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.

Dedifferentiated and Undifferentiated Ovarian Carcinoma: An Aggressive and Molecularly Distinct Ovarian Tumor Characterized by Frequent SWI/SNF Complex Inactivation.

Dedifferentiated and undifferentiated ovarian carcinomas (DDOC/UDOC) are rare neoplasms defined by the presence of an undifferentiated carcinoma. In this study, we detailed the clinical, pathological, immunohistochemical, and molecular features of a series of DDOC/UDOC. We collected a multi-institutional cohort of 23 DDOC/UDOC and performed immunohistochemistry for core switch/sucrose nonfermentable (SWI/SNF) complex proteins (ARID1A, ARID1B, SMARCA4, and SMARCB1), mismatch repair (MMR) proteins, and p53. Array-based genome-wide DNA methylation and copy number variation analyses were performed on a subset of cases with comparison made to a previously reported cohort of undifferentiated endometrial carcinoma (UDEC), small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and tubo-ovarian high-grade serous carcinoma (HGSC). The age of all 23 patients with DDOC/UDOC ranged between 22 and 71 years (with an average age of 50 years), and a majority of them presented with extraovarian disease (16/23). Clinical follow-up was available for 19 patients. Except for 2 patients, the remaining 17 patients died from disease, with rapid disease progression resulting in mortality within a year in stage II-IV settings (median disease-specific survival of 3 months). Eighteen of 22 cases with interpretable immunohistochemistry results showed loss of expression of core SWI/SNF protein(s) that are expected to result in SWI/SNF complex inactivation as 10 exhibited coloss of ARID1A and ARID1B, 7 loss of SMARCA4, and 1 loss of SMARCB1. Six of 23 cases were MMR-deficient. Two of 20 cases exhibited mutation-type p53 immunoreactivity. Methylation profiles showed coclustering of DDOC/UDOC with UDEC, which collectively were distinct from SCCOHT and HGSC. However, DDOC/UDOC showed an intermediate degree of copy number variation, which was slightly greater, compared with SCCOHT but much less compared with HGSC. Overall, DDOC/UDOC, like its endometrial counterpart, is highly aggressive and is characterized by frequent inactivation of core SWI/SNF complex proteins and MMR deficiency. Its molecular profile overlaps with UDEC while being distinct from SCCOHT and HGSC.

Lesions sub-diagnostic of endometrioid intra-epithelial neoplasia/atypical hyperplasia: value of morphology and immunohistochemistry in predicting neoplastic outcome.

AIMS: Areas of gland crowding that do not fulfil diagnostic criteria of endometrioid intra-epithelial neoplasia (EIN) are often encountered in endometrial biopsies. In this study, we document the prevalence of neoplastic outcome in patients with these subdiagnostic lesions (SL) and assess the utility of morphological features and a three-marker immunohistochemistry panel (PAX2, PTEN, beta-catenin) to predict outcome. METHODS AND RESULTS: Of 430 women with SL on endometrial sampling at Brigham and Women's Hospital between 2001 and 2021 with available follow-up biopsy, 72 (17%) had a neoplastic outcome (EIN or endometrioid carcinoma). Multilayered epithelium and mitoses in SL were statistically associated with a neoplastic outcome. Abnormal three-marker staining was observed in 93% (53 of 57) of SL with neoplastic outcome and 60% (37 of 62) of a control group with benign outcome. Among the 72 patients with neoplastic outcome, EIN/carcinoma tissue was available in 33; of these, 30 (91%) showed abnormal staining for one or more markers. Remarkably, in 84% of these cases the EIN/carcinoma had the aberrant expression seen in the preceding SL. Based on a prevalence of 17%, the positive and negative predictive values of abnormal staining in one or more markers were 24 and 97%, respectively. CONCLUSIONS: The presence of SL warrants clinical surveillance and repeat sampling because it is followed by endometrioid neoplasia in a significant subset of patients. Normal three-marker staining identifies women with a very low risk of neoplastic outcome. Conversely, abnormal staining is frequent in SL with benign outcome leading to poor specificity and positive predictive value.

Nearly 14-Fold Increased Risk of Manipulation Under Anesthesia After Total Knee Arthroplasty When Previous Contralateral Total Knee Arthroplasty Required Manipulation Under Anesthesia.

