A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment.

BACKGROUND: The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. METHODS: The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. RESULTS: In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68-1.00) for patient response prediction. CONCLUSIONS: The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.

Role of the fatty pancreatic infiltration in pancreatic oncogenesis.

Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.

Incidence and Risk Factors for Recurrence and Progression of HPV-Independent Vulvar Intraepithelial Neoplasia.

OBJECTIVES: Human papillomavirus (HPV)-independent vulvar intraepithelial neoplasia (VIN) is a rare yet aggressive precursor lesion of vulvar cancer. Our objectives were to estimate its long-term incidence, the risk of recurrent disease and progression to vulvar cancer, and risk factors thereof. MATERIALS AND METHODS: Patients with HPV-independent VIN between 1991 and 2019 in a selected region were identified from the Dutch Nationwide Pathology Databank (Palga). Data were collected from the pathology reports. Crude and European age-standardized incidence rates were calculated for 10-year periods. Kaplan-Meier analyses were performed to determine the cumulative recurrence and cancer incidence, followed by Cox regression analyses to identify associated risk factors. RESULTS: A total of 114 patients were diagnosed with solitary HPV-independent VIN without prior or concurrent vulvar cancer. The European age-standardized incidence rate increased from 0.09 to 0.69 per 100,000 women-years between 1991-2010 and 2011-2019. A cumulative recurrence and cancer incidence of 29% and 46% were found after 8 and 13 years of follow-up, respectively. Nonradical surgery was identified as the only independent risk factor for recurrent HPV-independent VIN. Risk factors associated with progression to cancer were increasing age and a mutant p53 immunohistochemical staining pattern. CONCLUSIONS: The incidence of detected HPV-independent VIN has substantially increased the last decade and the subsequent recurrence and vulvar cancer risks are high. Although HPV-independent VIN may present as a wide morphologic spectrum, surgical treatment should aim for negative resection margins followed by close surveillance, especially for p53 mutant lesions.

Upgrade Rates of Variant Lobular Carcinoma In Situ Compared to Classic Lobular Carcinoma In Situ Diagnosed in Core Needle Biopsies: A 10-Year Single Institution Retrospective Study.

The primary aim of this study was to determine the upgrade rates of variant lobular carcinoma in situ (V-LCIS, ie, combined florid [F-LCIS] and pleomorphic [P-LCIS]) compared with classic LCIS (C-LCIS) when diagnosed on core needle biopsy (CNB). The secondary goal was to determine the rate of progression/development of invasive carcinoma on long-term follow-up after primary excision. After institutional review board approval, our institutional pathology database was searched for patients with "pure" LCIS diagnosed on CNB who underwent subsequent excision. Radiologic findings were reviewed, radiologic-pathologic (rad-path) correlation was performed, and follow-up patient outcome data were obtained. One hundred twenty cases of LCIS were identified on CNB (C-LCIS = 97, F-LCIS = 18, and P-LCIS = 5). Overall upgrade rates after excision for C-LCIS, F-LCIS, and P-LCIS were 14% (14/97), 44% (8/18), and 40% (2/5), respectively. Of the total cases, 79 (66%) were deemed rad-path concordant. Of these, the upgrade rate after excision for C-LCIS, F-LCIS, and P-LCIS was 7.5% (5 of 66), 40% (4 of 10), and 0% (0 of 3), respectively. The overall upgrade rate for V-LCIS was higher than for C-LCIS (P = .004), even for the cases deemed rad-path concordant (P value: .036). Most upgraded cases (23 of 24) showed pT1a disease or lower. With an average follow-up of 83 months, invasive carcinoma in the ipsilateral breast was identified in 8/120 (7%) cases. Six patients had died: 2 of (contralateral) breast cancer and 4 of other causes. Because of a high upgrade rate, V-LCIS diagnosed on CNB should always be excised. The upgrade rate for C-LCIS (even when rad-path concordant) is higher than reported in many other studies. Rad-path concordance read, surgical consultation, and individualized decision making are recommended for C-LCIS cases. The risk of developing invasive carcinoma after LCIS diagnosis is small (7% with ∼7-year follow-up), but active surveillance is required to diagnose early-stage disease.

Analysis of the Differences between Bethesda Groups according to Conventional Smear and Liquid-Based Cytology Methods in Cervicovaginal Cytology: A Single-Center Experience with 165,915 Cases.

