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Background: Treatment option decisions for low-risk squamous cell carcinoma in situ (SCCIS) are hampered by a paucity of management-type-specific outcomes data., Objective: Describe SCCIS tumor outcomes managed by watchful waiting and risk factors associated with poor cancer outcomes., Materials and Methods: Retrospective cohort study. Setting: Single academic hospital in a rural setting. Patients: Adults with SCCIS diagnosed between January 01, 2014, and December 31, 2016. Main Outcomes and Measures: Hazard ratios (HRs) for local recurrence (LR), nodal metastases (NM), distant metastases (DM), and disease-specific death (DSD)., Results: A total of 411 consecutive SCCIS tumors that were considered clinically resolved at follow-up and managed with watchful waiting were included. Seventeen tumors recurred locally. No instances of NM, DM, or DSD were identified. Multivariate analysis found that solid-organ transplant recipient status conferred the highest risk of local recurrence [HR, 9.979 (95% CI, 2.249-39.69)]. Additional risk factors predicting LR include anatomic location on the vermilion lip or ear [HR, 9.744 (95% CI, 1.420-69.28)], anatomic location on the head and neck [HR, 6.687 (95% CI, 1.583-36.15)], and a biopsy with tumor extending to the deep edge [HR, 6.562 (95% CI, 1.367-39.04)]., Conclusion: Watchful waiting for SCCIS with a clinically resolved biopsy site has a local recurrence rate of 4%., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Endometroid intraepithelial neoplasia (EIN) is a premalignant lesion to endometrial cancer. Increasing number of gynecologic oncologists are performing sentinel lymph node (SLN) evaluation during hysterectomy for EIN to ensure complete staging if there is cancer on the final specimen. However, there are no clear guidelines and the benefits and risks to performing SLN evaluation for EIN patients are unclear., Areas Covered: This narrative review examines the advantages and disadvantages of SLN evaluation for EIN patients and provides an algorithm to assist clinicians in selectively applying the procedure for maximal patient benefit. Relevant articles up to March 2024 were obtained from a PubMed search on SLN use with endometrial pathology., Expert Opinion: Sentinel lymph node evaluation for patients with EIN is safe, feasible, and particularly important for the approximately 10% of patients with high-risk endometrial carcinoma on final pathology. However, as most diagnosed carcinomas are low-risk, SLN evaluation would have limited oncologic benefit. While SLN assessment may overtreat most patients with EIN, a significant minority of patients will be improperly staged. We propose an algorithm highlighting the importance of maximal preoperative endometrial sampling and stratifying patients via risk factors to selectively identify those who would benefit most from SLN evaluation.

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up., Materials and Methods: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 10 11 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF)., Results: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease., Conclusions: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Purpose: This study aimed to evaluate the clinical efficacy and safety of argon plasma coagulation (APC) therapy and interferon therapy in patients with grade I and II vaginal intraepithelial neoplasia (VaIN)., Methods: A total of 112 patients with VaIN were diagnosed via colposcopy-induced biopsy and classified into the APC group (n = 77) and interferon group (n = 35). Clinical data including age, grade, symptoms, historical or concomitant neoplasia of the lower genital tract, indications for hysterectomy, pregnancy history, cytology, human papillomavirus (HPV) subtype, treatment modalities, and clinical outcomes were analyzed, retrospectively. Complications and clinical outcomes were assessed at 6- and 12-month follow-ups., Results: There was no significant difference in the HPV clearance rate between the APC (53.42%) and interferon (33.33%) groups at 6 months after treatment. However, the 12-month follow-up of the APC group showed a significantly higher HPV clearance rate as compared to the interferon group (87.67% vs. 51.52%, P < 0.05). The APC group exhibited a significantly higher cure rate (79.22% vs. 40.0%) and lower persistence rate (12.99% vs. 37.14%) than the interferon group (P < 0.05). Adverse reaction analysis revealed that the primary reaction in the APC group was vaginal drainage, in contrast to the increased vaginal discharge in the interferon group; though the difference was significant (68.83% vs. 28.57%, P < 0.05), no serious complications were observed., Conclusions: Treatment with APC is a safe and more effective procedure against VaIN I and II, compared to interferon. APC may serve as a viable alternative to other physiotherapies., (© 2024. The Author(s).)