BACKGROUND: Stiffness remains a common complication after primary total knee arthroplasty (TKA). Manipulation under anesthesia (MUA) is the gold standard treatment for early postoperative stiffness; however, there remains a paucity of data on the risk of MUA after primary TKA if a prior contralateral TKA required MUA. METHODS: We performed a retrospective review of 3,102 patients who had staged primary TKAs between 2016 and 2021. The mean body mass index was 33 (range, 18 to 59) and the mean age was 67 years (range, 24 to 91). The mean preoperative range of motion for the first TKA was 2 to 104°, and for the contralateral TKA was 1 to 107°. The primary outcomes were MUA following first and second primary TKAs. Multivariable Poisson regressions were used to evaluate associations between risk factors and outcomes. RESULTS: The rate of MUA after the first TKA was 2.6% (n = 83 of 3,102) and 1.3% (n = 40 of 3,102) after the contralateral TKA. After adjustment, there was a nearly 14-fold higher rate of MUA after the second TKA if the patient had an MUA after the first TKA (relative risk, 13.80; 95% CI [confidence interval], 7.14 to 26.66). For the first TKA, increasing age (adjusted risk ratio [ARR], 0.65; 95% CI, 0.50 to 0.83) and increasing body mass index (ARR, 0.65; 95% CI, 0.47 to 0.90) were associated with lower risk for MUA. For the second TKA, increasing age was associated with a lower risk of MUA (ARR, 0.60; 95% CI, 0.45 to 0.80). CONCLUSIONS: For patients undergoing staged bilateral TKA, patients who undergo MUA following the first primary TKA are nearly 14-fold more likely to undergo an MUA following the contralateral primary TKA than those who did not have an MUA after their first TKA.

Systematic Review of Gender and Sex Terminology Use in Arthroplasty Research: There Is Room for Improvement.

BACKGROUND: There is increasing appreciation of the distinction between gender and sex as well as the importance of accurately reporting these constructs. Given recent attention regarding transgender and gender nonconforming (TGNC) and intersex identities, it is more necessary than ever to understand how to describe these identities in research. This study sought to investigate the use of gender- and sex-based terminology in arthroplasty research. METHODS: The 5 leading orthopaedic journals publishing arthroplasty research were reviewed to identify the first twenty primary clinical research articles on an arthroplasty topic published after January 1, 2022. Use of gender- or sex-based terminology, whether use was discriminate, and whether stratification or adjustment based on gender or sex was performed, were recorded. RESULTS: There were 98 of 100 articles that measured a construct of gender or sex. Of these, 15 articles used gender-based terminology, 45 used sex-based terminology, and 38 used a combination of gender- and sex-based terminology. Of the 38 articles using a combination of terminology, none did so discriminately. All articles presented gender and sex as binary variables, and 2 attempted to explicitly define how gender or sex were defined. Of the 98 articles, 31 used these variables for statistical adjustments, though only 6 reported stratified results. CONCLUSIONS: Arthroplasty articles infrequently describe how gender or sex was measured, and frequently use this terminology interchangeably. Additionally, these articles rarely offer more than 2 options for capturing variation in sex and gender. Future research should be more precise in the treatment of these variables to improve the quality of results and ensure findings are patient-centered and inclusive.

Molecular Landscape of Mullerian Clear Cell Carcinomas Identifies The Cancer Genome Atlas-like Prognostic Subgroups.