INTRODUCTION: Liquid-based cytology (LBC) has replaced conventional smear (CS) in the world. In this study, through a series with a large number of cases, we aimed to make a comparison and general evaluation in all groups, primarily epithelial abnormalities, according to LBC and CS methods. This study was carried out in a private pathology laboratory located in a metropolitan city, where cytological materials sent from many clinics were examined. MATERIAL AND METHODS: There were 165,915 cases whose smears were examined between 2012 and 2020, most of them conventional (131,224 CS, 34,691 LBC). Cases were evaluated on the basis of the Bethesda 2014 classification and divided into sub-diagnostic categories after they were divided into two main groups as "with epithelial abnormalities" and "without." χ2 and Fischer's precision statistical tests were conducted using SPSS 23.0 package. In the CS process, cervical samples were obtained using an endocervical brush and a spatula. Cells were directly spread onto the slides and promptly fixed in 95% ethanol, followed by staining with the standard Papanicolaou stain. For LBC ThinPrep, cervical specimens were gathered using a cervix brush. The brush was washed in a vial and discarded. Finally, cells were isolated through vacuum filtration and transferred to the slide using air pressure. RESULTS: Squamous cell abnormalities (atypical squamous cells of undetermined significance [ASC-US], atypical squamous cells - cannot exclude high-grade squamous intraepithelial lesion [ASC-H], low-grade squamous intraepithelial lesion [LSIL], high-grade squamous intraepithelial lesion [HSIL], squamous cell carcinoma, atypical glandular cells of undetermined significance) were reported in 5,696 (3.43%) cases. ASC (ASC-US + ASC-H)/SIL ratio (1.36/2.04) was found to be 0.67 (recommended Bethesda ratio is <3). ASC-US (p < 0.001), ASC-H (p < 0.001), and HSIL(p < 0.001) detection rate of LBC was found to be significantly higher than CS. ASC-US (1.8/1.2), ASC-H (0.08/0.008), and HSIL (0.6/0.3) case ratios of LBC/CS were found to be significantly higher in LBC. LSIL (1.72/1.66) rate was similar. CONCLUSION: LBC is superior to CS in detecting epithelial lesions. In addition to being used as a screening method, it is clear that it makes a great contribution to reducing cervical carcinomas due to HPV typing. Definitive comments regarding comparison of methods on reactive changes and microorganism detection are challenging. Preanalytical factors might account for these situations.

A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.

Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors.

We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid-liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The KrasG12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated KrasG12D. Mechanistically, KrasG12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-KrasG12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in KrasG12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in KrasG12D-dependent tumors.

Morphologic and Molecular Heterogeneity of High-grade Serous Carcinoma Precursor Lesions.

Serous tubal intraepithelial carcinoma (STIC) is the fallopian tube precursor lesion for most cases of pelvic high-grade serous carcinoma (HGSC). To date, the morphologic, molecular, and clinical heterogeneity of STIC and a less atypical putative precursor lesion, termed serous tubal intraepithelial lesion, has not been well characterized. Better understanding of precursor heterogeneity could impact the clinical management of women with incidental STICs (without concurrent carcinoma) identified in cases of prophylactic or opportunistic salpingectomy. This study analyzed morphologic and molecular features of 171 STICs and 21 serous tubal intraepithelial lesions. We assessed their histologic features, Ki-67 and p53 staining patterns, and genome-wide DNA copy number alterations. We classified all precursor lesions into 2 morphologic subtypes, one with a flat surface (Flat) and the other characterized by budding, loosely adherent, or detached (BLAD) morphology. On the basis of pathology review by a panel of 8 gynecologic pathologists, we found 87 BLAD, 96 Flat, and 9 indeterminate lesions. As compared with Flat lesions, BLAD lesions were more frequently diagnostic of STIC ( P <0.0001) and were found concurrently with HGSC ( P <0.0001). BLAD morphology was also characterized by higher Ki-67 proliferation index ( P <0.0001), presence of epithelial stratification ( P <0.0001), and increased lymphocyte density ( P <0.0001). BLAD lesions also exhibited more frequent DNA copy number gain/amplification at the CCNE1 or CMYC loci canonical to HGSCs ( P <0.0001). Both BLAD morphology and STIC diagnoses are independent risk factors for an elevated Ki-67 proliferation index. No correlation was observed between BLAD and Flat lesions with respect to patient age, presence of germline BRCA1/2 mutation, or p53 staining pattern. These findings suggest that tubal precursor lesions are morphologically and molecularly heterogeneous, laying the foundation for further studies on the pathogenesis of HGSC initiation and identifying histologic features predictive of poor patient outcomes.