Anal intraepithelial neoplasia (AIN) are precancerous lesions and are sequela of human papilloma virus (HPV) infection. AIN is classified as low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion. Screening with anal cytology and anoscopy should be considered for high-risk populations. Diagnosis is made through high resolution anaoscopy and biopsy. Options for treatment include ablation and several topical therapies; however, recurrence rates are high for all treatment options, and an ongoing surveillance is necessary to prevent progression to anal squamous cell carcinoma. HPV vaccination is recommended to prevent disease., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Differentiated vulvar intraepithelial neoplasia (dVIN) is a high-risk preinvasive vulvar lesion and precursor of human papillomavirus-independent vulvar squamous cell carcinoma (VSCC). Due to its rarity, literature data on its malignant potential are scant. The aim of the study is to assess the risk of developing VSCC in patients surgically treated for dVIN not associated with VSCC (solitary dVIN) and the risk of VSCC recurrence in patients treated for dVIN associated with VSCC (dVIN-VSCC) at first diagnosis., Material and Methods: A historical cohort study was performed in a northern Italy referral center for vulvar neoplasms. All consecutive women surgically treated for histologically confirmed dVIN from 1994 to 2021 were collected. Primary outcome was cancer risk or recurrent cancer risk, secondary outcomes were risk factors associated with VSCC development or recurrence. Kaplan-Meier method and log-rank test were used to estimate cancer risk or recurrent cancer risk differences and uni- and multivariate Cox regression analyses to identify risk factors associated with VSCC development in solitary dVIN and recurrence of dVIN-VSCC., Results: Seventy-six patients with dVIN at preoperative biopsy were included: at excisional specimens 44 were solitary dVIN and 32 were dVIN-VSCC. The absolute risk of VSCC development after solitary dVIN treatment was 43.2% with median time to to VSCC diagnosis of 25.4 months (range 3.5-128.0 months). VSCC recurrence absolute risk in treated dVIN-VSCC patients was 31.3% with median time to VSCC recurrence of 52.9 months (range 6.5-94.8 months). At uni- and multivariate regression analyses, only compliant topical ultrapotent corticosteroid treatment after solitary dVIN excision showed an ability to prevent VSCC development. No protective effect by corticosteroid treatment was shown for VSCC recurrence in dVIN-VSCC patients. Smoking was associated with higher cancer recurrence risk in dVIN-VSCC patients on both uni- and multivariate regression analyses., Conclusions: Patients with dVIN have a high risk of developing both primary and recurring VSCC. Early recognition, long-term follow up, and compliant ultrapotent topical corticosteroid treatment are recommended., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

The purpose of this study was to determine whether utilization of assisted reproductive technology following clearance of endometrial intraepithelial neoplasia (EIN) or early endometrial cancer (EC) shortens time to conception (TTC) and reduces recurrence. Patients aged 18 to 45 with EIN or early EC who achieved pathologic response following progesterone treatment were identified via retrospective chart review. Study groups included patients who pursued ovulation induction (OI), in vitro fertilization (IVF), and spontaneous pregnancy. Primary outcomes were TTC and recurrence rate. Three hundred forty-six charts were reviewed, with 86 patients meeting inclusion criteria and 53 attempting pregnancy. Of those 53 patients, 11 became pregnant and seven had a live birth. Median times to pregnancy were 183 days for IVF, 54 days for OI, and 347 days for spontaneous conception (p < 0.05). No differences were seen in recurrence or progression based on attempted pregnancy method, nor with duration of fertility treatment. Forty-two of 86 patients (49%) were lost to follow-up. For patients with a history of treated EIN or EC, OI may decrease TTC. Larger prospective studies are needed to definitively answer this question. Although no differences in recurrence or progression were identified, the significant loss to follow-up rate in this study is concerning and warrants further investigation., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Abstract: In the last 3 years, new and relevant information has been published on anal cancer and anal precancerous lesions epidemiology, screening, treatment, and vaccination. This information will likely change prevention and treatment strategies for these patients in the upcoming years., Competing Interests: The author has declared that there are no conflicts of interest., (Copyright © 2023, ASCCP.)