Mullerian clear cell carcinoma (CCC) is often aggressive and chemoresistant. The prognostic significance of molecular subclassification of endometrioid carcinomas is well established. However, less is known about the molecular landscape of CCC. The aim of this study was to better characterize the genetic landscape of a large cohort of CCC and correlate these findings with clinicopathologic features. CCC of the ovary (n = 72), endometrium (n = 24), and peritoneum/abdominal wall (n = 5) were retrospectively identified. Tumors had undergone tumor-only targeted sequencing using a hybrid capture next-generation sequencing panel. Median tumor mutational burden was 6.8 mutations/megabase (range, 1.3-185, 21% were ≥10 mutations/Mb). The most frequently mutated genes were ARID1A (48%), PIK3CA (45%), TP53 (23%), and PTEN (10%). ERBB2 amplification occurred in 4%. When classified according to the Cancer Genome Atlas/the Proactive Molecular Risk Classifier for Endometrial Cancer endometrial carcinoma molecular subgroups, 3 (3%) were POLE ultramutated, 5 (5%) were microsatellite instability-high (MSI-H), 20 (20%) were TP53-mutant subgroup, and 73 (72%) were no specific molecular profile (NSMP). Immunohistochemical expression of estrogen receptor, progesterone receptor, and programmed death-ligand 1 were not associated with the molecular subgroup. POLE and MSI-H tumors were characterized by an excellent prognosis, and the TP53-mutant subgroup had a worse disease-free survival than NSMP. NSMP tumors could be further substratified as high-risk NSMP if they lacked PIK3CA, PIK3R1, and ARID1A mutations, and/or harbored a TERT-promoter mutation. The Cancer Genome Atlas and NSMP-specific stratifications were prognostic for both the entire cohort and the subset of stage I ovarian tumors. On multivariable analysis, stage, lymphovascular invasion, and tumor mutational burden were prognostic for disease-free survival, whereas advanced stage and TP53-mutant subgroup - but not a TP53 mutation in isolation - were negative prognostic factors for overall survival. These data suggest that routine molecular profiling of Mullerian CCC may be warranted for both prognosis and identification of potential targeted treatments, such as immunotherapy and anti-HER2 agents.

Cellular context determines DNA methylation profiles in SWI/SNF-deficient cancers of the gynecologic tract.

SWI/SNF (SWItch/Sucrose Non-Fermentable) complex deficiency has been reported in a wide variety of cancers and is often associated with an undifferentiated phenotype. In the gynecologic tract SWI/SNF-deficient cancers are diagnostically challenging and little is known about their cellular origins. Here we show that undifferentiated endometrial carcinoma (UDEC), SMARCA4-deficient uterine sarcoma (SDUS), and ovarian small cell carcinoma, hypercalcemic type (SCCOHT) harbor distinct DNA methylation signatures despite shared morphology and SWI/SNF inactivation. Our results indicate that the cellular context is an important determinant of the epigenetic landscape, even in the setting of core SWI/SNF deficiency, and therefore methylation profiling may represent a useful diagnostic tool in undifferentiated, SWI/SNF-deficient cancers. Furthermore, applying copy number analyses and group-wise differential methylation analyses including endometrioid endometrial carcinomas and extracranial malignant rhabdoid tumors, we uncover analogous molecular features in SDUS and SCCOHT in contrast to UDEC. These results suggest that SDUS and SCCOHT represent chromosomally stable SWI/SNF-deficient cancers of the gynecologic tract, which are within the broader spectrum of malignant rhabdoid tumors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

STK11 Adnexal Tumor in an Adolescent Female: Diagnostic Pitfalls of a Recently Described Entity.

STK11 adnexal tumor is a recently described entity with less than 25 cases reported to date. These aggressive tumors typically occur in paratubal/paraovarian soft tissues, have characteristically striking morphologic and immunohistochemical heterogeneity, and harbor pathognomonic alterations in STK11. These occur almost exclusively in adult patients, with only one reported in a pediatric patient (to our knowledge). A previously healthy 16-year-old female presented with acute abdominal pain. Imaging studies revealed large bilateral solid and cystic adnexal masses, ascites, and peritoneal nodules. Following frozen section evaluation of a left ovarian surface nodule, bilateral salpingo-oophorectomy and tumor debulking were performed. Histologically, the tumor demonstrated distinctively variable cytoarchitecture, myxoid stroma, and mixed immunophenotype. A next generation sequencing-based assay identified a pathogenic STK11 mutation. We report the youngest patient to date with an STK11 adnexal tumor, highlighting key clinicopathologic and molecular features in order to contrast them with those of other pediatric intra-abdominal malignancies. This rare and unfamiliar tumor poses a considerable diagnostic challenge and requires a multidisciplinary integrated approach to diagnosis.

Genetic Risk Factors for End-Stage Hip Osteoarthritis Treated With Total Hip Arthroplasty: A Genome-wide Association Study.