Compressive stress triggers fibroblasts spreading over cancer cells to generate carcinoma in situ organization.

At the early stage of tumor progression, fibroblasts are located at the outer edges of the tumor, forming an encasing layer around it. In this work, we have developed a 3D in vitro model where fibroblasts' layout resembles the structure seen in carcinoma in situ. We use a microfluidic encapsulation technology to co-culture fibroblasts and cancer cells within hollow, permeable, and elastic alginate shells. We find that in the absence of spatial constraint, fibroblasts and cancer cells do not mix but segregate into distinct aggregates composed of individual cell types. However, upon confinement, fibroblasts enwrap cancer cell spheroid. Using a combination of biophysical methods and live imaging, we find that buildup of compressive stress is required to induce fibroblasts spreading over the aggregates of tumor cells. We propose that compressive stress generated by the tumor growth might be a mechanism that prompts fibroblasts to form a capsule around the tumor.

Clinical impacts of positive intraepithelial neoplasia at pancreatic transection margin in pancreatic cancer surgery.

BACKGROUND/OBJECTIVES: The outcomes of patients with intraepithelial neoplasia at the pancreatic transection margin after pancreatic cancer surgery remain unclear. We evaluated the clinical impact of pancreatic transection margin status. METHODS: This retrospective observational study included 171 patients who underwent surgery for pancreatic ductal adenocarcinoma between January 2008 and December 2019. Patients were classified into three groups: negative pancreatic transection margin (group N), positive low-grade (group L), and positive high-grade (group H) intraepithelial neoplasia. The clinicopathological findings and prognoses were analyzed for each group. RESULTS: There were 140, 14, and 9 patients in groups N, L, and H, respectively. The median age was significantly higher in group H (p = 0.035). There were no significant differences in male ratio, preoperative chemotherapy administration rate, pretreatment tumor markers, operative procedure, operative time, or blood loss. Overall survival and recurrence-free survival were not significantly different; however, the cumulative risk of recurrence in the remnant pancreas was significantly higher in group H (p = 0.018). CONCLUSIONS: Intraepithelial neoplasia at the pancreatic transection margin did not affect overall/recurrence-free survival. As patients with high-grade intraepithelial neoplasia at the pancreatic transection margin have an increased risk of recurrence in the remnant pancreas, careful postoperative follow-up is required.

Simple versus radical cholecystectomy and survival for pathologic stage T1B gallbladder cancer.

BACKGROUND: Radical cholecystectomy is recommended for T1B and greater gallbladder cancer, however, there are conflicting reports on the utility of extended resection for T1B disease. Herein, we characterize outcomes following simple and radical cholecystectomy for pathologic stage T1B gallbladder cancer. METHODS: The National Cancer Database (NCDB) was queried for patients with pathologic T1B gallbladder cancer diagnosed from 2004 to 2018. Patients were stratified by surgical management. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: Altogether, 950 patients were identified with pathologic T1B gallbladder cancer: 187 (19.7 %) receiving simple and 763 (80.3 %) radical cholecystectomy. Median OS was 89.5 (95 % CI 62.5-137) and 91.4 (95 % CI 75.9-112) months for simple and radical cholecystectomy, respectively (log-rank p = 0.55). Receipt of simple cholecystectomy was not associated with greater hazard of mortality compared to radical cholecystectomy (HR 1.23, 95 % CI 0.95-1.59, p = 0.12). DISCUSSION: In this analysis, we report comparable outcomes with simple cholecystectomy among patients with pathologic T1B gallbladder cancer. These findings suggest that highly selected patients, such as those with R0 resection and imaging at low risk for residual disease and/or nodal metastasis, may not benefit from extended resection; however, radical cholecystectomy remains standard of care until prospective validation can be achieved.

Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions.

BACKGROUND: High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes. METHODS: We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan-Meier methods to characterize 3-year breast cancer risk in patients without upgrade. RESULTS: Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5-23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8-22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3-26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%). CONCLUSIONS: Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

Proliferation and immunohistochemistry for p53, CD25 and CK20 in predicting prognosis of non-muscle invasive papillary urothelial carcinomas.