Anal intraepithelial neoplasms (AIN) are precursors to anal cancer. To date, there is not a significant body of literature to support screening, monitoring, and treatment of these precursor lesions, particularly in high risk populations. This review will detail the current monitoring and indications for treatment of such lesions, with the goal of preventing progression to invasive cancer., (© 2023 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Despite the knowledge of etiological association with high-risk human papilloma viruses and high-risk patient cohorts, the incidence of anal squamous cell carcinoma has continued to rise. The known precursor lesion (in particular, high-grade squamous intraepithelial lesion) makes it amenable to screening and surveillance strategies. However, the diagnosis of anal intraepithelial neoplasia suffers from interpretation challenges leading to high interobserver variability, along with numerous differential diagnoses and lingering terminology issues. Proper treatment of anal lesions requires accurate diagnosis, and while a variety of modalities are available for treatment, the rate of recurrence remains high and each modality has its own set of side effects and complications. The aim of this review article is to outline the diagnostic considerations and provide practical tips for diagnosing anal squamous intraepithelial lesions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The aim of the present study was to evaluate the incidence of concomitant vulvar cancers or premalignant lesions in women surgically treated for extramammary Paget's disease of the vulva (EMPDV) through a multicenter case series. The medical records of all women diagnosed with and treated for EMPDV from January 2010 to December 2020 were retrospectively analyzed. Women with EMPDV and synchronous vulvar cancer, vulvar intraepithelial neoplasia (VIN) and/or lichen sclerosus (LS) at the histology report were included in the study. A total of 69 women eligible for the present study were considered. Concomitant vulvar lesions occurred in 22 cases (31.9%). A total of 11 cases of synchronous VIN (50%) and 14 cases (63.6%) of concomitant LS were observed. One patient (4.5%) had synchronous vulvar SCC (FIGO stage 1B). Women with EMPDV and concomitant premalignant/malignant vulvar lesions had a significantly higher rate of invasive EMPDV and wider lesions with an extravulvar involvement. The specific meaning of the association between EMPDV, VIN, SCC and LS remains unclear. The potential overlapping features between different vulvar lesions highlight the importance of dedicated gynecologists and pathologists in referral centers.

Purpose: The prognosis of local invasive recurrence (LIR) after prior carcinoma in situ (CIS) of the breast has not been widely studied and existing data are conflicting, especially considering the specific prognosis of this entity, compared to de novo invasive breast cancer (de novo IBC) and with LIR after primary IBC., Methods: We designed a retrospective study using data from the specialized Côte d'Or Breast and Gynecological cancer registry, between 1998 and 2015, to compare outcomes between 3 matched groups of patients with localized IBC: patients with LIR following CIS (CIS-LIR), patients with de novo IBC (de novo IBC), and patients with LIR following a first IBC (IBC-LIR). Distant relapse-free (D-RFS), overall survival (OS), clinical, and treatment features between the 3 groups were studied., Results: Among 8186 women initially diagnosed with IBC during our study period, we retrieved and matched 49 CIS-LIR to 49 IBC, and 46 IBC-LIR patients. At diagnosis, IBC/LIR in the 3 groups were mainly stage I, grade II, estrogen receptor-positive, and HER2 negative. Metastatic diseases at diagnosis were higher in CIS-LIR group. A majority of patients received adjuvant systemic treatment, with no statistically significant differences between the 3 groups. There was no significant difference between the 3 groups in terms of OS or D-RFS., Conclusion: LIR after CIS does not appear to impact per se on survival of IBC., (© 2022. The Author(s).)