BACKGROUND: Although a genetic component to hip osteoarthritis (OA) has been described, focused evaluation of the genetic components of end-stage disease is limited. We present a genomewide association study for patients undergoing total hip arthroplasty (THA) to characterize the genetic risk factors associated with end-stage hip osteoarthritis (ESHO), defined as utilization of the procedure. METHODS: Patients who underwent primary THA for hip OA were identified in a national patient data repository using administrative codes. Fifteen thousand three hundred and fifty-five patients with ESHO and 374,193 control patients were identified. Whole genome regression of genotypic data for patients who underwent primary THA for hip OA corrected for age, sex, and body mass index (BMI) was performed. Multivariate logistic regression models were used to evaluate the composite genetic risk from the identified genetic variants. RESULTS: There were 13 significant genes identified. Composite genetic factors resulted in an odds ratio 1.04 for ESHO (P < .001). The effect of genetics was lower than that of age (Odds Ratio (OR): 2.38; P < .001) and BMI (1.81; P < .001). CONCLUSION: Multiple genetic variants, including 5 novel loci, were associated with end-stage hip OA treated with primary THA. Age and BMI were associated with greater odds of developing end-stage disease when compared to genetic factors.

Predicting Postoperative Anemia and Blood Transfusion Following Total Knee Arthroplasty.

BACKGROUND: While transfusion and clinically relevant anemia after elective primary total knee arthroplasty (TKA) are uncommon, there remains a question of who needs postoperative hemoglobin monitoring, especially in the setting of increasing incidence of outpatient TKA. The purpose of this study was to create predictive models for postoperative anemia and blood transfusion to guide clinical decision-making. METHODS: The records of consecutive TKA patients were reviewed from February 2016 to December 2020 at a single institution. Two multivariable logistic regression models, for postoperative anemia (hemoglobin < 10 g/dL) and allogeneic blood transfusion included 8 variables: age, sex, body mass index, preoperative hemoglobin level, tranexamic acid total dose, American Society of Anesthesiologists level, operative time, and drain use. Model performance was assessed using accuracy, area under the curve (AUC), sensitivity, and specificity. RESULTS: The records of 14,901 patients were included in this study. Patients had a mean (± standard deviation) age of 67.9 ± 9.2 years and mean body mass index of 31.3 ± 6.5 kg/m2. The postoperative anemia model had an accuracy of 88% (95% confidence interval [CI], 87%-89%) and AUC of 0.88 (95% CI, 0.87-0.89). The blood transfusion model had an accuracy of 97% (95% CI, 96%-97%) and AUC of 0.90 (95% CI, 0.87-0.93). CONCLUSION: The postoperative anemia and blood transfusion model accurately predicted each outcome. Patients with less than a 5% probability of postoperative anemia may not benefit from a complete blood count at postoperative day 1. Application of these criteria may save the healthcare system hundreds of millions of dollars. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Providence Bracing: Predicting the Progression to Surgery in Patients With Braced Idiopathic Scoliosis.

BACKGROUND: Idiopathic scoliosis (IS) is a common spinal abnormality, in which orthotic management can reduce progression to surgery. However, predictors of bracing success are still not fully understood. We studied a large patient population treated with the nighttime Providence orthosis, utilizing multivariable logistic regression to assess results and predict future spine surgery. METHODS: We retrospectively reviewed patients with IS meeting Scoliosis Research Society inclusion and assessment criteria presenting from April 1994 to June 2020 at a single institution and treated with a Providence orthosis. A predictive logistic regression model was developed utilizing the following candidate features: age, sex, body mass index, Risser classification, Lenke classification, curve magnitude at brace initiation, percentage correction in a brace, and total months of brace use. Model performance was assessed using the area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity. The importance of individual features was assessed using the variable importance score. RESULTS: There were 329 consecutive patients with IS with a mean age of 12.8 ± 1.4 years that met inclusion and assessment criteria. Of these, 113 patients (34%) ultimately required surgery. The model's area under the curve (AUC) was 0.72 on the testing set, demonstrating good discrimination. The initial curve magnitude (Importance score: 100.0) and duration of bracing (Importance score: 82.4) were the 2 most predictive features for curve progression leading to surgery. With respect to skeletal maturity, Risser 1 (Importance score: 53.9) had the most predictive importance for future surgery. For the curve pattern, Lenke 6 (Importance score: 52.0) had the most predictive importance for future surgery. CONCLUSION: Out of 329 patients with IS treated with a Providence nighttime orthosis, 34% required surgery. This is similar to the findings of the BrAist study of the Boston orthosis, in which 28% of monitored braced patients required surgery. In addition, we found that predictive logistic regression can evaluate the likelihood of future spine surgery in patients treated with the Providence orthosis. The severity of the initial curve magnitude and total months of bracing were the 2 most important variables when assessing the probability of future surgery. Surgeons can use this model to counsel families on the potential benefits of bracing and risk factors for curve progression.

