Utility of methylated DNA markers for the diagnosis of malignant biliary strictures.

BACKGROUND AND AIMS: Early identification of malignant biliary strictures (MBSs) is challenging, with up to 20% classified as indeterminants after preliminary testing and tissue sampling with endoscopic retrograde cholangiopancreatography. We aimed to evaluate the use of methylated DNA markers (MDMs) from biliary brushings to enhance MBS detection in a prospective cohort. APPROACH: Candidate MDMs were evaluated for their utility in MBS diagnosis through a series of discovery and validation phases. DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific droplet digital polymerase chain reaction.  Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. RESULTS: Fourteen candidate MDMs were evaluated in the discovery phase, with top-performing and new markers evaluated in the technical validation phase. The top 4 MDMs were TWIST1, HOXA1, VSTM2B, and CLEC11A, which individually achieved AUC values of 0.82, 0.81, 0.83, and 0.78, respectively, with sensitivities of 59.4%, 53.1%, 62.5%, and 50.0%, respectively, at high specificities for malignancy of 95.2%-95.3% for the final biologic validation phase. When combined as a panel, the AUC was 0.86, achieving 73.4% sensitivity and 92.9% specificity, which outperformed cytology and fluorescence in situ hybridization (FISH). CONCLUSIONS: The selected MDMs demonstrated improved performance characteristics for the detection of MBS compared to cytology and FISH. Therefore, MDMs should be considered viable candidates for inclusion in diagnostic testing algorithms.

Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and has a poor prognosis. Surgical resection is the standard of care for patients with resectable disease, representing 30-40% of cases. Increasingly, neoadjuvant systemic therapy is being utilized in patients due to high-risk anatomic or biologic considerations. However, data on the clinical effect of this approach are limited. We performed a cohort study to evaluate the effect of neoadjuvant therapy in patients with oncologically high-risk iCCA. METHODS: iCCA patients (n = 181) between the years 2014-2020 were reviewed for clinical, histopathologic, treatment, and outcome-related data. Tumor regression grade was scored per CAP criteria for gastrointestinal carcinomas. RESULTS: 47 iCCA patients received neoadjuvant therapy and 72 did not. Neoadjuvant treatment led to objective response and tumor regression by CAP score. After adjustment for age, clinical stage, and tumor size, the outcomes of patients who had neoadjuvant therapy followed by surgery were not significantly different from those patients who had surgery first. DISCUSSION: In conclusion, neoadjuvant therapy in iCCA facilitated surgical care. The progression-free and overall survival for surgical patients with and without neoadjuvant therapy were not significantly different suggesting this approach needs further exploration as an effective treatment paradigm.

WITHDRAWN: Neoadjuvant therapy leads to objective response in intrahepatic cholangiocarcinoma.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.hpb.2024.04.011. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Outcomes of Immunotherapy in Sinonasal Mucosal Melanoma Patients With Recurrent and Metastatic Disease.

Sinonasal mucosal melanoma (SNMM) is a rare malignancy with poor prognosis and high recurrence rate. In those with recurrence, survival is dismal. Immunotherapy is an emerging area of investigation; however, there is a scarcity of data on immunotherapy outcomes in SNMM patients with recurrence. We report outcomes of immunotherapy in recurrent SNMM patients with distant versus nondistant recurrence. Fifty-four patients with recurrent SNMM were identified, and 31 (57.4%) had distant recurrence. One-year overall survival (OS) following recurrence was 47.5% (95% confidence interval [CI]: 34.0%-60.9%), with a median survival of 2.8 years (95% CI: 2.0-5.3). In those with distant recurrence, receipt of immunotherapy was associated with better OS compared to those without immunotherapy (hazard ratio [HR] = 0.29 [95% CI: 0.12-0.68], P = .004). While patients with nondistant recurrence (n = 23), who received immunotherapy (n = 6) had worse OS compared to those who did not receive immunotherapy (HR = 4.76 [95% CI: 1.36, 15.89], P = .02). LEVEL OF EVIDENCE: Level IV.

Breast Cancer Risk Perceptions Among Underserved, Hispanic Women: Implications for Risk-Based Approaches to Screening.