Purpose of Review: This review aims to analyze the current place of active surveillance (AS) in non-muscle-invasive bladder cancer (NMIBC)., Recent Findings: A growing body of evidence suggests that AS protocols for pTa low-grade (TaLG) NMIBC are safe and feasible. However, current guidelines have not implemented AS due to a lack of high-quality data. Available studies included pTa tumors, with only one study excluding pT1-NMIBC. Inclusion/exclusion criteria were heterogeneously defined based on tumor volume, number of tumors, carcinoma in situ (CIS), or high-grade (HG) NMIBC. Tumor volume <10 mm and <5 lesions were used as cut-offs. Positive urinary cytology (UC) or cancer-related symptoms precluded inclusion. Surveillance within the first year consisted of quarterly cystoscopy. AS stopped upon the presence of cancer-related symptoms, change in tumor morphology, positive UC, or patient's request. With a median time on AS of 16 months, two-thirds of the patients failed AS. Progression to muscle-invasive bladder cancer (MIBC) was rare and occurred only in patients with pT1-NIMBC at inclusion., Summary: AS in NMIBC is an attractive concept in the era of personalized medicine, but strong evidence is still awaited. A more precise definition of patient inclusion, follow-up, and failure criteria is required to improve its implementation in daily clinical practice., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: Squamous cell carcinoma in situ (SCCIS) and squamous cell carcinoma (SCC) are prevalent conditions that are increasing in incidence worldwide. Many nonexcisional treatments are commonly used, but the efficacy of these treatments has not been well delineated., Objectives: To examine the recurrence rates of SCCIS and SCC treated with nonexcisional treatment modalities., Methods: A systematic review and meta-analysis were performed for SCCIS and SCC treated with 5-fluorouracil, imiquimod, electrodessication, curettage, photodynamic therapy, ablative lasers, or cryotherapy., Results: We included 186 studies describing the treatment of 9336 tumors. The recurrence rates of SCC and SCCIS following electrodessication with curettage (2.0%; 95% CI, 1.1-3.0) or following cryotherapy with curettage (1.6%; 95% CI, 0.4-2.8) were lower than those of SCC and SCCIS managed with other treatments, such as photodynamic therapy (29.0%; 95% CI, 25.0-33.0), 5-fluorouracil (26.6%; 95% CI, 16.9-36.4), or imiquimod (16.1%; 95% CI, 10.3-21.8)., Limitations: The limitations included a publication bias in mostly observational data and heterogeneity of treatment regimens., Conclusions: Electrodessication and cryotherapy, in combination with curettage, are more effective than photodynamic therapy, 5-fluorouracil, or imiquimod in treating SCCIS and SCC., Competing Interests: Conflicts of interests None disclosed., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To analyse the incidence, treatment strategies and complications associated with penile intraepithelial neoplasia (PeIN) in Sweden over a period of 20 years., Materials and Methods: Data on PeIN from the Swedish National Penile Cancer Register were analysed regarding treatment in relation to age, size of the PeIN lesion, localization of the PeIN lesion and complications using chi-squared tests and logistic regression. The incidence of PeIN was calculated and age-standardized according to the European Standard population., Results: Between 2000 and 2019 a total of 1113 PeIN cases were reported. The age-standardized incidence of PeIN was 1.40 per 100 000 men (95% confidence interval [CI] 1.32-1.49). An increase in incidence over time was seen, with a standardized incidence rate of 2.37 (95% CI 1.56-3.70) in 2019 compared to the baseline year, 2000. Surgical or topical treatments were given in 75.0% and 14.6% of cases, respectively. The complication rate was higher in laser surgery (12.1%, 7/58) compared to local surgery (4.6%, 16/348; P = 0.03) with an age-adjusted odds ratio (OR) of 2.82 (95% CI 1.10-7.19; P = 0.03). Local surgery was more common than laser surgery in the last 5 years compared to the first 5 years of the study period: OR 5.75 (95% CI 2.94-11.27). Treatments with imiquimod and topical 5-fluorouracil (5-FU) were more common than destructive methods such as photodynamic therapy, cryotherapy, curettage and electrocautery in the last 5 years compared to the first 5 years: OR 9.48 (95% CI 2.29-39.24)., Conclusions: A twofold increase in the age-standardized incidence of PeIN was seen in Sweden over 20 years. Complications were three times more common in laser surgery compared to local surgery. Changes in treatment showed an increase of treatment strategies such as local surgery and treatment with imiquimod and topical 5-FU over time., (© 2022 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Introduction: The aim of this multicenter study was to investigate the role of age (cut-off 70 years) at diagnosis in predicting