A Subset of SMARCB1 (INI-1)-deficient vulvar neoplasms express germ cell markers.

AIMS: SMARCB1 (INI-1)-deficient vulvar neoplasms comprise a group of rare tumours that include epithelioid sarcoma (ES), myoepithelial carcinoma (MEC), the recently described myoepithelioma-like tumour of the vulvar region (MELTVR), and sarcomas that are difficult to classify. It has been suggested that so-called vulvar yolk sac tumours (YST) may represent morphologic variants of SMARCB1-deficient tumours; thus, we investigated the immunoreactivity of germ cell markers in SMARCB1-deficient vulvar neoplasms. METHODS AND RESULTS: Ten SMARCB1-deficient vulvar neoplasms were stained with germ cell tumour markers (SALL4, glypican-3, OCT3/4, and AFP) and re-reviewed for morphologic features. The tumours occurred in adult females (median age 41 years) and included ES (n = 7), MELTVR (n = 2), and MEC (n = 1). All cases showed loss of SMARCB1 expression. Four cases (40%) were focally positive for SALL4 in areas with morphology of typical-appearing ES. One of these cases also showed focal staining for OCT3/4. One ES showed a transition from typical-appearing ES to YST-like morphology, with diffuse expression of SALL4 and glypican-3, and focal expression of AFP, in these latter areas. All other tested cases were negative for AFP. CONCLUSION: Our study reveals that SALL4, glypican-3, and OCT3/4 are positive in a subset of SMARCB1-deficient vulvar neoplasms, which may pose a diagnostic challenge and result in consideration of a germ cell tumour. We also highlight a case with transition from ES to YST-like morphology, lending further support that YSTs of the vulva are somatically derived SMARCB1-deficient neoplasms and do not represent true germ-cell neoplasia.

Reversible association with motor proteins (RAMP): A streptavidin-based method to manipulate organelle positioning.

We report the development and characterization of a method, named reversible association with motor proteins (RAMP), for manipulation of organelle positioning within the cytoplasm. RAMP consists of coexpressing in cultured cells (i) an organellar protein fused to the streptavidin-binding peptide (SBP) and (ii) motor, neck, and coiled-coil domains from a plus-end-directed or minus-end-directed kinesin fused to streptavidin. The SBP-streptavidin interaction drives accumulation of organelles at the plus or minus end of microtubules, respectively. Importantly, competition of the streptavidin-SBP interaction by the addition of biotin to the culture medium rapidly dissociates the motor construct from the organelle, allowing restoration of normal patterns of organelle transport and distribution. A distinctive feature of this method is that organelles initially accumulate at either end of the microtubule network in the initial state and are subsequently released from this accumulation, allowing analyses of the movement of a synchronized population of organelles by endogenous motors.

Substantial Inconsistency and Variability Exists Among Minimum Clinically Important Differences for Shoulder Arthroplasty Outcomes: A Systematic Review.