Non-muscle invasive papillary urothelial carcinoma is a prevalent disease with a high recurrence tendency. Good prognostic and reproducible biomarkers for tumor recurrence and disease progression are lacking. Currently, WHO grade and tumor stage are essential in risk stratification and treatment decision-making. Here we present the prognostic value of proliferation markers (Ki67, mitotic activity index (MAI) and PPH3) together with p53, CD25 and CK20 immunohistochemistry (IHC). In this population-based retrospective study, 349 primary non-muscle invasive bladder cancers (NMIBC) were available. MAI and PPH3 were calculated manually according to highly standardized previously described methods, Ki-67 by the semi-automated QPRODIT quantification system, p53 and CD25 by the fully automated digital image analysis program Visipharm® and CK20 with the help of the semi-quantitative immunoreactive score (IRS). Survival analyses with log rank test, as well as univariate and multivariate Cox regression analyses were performed for all investigated variables. Age and multifocality were the only significant variables for tumor recurrence. All investigated variables, except gender, were significantly associated with stage progression. In multivariate analysis, MAI was the only prognostic variable for stage progression (p<0.001).

Anal and Perianal Preneoplastic Lesions.

Anal cancer, mainly squamous cell carcinoma, is rare but increasing in prevalence, as is its precursor lesion, anal squamous dysplasia. They are both strongly associated with human papillomavirus infection. The 2-tiered Lower Anogenital Squamous Terminology classification, low-grade SIL and high-grade SIL, is preferred to the 3-tiered anal intraepithelial neoplasia classification because of better interobserver agreement and clearer management implications. Immunohistochemistry with p16 is helpful to corroborate the diagnosis of squamous dysplasia. Similarly, immunohistochemistry is helpful to differentiate primary Paget disease from secondary Paget disease, which is usually due to anal squamous mucosal/epidermal involvement by primary rectal adenocarcinoma.

Use of Cemiplimab, an Immune Checkpoint Inhibitor for Conjunctival Intraepithelial Neoplasia.

PURPOSE: Immune checkpoint inhibitors (ICIs) have been recently introduced for the treatment of locally unresectable conjunctival squamous cell carcinoma. We present 2 cases with conjunctival intraepithelial neoplasia (CIN) who were treated with ICIs. METHODS: A report of 2 cases with CIN who were treated with systemic cemiplimab (350 mg IV every 3 weeks). RESULTS: A 70-year-old man was treated with cemiplimab for metastatic cutaneous squamous cell carcinoma. The pre-existing CIN continued to progress over the nasal bulbar conjunctiva and cornea, while the other metastatic sites, including parotid glands, and neck lymph nodes showed a complete response after 16 cycles of treatment. An 84-year-old woman had bilateral diffuse CIN involving bulbar and lower eyelid palpebral conjunctiva. Cemiplimab was started because of the extent of involvement. While the bulk of CIN was reduced, it progressed over the cornea and forniceal conjunctiva on OU after 10 cycles of treatment. Excisional biopsies of conjunctival lesions after cemiplimab confirmed CIN in both patients. CONCLUSIONS: Although conjunctival squamous cell carcinoma tumors are reported to be highly responsive to ICIs, a similar effect has not been observed in 2 patients with CIN. Further studies are needed to evaluate ICIs in the management of CIN.

Adenomyomas of the Gallbladder: An Analysis of Frequency, Clinicopathologic Associations, and Relationship to Carcinoma of a Malformative Lesion.

CONTEXT.­: The nature and associations of gallbladder (GB) "adenomyoma" (AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. OBJECTIVE.­: To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. DESIGN.­: Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. RESULTS.­: Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio = 1.9 (177:94) and mean size = 1.3 cm (range, 0.3-5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive ("adenomyomatosis"). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat-type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma arose from AM (invasion was confined to AM, and dysplasia was predominantly in AM). CONCLUSIONS.­: AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component (ie, the name "adeno-myoma" is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flat-type high-grade dysplasia or carcinoma in situ, and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer. Working Group 2: Grading of Mixed Grade, Invasive Urothelial Carcinoma Including Histologic Subtypes and Divergent Differentiations, and Non-Urothelial Carcinomas.