BACKGROUND: Understanding factors that shape breast cancer risk perceptions is essential for implementing risk-based approaches to breast cancer detection and prevention. This study aimed to assess multilevel factors, including prior screening behavior, shaping underserved, Hispanic women's perceived risk for breast cancer. METHODS: Secondary analysis of survey data from Hispanic women (N = 1325, 92% Spanish speaking, 64% < 50) enrolled in a large randomized controlled trial. Analyses were performed in two cohorts to account for the role of age on screening guideline recommendations (< 50 and 50 +). For each cohort, we examined differences in three common measures of perceived risk of breast cancer (percent lifetime, ordinal lifetime, comparative) by participant factors with chi-square or Kruskal-Wallis tests, as appropriate. Multivariate analyses examined the association between mammography history with percent perceived lifetime risk (outcome > 10 vs ≤ 10%). RESULTS: Overall, 75% reported a lifetime risk between 0 and 10%, 96% rated their ordinal risk as "not high," and 50% rated their comparative risk as "much lower." Women < 50 with a family history of breast cancer reported significantly higher levels of perceived risk across all three measures. Among women 50 + , those reporting lower levels of perceived risk were significantly more likely to be Spanish speaking. No significant association was observed between mammography history and percent lifetime risk of breast cancer. CONCLUSION: Factors shaping breast cancer risk perceptions differ by age. Prior screening may play less of role in constructing risk perceptions. Research is needed to develop culturally and linguistically appropriate strategies to improve implementation of risk-based screening.

A Survey of Patient Experience During Molecular Breast Imaging.

Molecular breast imaging (MBI) is one of several options available to patients seeking supplemental screening due to mammographically dense breasts. Patient experience during MBI may influence willingness to undergo the test but has yet to be formally assessed. We aimed to assess patient comfort level during MBI, to compare MBI comfort with mammography comfort, to identify factors associated with MBI discomfort, and to evaluate patients' willingness to return for future MBI. Methods: A 10-question survey was sent by e-mail to patients undergoing MBI between August and December 2022 to obtain quantitative assessments and qualitative opinions about MBI. Results: Of 561 invited patients, 209 (37%) completed the survey and provided study consent. Their average age was 60.1 y (range, 40-81 y). Of the 209 responders, 202 (97%) were presenting for screening MBI, 195 (94%) had dense breasts, and 46 (22%) had a personal history of breast cancer. The average rating of MBI comfort was 2.9 (SD, 1.5; median, 3.0) on a 7-point scale (1 indicating extremely comfortable and 7 indicating extremely uncomfortable). The rating distribution was as follows: 140 (67%) comfortable (rating, 1-3); 24 (12%) neither comfortable nor uncomfortable (rating, 4); and 45 (22%) uncomfortable (rating, 5 or 6). No responders gave a 7 rating. The most frequently mentioned sources of discomfort included breast compression (n = 16), back or neck discomfort (n = 14), and maintaining position during the examination (n = 14). MBI comfort was associated with responder age (74% ≥55 y old were comfortable, versus 53% <55 y old [P = 0.003]) and history of MBI (71% with prior MBI were comfortable, versus 61% having a first MBI [P = 0.006]). Of 208 responders with a prior mammogram, 148 (71%) said MBI is more comfortable than mammography (a significant majority [P < 0.001]). Of 202 responders to the question of whether they were willing to return for a future MBI, 196 (97%) were willing. A notable factor in positive patient experience was interaction with the MBI nuclear medicine technologist. Conclusion: Most responders thought MBI to be a comfortable examination and more comfortable than mammography. Patient experience during MBI may be improved by ensuring back support and soliciting patient feedback at the time of positioning and throughout the examination. Methods under study to reduce imaging time may be most important for improving patient experience.

Prognostic Immunohistochemistry for Ki-67 and OTP on Small Biopsies of Pulmonary Carcinoid Tumors: Ki-67 Index Predicts Progression-free Survival and Atypical Histology.