BACKGROUND: As the value of patient-reported outcomes becomes increasingly recognized, minimum clinically important difference (MCID) thresholds have seen greater use in shoulder arthroplasty. However, MCIDs are unique to certain populations, and variation in the modes of calculation in this field may be of concern. With the growing utilization of MCIDs within the field and value-based care models, a detailed appraisal of the appropriateness of MCID use in the literature is necessary and has not been systematically reviewed. QUESTIONS/PURPOSES: We performed a systematic review of MCID quantification in existing studies on shoulder arthroplasty to answer the following questions: (1) What is the range of values reported for the MCID in commonly used shoulder arthroplasty patient-reported outcome measures (PROMs)? (2) What percentage of studies use previously existing MCIDs versus calculating a new MCID? (3) What techniques for calculating the MCID were used in studies where a new MCID was calculated? METHODS: The Embase, PubMed, and Ovid/MEDLINE databases were queried from December 2008 through December 2020 for total shoulder arthroplasty and reverse total shoulder arthroplasty articles reporting an MCID value for various PROMs. Two reviewers (DAK, MAM) independently screened articles for eligibility, specifically identifying articles that reported MCID values for PROMs after shoulder arthroplasty, and extracted data for analysis. Each study was classified into two categories: those referencing a previously defined MCID and those using a newly calculated MCID. Methods for determining the MCID for each study and the variability of reported MCIDs for each PROM were recorded. The number of patients, age, gender, BMI, length of follow-up, surgical indications, and surgical type were extracted for each article. Forty-three articles (16,408 patients) with a mean (range) follow-up of 20 months (0.75 to 68) met the inclusion criteria. The median (range) BMI of patients was 29.3 kg/m2 (28.0 to 32.2 kg/m2), and the median (range) age was 68 years (53 to 84). There were 17 unique PROMs with MCID values. Of the 112 MCIDs reported, the most common PROMs with MCIDs were the American Shoulder and Elbow Surgeons (ASES) (23% [26 of 112]), the Simple Shoulder Test (SST) (17% [19 of 112]), and the Constant (15% [17 of 112]). RESULTS: The ranges of MCID values for each PROM varied widely (ASES: 6.3 to 29.5; SST: 1.4 to 4.0; Constant: -0.3 to 12.8). Fifty-six percent (24 of 43) of studies used previously established MCIDs, with 46% (11 of 24) citing one study. Forty-four percent (19 of 43) of studies established new MCIDs, and the most common technique was anchor-based (37% [7 of 19]), followed by distribution (21% [4 of 19]). CONCLUSION: There is substantial inconsistency and variability in the quantification and reporting of MCID values in shoulder arthroplasty studies. Many shoulder arthroplasty studies apply previously published MCID values with variable ranges of follow-up rather than calculating population-specific thresholds. The use of previously calculated MCIDs may be acceptable in specific situations; however, investigators should select an anchor-based MCID calculated from a patient population as similar as possible to their own. This practice is preferable to the use of distribution-approach MCID methods. Alternatively, authors may consider using substantial clinical benefit or patient-acceptable symptom state to assess outcomes after shoulder arthroplasty. CLINICAL RELEVANCE: Although MCIDs may provide a useful effect-size based alternative to the traditional p value, care must be taken to use an MCID that is appropriate for the particular patient population being studied.

Does Low Back Pain Improve Following Total Hip Arthroplasty?

BACKGROUND: Frequently, patients indicated for total hip arthroplasty (THA) present with low back pain (LBP) and hip pain. The purpose of this study was to compare patients whose back pain resolved after THA with those where back pain did not resolve and identify how to predict this using spinopelvic parameters. METHODS: We reviewed a series of 500 patients who underwent THA for unilateral hip osteoarthritis by 2 surgeons. Patients underwent biplanar standing and sitting EOS radiographs pre-operatively. Patients with previous spine surgery or femoral neck fracture were excluded. Demographic data was analyzed at baseline. The Oswestry Disability Index (ODI) scores were calculated pre-operatively and at 1 year postoperatively. Spinopelvic parameters included, pelvic incidence and sacral slope (SS) change from standing to sitting. RESULTS: Two hundred and four patients (41%) had documented LBP before THA. The Oswestry Disability Index (ODI) for patients improved from 38.9 ± 17.8 pre-operatively to 17.0 ± 10.6 at 1 year post-operatively (P < .001). At 1- and 2-year follow-up, resolution of back pain occurred in 168 (82.4%) and 187 (91.2%) patients, respectively. Pelvic incidence was not predictive of back pain resolution. All patients whose back pain resolved had a sacral slope change from standing to sitting of >10°, while those patients whose back pain did not resolve had a change of <10°. CONCLUSION: This study demonstrates that symptomatic low back pain (LBP) resolves in 82% of patients after THA. The results of this study may be used to counsel patients on back pain and its resolution following total hip replacement.

Detection of ERBB2 amplification in uterine serous carcinoma by next-generation sequencing: an approach highly concordant with standard assays.