The 2022 International Society of Urological Pathology (ISUP) Consensus Conference on Urinary Bladder Cancer Working Group 2 was tasked to provide evidence-based proposals on the applications of grading in noninvasive urothelial carcinoma with mixed grades, invasive urothelial carcinoma including subtypes (variants) and divergent differentiations, and in pure non-urothelial carcinomas. Studies suggested that predominantly low-grade noninvasive papillary urothelial carcinoma with focal high-grade component has intermediate outcome between low- and high-grade tumors. However, no consensus was reached on how to define a focal high-grade component. By 2004 WHO grading, the vast majority of lamina propria-invasive (T1) urothelial carcinomas are high-grade, and the rare invasive low-grade tumors show only limited superficial invasion. While by 1973 WHO grading, the vast majority of T1 urothelial carcinomas are G2 and G3 and show significant differences in outcome based on tumor grade. No consensus was reached if T1 tumors should be graded either by the 2004 WHO system or by the 1973 WHO system. Because of the concern for underdiagnosis and underreporting with potential undertreatment, participants unanimously recommended that the presence of urothelial carcinoma subtypes and divergent differentiations should be reported. There was consensus that the extent of these subtypes and divergent differentiations should also be documented in biopsy, transurethral resection, and cystectomy specimens. Any distinct subtype and divergent differentiation should be diagnosed without a threshold cutoff, and each type should be enumerated in tumors with combined morphologies. The participants agreed that all subtypes and divergent differentiations should be considered high-grade according to the 2004 WHO grading system. However, participants strongly acknowledged that subtypes and divergent differentiations should not be considered as a homogenous group in terms of behavior. Thus, future studies should focus on individual subtypes and divergent differentiations rather than lumping these different entities into a single clinicopathological group. Likewise, clinical recommendations should pay attention to the potential heterogeneity of subtypes and divergent differentiations in terms of behavior and response to therapy. There was consensus that invasive pure squamous cell carcinoma and pure adenocarcinoma of the bladder should be graded according to the degree of differentiation. In conclusion, this summary of the International Society of Urological Pathology Working Group 2 proceedings addresses some of the issues on grading beyond its traditional application, including for papillary urothelial carcinomas with mixed grades and with invasive components. Reporting of subtypes and divergent differentiation is also addressed in detail, acknowledging their role in risk stratification. This report could serve as a guide for best practices and may advise future research and proposals on the prognostication of these tumors.

Aesthetic Outcome and Psychosexual Distress After Treatment for Vulvar High-Grade Squamous Intraepithelial Lesions.

OBJECTIVES: This study compared aesthetic outcome, psychosexual distress, and treatment satisfaction between women receiving surgical treatment or medical treatment with imiquimod for vulvar high-grade squamous intraepithelial lesion. MATERIALS AND METHODS: This is an extended analysis of the multicenter, randomized noninferiority trial "topical imiquimod versus surgery for vulvar intraepithelial neoplasia." Patients were randomized to primary topical treatment or surgery and stratified by unifocal or multifocal disease. Digital photos of vulvar appearance were subsequently assessed for aesthetic outcome by 3 investigators blinded to group allocation. Psychosexual distress and treatment satisfaction were assessed with the Cervical Dysplasia Distress Questionnaire, the Sexual Activity Questionnaire, and the Client Satisfaction Questionnaire at baseline and follow-up. RESULTS: One hundred ten patients aged between 19 and 82 years were enrolled. Per-protocol analysis showed complete clinical response in 80% (37/46) using imiquimod, compared with 79% (41/52) after one surgical intervention. Photodocumentation at baseline and 6-month follow-up was available for 84 of these patients (44 imiquimod, 40 surgery). Blinded reviewer assessments of lesion size and lesion severity showed improvement from baseline to follow-up, with no differences between treatment groups. Sexual pleasure, discomfort, and distress remained stable from baseline to follow-up in both groups. CONCLUSIONS: Good aesthetic outcome of vulvar high-grade squamous intraepithelial lesion treatment can be achieved with imiquimod and surgery, consisting of ablation or local excision. Treatment satisfaction and stable psychosexual health may not be dependent on chosen treatment modality, but rather on counseling in accordance with patients' preferences.

Intraductal papillary neoplasm of the bile duct with metachronous development in the downstream bile duct after radical resection.

We report a case of intraductal papillary neoplasms of the bile duct (IPNB) that metachronously developed twice in the downstream bile duct after radical resection. The first lesion was located in the left intrahepatic bile duct, the second lesion in the perihilar bile duct, and the third lesion in the distal bile duct. All lesions were IPNBs with associated invasive carcinoma (pancreatobiliary type). The depth of invasion was to the Glisson's capsule in the first lesion, to the subserosa in the second lesion, and to the fibromuscular layer in the third lesion, without lympho-vascular/perineural invasion and lymph-node metastasis. These were resected radically and had no biliary intraepithelial neoplasia and hyperplasia in the surrounding mucosa. In immunohistochemical examination, each lesion showed a different pattern. Although the downstream occurrence suggests intrabiliary dissemination, the mechanism of these metachronous developments may be multicentric. A literature review revealed that most metachronous cholangiocarcinomas have a grossly papillary appearance and tend to arise downstream. Our findings suggest that IPNB may develop metachronously in the residual bile duct after radical surgery, which may assist in early detection.