oncologic behavior of pure carcinoma in situ of the bladder., Material and Methods: Inclusion criteria were: patients with pure CIS confirmed and that followed intravesical BCG treatment. Pure CIS was defined at any CIS not associated with another urothelial cancer. Exclusion criteria were: any CIS associated with invasive urothelial carcinoma. A total of 172 with pure CIS treated between January 1, 2002 and December 31, 2012 at 8 academic institutions met the inclusion criteria. The maintenance schedule was generally according to the EAU guidelines at the time RESULTS: A total of 99 (57.6%) patients had an age >70 years prior to TURBT. There was no difference between clinico-pathologic features among groups (group 1, age ≤ 70 years and group 2, age > 70 years), except that patients aged ≤ 70 years presented a larger size of CIS (35.6% vs. 21.2%), P = .02. In multivariable Cox regression analyses, the same clinico-pathologic factors (age, multifocality, and recurrent tumor state) were independently associated with worse RFS. Harrell's C-index was 65.75.In multivariable Cox regression analyses in addition to age (P = .006) and multifocality (P < .001) also BMI (P = .04) was independently associated with worse PFS. Harrell's C-index was 74.71 CONCLUSION: Advanced age at diagnosis appears to be associated with an increased risk of recurrence and progression of pure carcinoma in situ of the bladder. Elderly patients might fail to respond to BCG therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. It accounts for 25% of all breast cancers diagnosed, as a result of the expansion of breast cancer screening and is associated with a high survival rate. DCIS is particularly clinically challenging, due to its heterogeneous pathological and biological traits and its management is continually evolving towards more personalized and less aggressive therapies. This article suggests evidence-based guidelines for proper DCIS clinical management, which should be discussed within a multidisciplinary team in order to propose the most suitable approach in clinical practice, taking into account recent scientific studies. Here we include updated multidisciplinary treatment protocols and techniques in accordance with the most recent contributions published on this topic in the peer-reviewed medical literature, and we outline future perspectives., Competing Interests: Declaration of competing interest All the authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

As the first node in treatment algorithms for breast disease, pathologists have the potential to play a critical role in refining appropriate therapy for lesions in the atypical ducal hyperplasia-ductal carcinoma in situ (ADH-DCIS) spectrum by conservatively approaching diagnosis of lesions limited in size on core needle biopsy. Appropriate efforts to downgrade the diagnosis of lesions at the borderline of ADH and DCIS will certainly lead to more breast conservation and avoid the common morbidities of mastectomy, sentinel node biopsy, and radiation therapy. Whether results of clinical trials of active surveillance will successfully identify a subset of women who may successfully forgo even limited breast-conserving surgery is eagerly anticipated. Given the increasing concern that a significant number of women with DCIS are overtreated, identification of patients at very low risk for progression who may forgo surgery and radiation therapy safely is of significant interest., Competing Interests: Disclosure The author has nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Penile intraepithelial neoplasia (PeIN) is a histological term for precancerous penile lesions. PeIN is important due to the high morbidity and mortality associated with progression to penile squamous cell carcinoma (PSSC). But PeIN is rare, contributing to a limited evidence-base for the relative efficacy of available treatment options., Objectives & Methods: To consolidate and expand knowledge about PeIN and its treatment, we describe the clinical and histological characteristics, treatments and outcomes of 345 patients with PeIN, managed by our multidisciplinary team. Our results are compared and contrasted with those in the literature, following comprehensive review., Results: 8.7% of patients had concomitant, invasive PSCC, whilst 91.3% demonstrated PeIN alone. 84% had undifferentiated PeIN, and 10.7% differentiated PeIN (5.2%, not specified). Clinical or histological evidence of HPV alone was present in 58%; features of lichen sclerosus alone in 12%; features of both in 29.4%. Only 14.4% of patients could be treated solely with topical agents or cryotherapy, whereas the remaining 85.6% underwent some form of surgical intervention, circumcision being the mainstay. Just 2.6% progressed to PSCC., Conclusions: Clinical management of PeIN can be rationally optimized with excellent outcomes. Circumcision is important. Topical treatments alone are disappointing.

Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive cancer, and its detection, diagnosis, and management are controversial. DCIS incidence grew with the expansion of screening mammography programs in the 1980s and 1990s, and DCIS is viewed as a major driver of overdiagnosis and overtreatment. For pathologists, the diagnosis and classification of DCIS is challenging due to undersampling and interobserver variability. Understanding the progression from normal breast tissue to DCIS and, ultimately, to invasive cancer is limited by a paucity of natural history data with multiple proposed evolutionary models of DCIS initiation and progression. Although radiologists are familiar with the classic presentation of DCIS as asymptomatic calcifications at mammography, the expanded pool of modalities, advanced imaging techniques, and image analytics have identified multiple potential biomarkers of histopathologic characteristics and prognosis. Finally, there is growing interest in the nonsurgical management of DCIS, including active surveillance, to reduce overtreatment and provide patients with more personalized management options. However, current biomarkers are not adept at enabling identification of occult invasive disease at biopsy or accurately predicting the risk of progression to invasive disease. Several active surveillance trials are ongoing and are expected to better identify women with low-risk DCIS who may avoid surgery., (© RSNA, 2021.)

Background: Merkel cell carcinoma (MCC) is a rare primary cutaneous neuroendocrine tumour. While dermally invasive MCC is known to have a five-year survival of only 30-40%, the prognosis and management of MCC in situ (MCCis) is not widely reported., Objective: We present a systematic review to elucidate the prognosis and management of MCCis., Methods: We performed a systematic review, searching three databases to 01 June 2021. Case reports, cohort studies, clinical trials and literature reviews were considered for inclusion., Results: We identified 26 cases of MCCis published in the literature with a median age of 74 years and involving 19 males and 7 females. Most cases were on the face and neck (n = 17), followed by upper limb (n = 8) and lower limb (n = 1). Sentinel lymph node biopsy was performed in three patients, and all were negative. One subject underwent adjuvant radiotherapy. No MCCis-associated deaths were reported., Conclusion: This review suggests that MCCis has an excellent prognosis with minimal, if any, risk of mortality and a very low risk of dermal invasion and recurrence when treated with wide local excision alone. Sentinel lymph node biopsy is unlikely to be useful for MCCis., (© 2021 The Australasian College of Dermatologists.)

Context: The European Association of Urology (EAU) has released an updated version of the guidelines on non-muscle-invasive bladder cancer (NMIBC)., Objective: To present the 2021 EAU guidelines on NMIBC., Evidence Acquisition: A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines since the 2020 version was performed. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned., Evidence Synthesis: Tumours staged as Ta, T1 and carcinoma in situ (CIS) are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of tissue obtained via transurethral resection of the bladder (TURB) for papillary tumours or via multiple bladder biopsies for CIS. For papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. In cases for which the initial resection is incomplete, there is no muscle in the specimen, or a T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risk of progression may be estimated for individual patients using the 2021 EAU scoring model. On the basis of their individual risk of progression, patients are stratified as having low, intermediate, high, or very high risk, which is pivotal to recommending adjuvant treatment. For patients with tumours presumed to be at low risk and for small papillary recurrences detected more than 1 yr after a previous TURB, one immediate chemotherapy instillation is recommended. Patients with an intermediate-risk tumour should receive 1 yr of full-dose intravesical bacillus Calmette-Guérin (BCG) immunotherapy or instillations of chemotherapy for a maximum of 1 yr. For patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. For patients at very high risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is also recommended for BCG-unresponsive tumours. The extended version of the guidelines is available on the EAU website at https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/., Conclusions: These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice., Patient Summary: The European Association of Urology has released updated guidelines on the classification, risk factors, diagnosis, prognostic factors, and treatment of non-muscle-invasive bladder cancer. The recommendations are based on the literature up to 2020, with emphasis on the highest level of evidence. Classification of patients as having low, intermediate, or and high risk is