Uterine serous carcinoma is an aggressive subtype of endometrial cancer that accounts for fewer than 10% of endometrial carcinomas but is responsible for about half of deaths. A subset of cases has HER2 overexpression secondary to ERBB2 gene amplification, and these patients may benefit from anti-HER2 therapies, such as trastuzumab. HER2 protein overexpression is currently assessed by immunohistochemistry (IHC) and ERBB2 gene amplification by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing (NGS) is increasingly used to routinely identify predictive and prognostic molecular abnormalities in endometrial carcinoma. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification, we identified cases of uterine serous carcinoma (n = 93) and compared HER2 expression by IHC and copy number assessed by FISH with copy number status assessed by NGS. ERBB2 copy number status using a combination of IHC and FISH was interpreted using the 2018 ASCO/CAP guidelines for breast carcinoma. ERBB2 amplification by NGS was determined by the relative number of reads mapping to ERBB2 in tumor DNA compared to control nonneoplastic DNA. Cases with copy number ≥6 were considered amplified and copy number <6 were non-amplified. By IHC, 70 specimens were classified as negative (0 or 1+), 19 were classified as equivocal (2+), and 4 were classified as positive (3+). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6. In this series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in uterine serous carcinoma and provides an alternative to measurement by IHC and FISH.

EWSR1-WT1 gene fusions in neoplasms other than desmoplastic small round cell tumor: a report of three unusual tumors involving the female genital tract and review of the literature.

Desmoplastic small round cell tumor (DSRCT) is a high-grade round cell sarcoma that typically arises in the abdominopelvic cavity of young males, co-expresses keratins and desmin, and carries a pathognomonic EWSR1-WT1 gene fusion. The EWSR1-WT1 gene fusion is generally considered specific for DSRCT, although there are two reports of this fusion in tumors otherwise lacking features of DSRCT. We report three female genital tract tumors with EWSR1-WT1 fusions but showing morphologic and immunohistochemical features incompatible with DSRCT. The tumors occurred in the uterine cervix, uterine corpus/ovaries, and vagina, respectively, of 46, 30, and 20-year-old women. Two tumors consisted of a sheet-like to fascicular proliferation of relatively uniform spindled to occasionally more epithelioid cells arrayed about thick-walled, hyalinized, and capillary-sized vessels, with distinctive areas of pseudovascular change, and absence of desmoplastic stroma. The third tumor resembled a monomorphic spindle cell sarcoma with necrosis. All had diffuse desmin and variable but more limited keratin expression, two of three expressed smooth muscle actin, and all were negative for h-caldesmon, CD10, estrogen receptor, myogenin, N-terminus WT-1, and S100 protein. One patient received neoadjuvant chemotherapy and radiation therapy followed by resection and is disease-free 42 months after diagnosis. Another patient was managed by resection only and is disease-free 9 months after initial diagnosis. The remaining patient recently underwent resection of multifocal pelvic disease. Comprehensive differential gene expression analysis on two tumors compared to two classic DSRCTs with known EWSR1-WT1 fusions resulted in 1726 genes that were differentially expressed (log2 fold change >2 or < -2) and statistically significant (FDR < 5%). In combination with previous reports, our findings suggest pleiotropy of the EWSR1-WT1 fusion is possible and not limited to DSRCT. Subsets of non-DSRCT EWSR1-WT1 positive tumors may represent discrete entities, but further study is necessary.

Interobserver reproducibility of the diagnosis of differentiated exophytic vulvar intraepithelial lesion (DEVIL) and the distinction from its mimics.