Prognostic stratification of pulmonary carcinoids into "typical" and "atypical" categories requires examination of large tissue volume. However, there is a need for tools that provide similar prognostic information on small biopsy samples. Ki-67 and OTP immunohistochemistry have shown promising prognostic value in studies of resected pulmonary carcinoids, but prognostic value when using biopsy/cytology specimens is unclear. Ki-67 immunohistochemistry was performed on small biopsy/cytology specimens from pulmonary carcinoid tumors (n=139), and labeling index was scored via automated image analysis of at least 500 cells. OTP immunohistochemistry was performed on 70 cases with sufficient tissue and scored as positive or negative (<20% tumor nuclei staining). Higher Ki-67 index was associated with worse disease-specific progression-free survival (ds-PFS), with 3% and 4% thresholds having similarly strong associations with ds-PFS ( P <0.001, hazard ratio ≥11). Three-year ds-PFS was 98% for patients with Ki-67 <3% and 89% for patients with Ki-67≥3% ( P =0.0006). The optimal Ki-67 threshold for prediction of typical versus atypical carcinoid histology on subsequent resection was 3.21 (AUC 0.68). Negative OTP staining approached significance with atypical carcinoid histology ( P =0.06) but not with ds-PFS ( P =0.24, hazard ratio=3.45), although sample size was limited. We propose that Ki-67 immunohistochemistry may contribute to risk stratification for carcinoid tumor patients based on small biopsy samples. Identification of a 3% hot-spot Ki-67 threshold as optimal for prediction of ds-PFS is notable as a 3% Ki-67 threshold is currently used for gastrointestinal neuroendocrine tumor stratification, allowing consideration of a unified classification system across organ systems.

Clinicopathologic Features of IgG4-Related Kidney Disease.

Introduction: IgG4-related disease (IgG4-RD) is a systemic immune-mediated disease that can involve nearly any organ. IgG4-RD can affect the kidney in different disease patterns, collectively referred to as IgG4-related kidney disease (IgG4-RKD). Methods: We conducted a tissue-based cohort study with clinicopathological correlation in 125 patients with IgG4-RKD. Results: The mean age at biopsy (n = 120) or nephrectomy (n = 5) was 63 years; 80% were male. One hundred eighteen patients (94%) had IgG4-related tubulointerstitial nephritis (IgG4-TIN); 20 patients (16%) had IgG4-related membranous glomerulonephritis (IgG4-MGN; 13 with concurrent IgG4-TIN). The primary clinical indication for biopsy/nephrectomy was acute or chronic renal failure in 78%, proteinuria in 17%, and mass lesion(s) in 15% (with overlap in primary indication). Fifty-two percent patients (41/79) had abnormal radiographic findings, including masses in 30% (24/79). All patients with IgG4-MGN had proteinuria. Extrarenal involvement by IgG4-RD was present in 79%. Median serum creatinine at presentation was 2.5 mg/dl (range 0.7-12). Serum IgG and/or IgG4 was increased in 91% (53/58); hypocomplementemia was present in 56% (43/77). Light microscopy showed plasma cell-rich interstitial nephritis in all cases of IgG4-TIN. Ninety-two percent of patients showed increased IgG4+ plasma cells. Seven percent showed an acute interstitial nephritis (AIN) pattern, and 5% showed non-necrotizing arteritis. Tubular basement membrane immune deposits were present in 83% of IgG4-TIN. Treatment information was available for 71 patients; 62 were treated with immunosuppression. Of those with elevated creatinine, 72% (41/57) showed a treatment response. Conclusion: This largest tissue-based series more clearly defines the disease phenotype of IgG4-RKD.

Comparing loss of p16 and MTAP expression in detecting CDKN2A homozygous deletion in pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytomas (PXAs) harbor CDKN2A homozygous deletion in >90% of cases, resulting in loss of p16 expression by immunohistochemistry. Considering the proximity of MTAP to CDKN2A and their frequent concurrent deletions, loss of MTAP expression may be a surrogate for CDKN2A homozygous deletion. We evaluated p16 and MTAP expression in 38 patient PXAs (CNS WHO grade 2: n = 23, 60.5%; grade 3: n = 15, 39.5%) with available chromosomal microarray data to determine whether MTAP can be utilized independently or in combination with p16 to predict CDKN2A status. CDKN2A, CDKN2B, and MTAP homozygous deletion were present in 37 (97.4%), 36 (94.7%), and 25 (65.8%) cases, respectively. Expression of p16 was lost in 35 (92.1%) cases, equivocal in one (2.6%), and failed in 2 (5.3%), while MTAP expression was lost in 27 (71.1%) cases, retained in 10 (26.3%), and equivocal in one (2.6%). This yielded a sensitivity of 94.6% for p16 and 73.0% for MTAP in detecting CDKN2A homozygous deletion through immunohistochemistry. MTAP expression was lost in the 2 cases with failed p16 staining (combined sensitivity of 100%). Our findings demonstrate that combined p16 and MTAP immunostains correctly detect CDKN2A homozygous deletion in PXA, while MTAP expression alone shows reduced sensitivity.

