SARS-CoV-2 infection (from June 1, 2020, to December 30, 2020) were reviewed. Effusion fluids with metastatic carcinoma were excluded. Differential cell counts, cytomorphology, and relevant immunostains for effusion fluids were retrospectively evaluated and compared between patients with active infection (positive on a SARS-CoV-2 nucleic acid amplification test [NAAT] within 2 months; n = 23) and those in the recovery phase from COVID-19 (negative on a SARS-CoV-2 NAAT for >2 months; n = 13). RESULTS: The cytology diagnoses were negative for malignancy (n = 31), atypical (n = 4), and suspicious for malignancy (n = 1). Active infection cases showed more atypical mesothelial cells than recovery cases (P < .05); some had enlarged nuclei, prominent nucleoli, occasional multinucleation, and bizarre nuclei. Immunostains were performed more often in active infection cases than recovery cases (47.8% vs 7.7%; P < .05). Differential cell counts (available for 28 cases) showed no significant differences between the active infection and recovery groups. CONCLUSIONS: This study found atypical and bizarre mesothelial cells more often in effusions of cases with active COVID-19 infection in comparison with patients in recovery. It is important for cytopathologists to become familiar with the cytomorphologic effects of SARS-CoV-2 on effusion cytology so that these cases can be properly triaged.

Impact of clinical characteristics on human chorionic gonadotropin regression after molar pregnancy.

OBJECTIVES: This study aimed to determine the effects of age, race/ethnicity, body mass index, and contraception on human chorionic gonadotropin (hCG) regression following the evacuation of a molar pregnancy. METHODS: This was a retrospective cohort study of 277 patients with molar pregnancies between January 1, 1994 and December 31, 2015. The rate of hCG regression was estimated using mixed-effects linear regression models on daily log-transformed serum hCG levels after evacuation. RESULTS: There were no differences in hCG half-lives among age (p=0.13) or race/ethnicity (p=0.16) groups. Women with obesity and hormonal contraceptive use demonstrated faster hCG regression than their counterparts (3.2 versus. 3.7 days, p=0.02 and 3.4 versus. 4.0 days, p=0.002, respectively). CONCLUSION: Age and race/ethnicity were not associated with hCG regression rates. Hormonal contraceptive use and obesity were associated with shorter hCG half-lives, but with unlikely clinical significance. It is important to understand whether the clinical characteristics of patients may influence the hCG regression curve, as it has been proposed as a way to predict the risk of gestational trophoblastic neoplasia.