AIMS: Most vulvar squamous cell carcinomas are human papillomavirus (HPV)-associated or TP53-mutant. A third category of HPV-independent TP53-wild-type lesions is uncommon and not fully understood. Differentiated exophytic vulvar intraepithelial lesion (DEVIL) has been characterised as a precursor of this latter category. The reproducibility of the diagnosis of DEVIL and its distinction from lesions with overlapping morphology has not been studied. Our aim was to establish the interobserver agreement in the diagnosis of DEVIL and its distinction from neoplastic and reactive conditions of the vulva on haematoxylin and eosin evaluation. METHODS AND RESULTS: A set of 35 slides was evaluated by eight reviewers (two trainees and six practising gynaecological pathologists). The set included DEVIL, condyloma, established vulvar precursors [high-grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN)] with superimposed acanthosis or verruciform growth, lichen simplex chronicus (LSC), and psoriasis. Kappa (κ) values were calculated. Overall, interobserver agreement was moderate (κ = 0.56), improving to substantial (κ = 0.7) when evaluation was performed by practising pathologists. Agreement was strong for the diagnosis of HSIL (κ = 0.88), and substantial for the diagnosis of DEVIL (κ = 0.61), condyloma (κ = 0.79), and LSC (κ = 0.72). Agreement was moderate for the diagnosis of dVIN (κ = 0.59) and psoriasis (κ = 0.53). Perfect agreement (6/6) among practising pathologists was observed in 43% of cases, and majority agreement (5/6 or 4/6) was observed in 48% of cases. CONCLUSIONS: Reproducibility in the diagnosis of verruciform vulvar lesions, including the novel DEVIL, is acceptable overall. Reproducibility is higher for well-known lesions such as HSIL and condyloma than for more challenging diagnoses such as DEVIL, dVIN, and psoriasis. Agreement is higher among practising gynaecological pathologists, suggesting that training and experience improve reproducibility. Our findings support the inclusion of DEVIL as a diagnostic entity in the classification of vulvar squamous lesions.

Projected Economic Burden of Periprosthetic Joint Infection of the Hip and Knee in the United States.

BACKGROUND: In addition to the significant morbidity and mortality associated with periprosthetic joint infection (PJI), the cost of treating PJI is substantial. Prior high-quality national estimates of the economic burden of PJI utilize data up to 2009 to project PJI growth in the United States through 2020. Now in the year 2020, it is appropriate to evaluate these past projections and incorporate the latest available data to better understand the current scale and burden of PJI in the United States. METHODS: The Nationwide Inpatient Sample (2002-2017) was used to identify rates and associated inpatient costs for primary total knee arthroplasty (TKA) and total hip arthroplasty (THA) and PJI-related revision TKA and THA. Poisson regression was utilized to model past growth and project future rates and cost of PJI of the hip and knee. RESULTS: Using the most recent data, the combined annual hospital costs related to PJI of the hip and knee were estimated to be $1.85 billion by 2030. This includes $753.4 million for THA PJI and $1.1 billion for TKA PJI, in that year. Increases in PJI costs are mainly attributable to increases in volume. Although the growth in incidence of primary THA and TKA has slowed in recent years, the incidence of PJI and the cost per case of PJI remained relatively constant from 2002 to 2017. DISCUSSION: Understanding the current and potential future financial burden of PJI for surgeons, patients, and healthcare systems is essential. There is an urgent need for efficacious preventive strategies in reducing rates of PJI after THA and TKA.

Three Degrees External to the Posterior Condylar Axis Has Little Relevance in Femoral Component Rotation: A Computed Tomography-Based Total Knee Arthroplasty Simulation Study.

BACKGROUND: Femoral component rotation in total knee arthroplasty (TKA) has a significant impact on balance and patellofemoral kinematics. However, normal anatomic relationships between rotational axes are poorly understood. As such, we sought to characterize anatomic femoral rotational axes in patients undergoing primary TKA. METHODS: We identified 100 patients who underwent a primary TKA with a preoperative computed tomography scan. The angles between the surgical epicondylar axis (SEA) and the anterior-posterior (AP) axis to the posterior condylar axis (PCA) were measured independently by a musculoskeletal fellowship-trained radiologist and a fellowship-trained arthroplasty surgeon. We simulated an ideal TKA in which the femoral component was placed exactly 3° external to the PCA and measured resulting rotation. RESULTS: The SEA was on average 1.5° externally rotated to the PCA (range 3.1° internal to 7.0° external). The AP axis was on average 4.5° externally rotated to the PCA (range 2.3° internal to 10.3° external). The AP axis was a mean 2.7° externally rotated to the SEA (range 6.3° internal to 10.3° external). Routinely setting femoral rotation 3° external to the PCA would result in only 51 (51%) TKAs within ±2° of the SEA and 23 (23%) femoral components internally rotated relative to the SEA. CONCLUSION: Normal anatomic rotational axes of arthritic knees are highly variable, with a 10° range in the SEA and 16° range in the AP axis. Routinely setting femoral rotation 3° external to the PCA will yield significant error in aligning the femoral component with either the SEA or AP axis.