Comparison of a modified staging system with 8th edition AJCC criteria in a North American cohort of pT2/pT3 HPV-negative penile squamous cell carcinoma.

The staging for pT2/pT3 penile squamous cell carcinoma (pSCC) has undergone major changes. Some authors proposed criteria wherein the distinction between pT2/pT3 was made using the same histopathological variables that are currently utilized to differentiate pT1a/pT1b. In this single-institution, North American study, we focused on (HPV-negative) pT2/3 pSCCs (i.e., tumors invading corpus spongiosum/corpus cavernosum), and compared the prognostic ability of the following systems: (i) AJCC (8th edition) criteria; (ii) modified staging criteria proposed by Sali et al. (Am J Surg Pathol. 2020; 44:1112-7). In the proposed system, pT2 tumors were defined as those devoid of lymphovascular invasion (LVI) or perineural invasion (PNI), and were not poorly differentiated; whereas pT3 showed one or more of the following: LVI, PNI, and/or grade 3. 48 pT2/pT3 cases were included (AJCC, pT2: 27 and pT3: 21; Proposed, pT2: 22 and pT3: 26). The disease-free survival (DFS) and progression-free survival (PFS) did not differ between pT2 and pT3, following the current AJCC definitions (p = 0.19 and p = 0.10, respectively). When the pT2/3 stages were reconstructed using the modified criteria, however, a statistically significant difference was present in both DFS and PFS between pT2 and pT3 (p = 0.004 and p = 0.003, respectively). The proposed staging system has the potential to improve the prognostication of pT2/pT3 tumors in pSCC. Each of these histopathologic variables has been shown to have a significant association with outcomes in pSCC, which is an advantage. Further studies are needed to demonstrate the utility of this modified staging system in patient populations from other geographic regions.

High-risk human papilloma virus status & outcomes for penile squamous cell carcinoma: A single institution experience.

OBJECTIVES: There is a paucity of data on North American cohorts of patients with penile squamous cell carcinoma (pSCC). Herein, we aimed to assess the sensitivity of various modalities to identify human papillomavirus (HPV) status, determine the prevalence of high-risk HPV-positivity, and evaluate the prognostic impact of relevant clinicopathologic variables. METHODS: Patients with pSCC (n = 121) consecutively treated with partial/total penectomy (2000-2022) at a single institution were included. HPV status (based on immunohistochemistry [IHC], in situ hybridization [ISH], and panviral metagenomic sequencing [PMS]), histologic features, and outcomes were reviewed. Outcome events included death due to disease and progression. RESULTS: The majority of patients were white (105/121, 86.8%). Thirty-seven (30.6%) were high-risk HPV-positive, and morphologic evaluation had a sensitivity of 97.3% (95% confidence interval [CI], 86.2-99.5) for predicting high-risk HPV status compared to IHC/ISH/PMS. Disease progression was more common among high-risk HPV-negative compared to high-risk HPV-positive patients (HR 2.74, CI 1.12-8.23, P = 0.03). Moreover, among high-risk HPV-negative patients, those with moderate-poorly differentiated tumors had increased disease-specific mortality (32.6%, CI 17.1-48.1) compared to those with well-differentiated tumors (0%). Among high-risk HPV-positive patients, those with basaloid morphology had lower disease-specific mortality (0% vs 14.4%, CI 0.0-33.1). CONCLUSIONS: We demonstrate high-risk HPV-positivity in approximately one-third of patients with pSCC. Morphologic evaluation alone had a high sensitivity in correctly determining HPV status. Our results suggest that high-risk HPV status and morphologic features (differentiation in high-risk HPV-negative, and basaloid subtype in high-risk HPV-positive pSCC) may have prognostic value.