essential in deciding on suitable treatment. Surgical removal of the bladder should be considered for tumours that do not respond to bacillus Calmette-Guérin (BCG) treatment and tumours with the highest risk of progression., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To describe the risk factors, clinical presentation, management, and outcomes of patients with bilateral ocular surface squamous neoplasia (OSSN)., Methods: Retrospective case series., Results: Of the 25 patients with bilateral OSSN, the mean age at diagnosis of OSSN was 31 years (median, 24 years; range, 2-60 years). Risk factors for bilateral OSSN included xeroderma pigmentosum ( n  = 15, 60%), human immunodeficiency virus infection ( n  = 3, 12%), conjunctival xerosis ( n  = 1, 4%), and topical steroid use ( n  = 1, 4%). There were no identifiable ocular or systemic risk factors in 7 (28%) patients. Presentation was synchronous in 14 (56%) and metachronous in 11 (44%) patients. Tumor morphology was bilaterally similar in 12 (48%) patients. Histopathological examination ( n  = 36) revealed conjunctival intraepithelial neoplasia (CIN) grade 1 in 4 (8%); grade 2 in 7 (14%); carcinoma in situ in 5 (10%), and invasive carcinoma in 20 (40%). Primary management of OSSN ( n  = 49) included excisional biopsy ( n  = 31, 62%), topical immunotherapy (IFN α2B) ( n  = 11; 22%), topical Mitomycin C (MMC) ( n  = 3, 6%), enucleation ( n  = 1, 2%), orbital exenteration ( n  = 2, 4%), and plaque brachytherapy (PBT) ( n  = 1, 2%). One patient was lost to follow-up after detection of tumor in the second eye. Recurrent tumors were noted in 16 (32%) eyes and binocular globe salvage was achieved in 16 (64%) patients at a mean follow up of 41 months (median 30 months; range, 1-164 months)., Conclusion: OSSN occurrence can be synchronous or metachronous. Meticulous examination of the fellow eye is important for an early diagnosis of OSSN.

Anal Squamous Cell Carcinoma (ASCC) is an uncommon cancer with a recognised precursor Anal Intraepithelial Neoplasia (AIN). Although there are consistent evidence-based guidelines for the management of ASCC, historically this has not been the case for AIN and as a result there have been geographical variations in the recommendations for the treatment of AIN. More recently there have been updates in the literature to the recommendations for the management of AIN. To assess whether we are now closer to achieving an international consensus, we have completed a systematic scoping review of available guidelines for the screening, treatment and follow-up of AIN as a precursor to ASCC. MEDLINE and EMBASE were systematically searched for available clinical guidelines endorsed by a recognised clinical society that included recommendations on either the screening, treatment or follow-up of AIN. Nine clinical guidelines from three geographical areas were included. The most recent guidelines agreed that screening for AIN in high-risk patients and follow-up after treatment was necessary but there was less consensus on the modality of screening. Six Guidelines recommended the treatment of high-grade AIN and four guidelines describe a follow-up protocol of patients diagnosed with AIN. There appears to be increasing consensus on the treatment and follow-up of patients despite a poor evidence base. There is still significant discrepancy in guidance on the method to identify patients at risk of ASCC and AIN despite consensus between geographical regions on which patient subgroups are at the highest risk., (© 2021. The Author(s).)

Purpose: To assess margins and the rate of local recurrence of ocular surface squamous neoplasia after excision with a 2 mm margin and cryotherapy at a single ophthalmic oncology center., Outcome Measures: (1) Conjunctival margin were assessed as positive, negative, or indeterminate margins. (2) Feasibility of repair without a graft. (3) Local recurrence., Methods: Retrospective chart review of histologically proven conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma cases that underwent excision with a 2 mm margin and cryotherapy., Results: Eighty cases met inclusion criteria for the quantitative analysis. The margin was positive in six cases (7.5%), four of which were treated with post-op topical immunotherapy/chemotherapy. Of the six positive margin cases, there was one recurrence which occurred in the patient who did not receive post-op topical adjuvant therapy, however resolved after starting topical treatment. Conjunctival repair without use of a graft was feasible in 74 (93%) cases with a mean basal diameter of 6.4 mm. Total number of local recurrence was seen in three cases (4%), which were successfully treated with adjuvant topical treatment (one positive margin case, one indeterminate margin case) or repeat resection followed by episcleral plaque brachytherapy (one negative margin case)., Conclusion: Excision with 2 mm margin of OSSN is not associated with high rates of positive surgical margins. Even those with positive margins, when treated with adjuvant topical therapy did not develop recurrence. While achieving low rates of local recurrence, the conjunctiva is conserved, thereby minimizing the need for amniotic membrane or free conjunctival grafts for conjunctival repair., (© 2021. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Opinion Statement: Dysplasia and early laryngeal cancer lie on a spectrum of cellular changes. These start with early changes to the cells including epithelial hyperplasia and expand to dysplasia, squamous cell carcinoma in situ and finally developing in to invasive cancer. Dysplasia can range from low to high grade, with each being treated in a different manner. Treatment options are typically determined by where the dysplasia/invasive cancer lie on this spectrum along with the site within the larynx. Hyperkeratosis, mild dysplasia and moderate dysplasia typically involve primary endoscopic excision. Severe dysplasia and squamous cell carcinoma in situ involve primary endoscopic resection with the addition of possible laser resection and/or ablation. At this stage, surgery will be followed by close surveillance. Finally, early laryngeal cancer such as T1 and T2 lesions is typically more involved. Treatment depends on the site and degree of involvement of the structures, along with spread to surrounding structures. Typical treatment options of more involved early laryngeal cancer can range from radiation therapy, endoscopic transoral laser resection, endoscopic transoral robotic resection to open resection. Often times, my choice of treatment will be aimed at voice preservation but patient preference will also play a role in the decision making between treatment modalities. Chemotherapy and immunotherapy are typically not used in early stage laryngeal cancer., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Reliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213-231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation., (© 2021. The Author(s).)

Clinical diagnosis of preinvasive malignant lesions of the penis is difficult and there are numerous differential diagnoses. Recent decades have been witness to several changes in the terminology of histopathological diagnoses. In the current World Health Organization classification, penile intraepithelial neoplasia (PeIN) is defined, of which several subtypes exist. Just like in invasive carcinoma, the principal classification of PeIN subtypes corresponds with pathogenesis and includes human papilloma virus (HPV)-related and non-HPV-related forms. Subdivision is important for prognosis. Several therapeutic options exist, including surgical and nonsurgical procedures., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Vulvar carcinomas represent 4% of all gynaecological cancers with 838 new cases in France in 2018. The precursor lesions of vulvar carcinomas are differentiated vulvar intraepithelial lesion (dVIN) in a context of lichen sclerosus and vulvar high-grade squamous intraepithelial lesion (HSIL) link to human papillomavirus (HPV) infection. Three typical clinical forms of HSIL are described: the Bowenoid papulosis, the Bowen's disease and the confluent VIN. Histopathology cannot differentiate effectively these two types of lesions. P16 and P53 immunostaining are valuable tools to respectively assess HPV infection and divide different types of dVIN. However, P53 immunostaining is still lacking sensibility to detect dVIN. First line therapies are medical treatment excluding the cases with a doubt of invasion. The gold standard treatment for dVIN and vulvar HSIL are respectively topical corticosteroids and imiquimod. Primary prevention for vulvar HSIL and dVIN are respectively HPV vaccination and early treatment of lichen sclerosus. Destructive therapy can be used in case of medical treatment failure such as CO2 laser, cryotherapy, dynamic phototherapy. Surgical indications should be carefully assessed between the risk of recurrence, the spread of the lesions, the aesthetic and functional aspect. Surgical procedures consist in either superficial vulvectomy or radical vulvectomy with or without flap reconstruction. Recurrence rate after surgery is around 20%., (Copyright © 2020. Published by Elsevier Masson SAS.)

Introduction: To determine whether progestin type or number of dilation and curettage procedures (D&Cs) were associated with intrauterine synechiae (IS) or pregnancy outcomes in patients conservatively treated for endometrial intraepithelial neoplasia (EIN) or endometrial cancer (EC)., Materials and Methods: We evaluated patients conservatively treated for EIN or EC from 2000 to 2017 at an academic center. IS were identified hysteroscopically. We calculated proportions for categorical variables and tested associations between D&C number, progestin, and pregnancy outcomes using Pearson chi-squared and Fisher's exact tests. A post-hoc power analysis indicated sufficient power to detect livebirth., Results: We analyzed 54 patients, 15 with EIN (28 %) and 39 with EC (72 %), with a mean age of 34 ± 1.2 years. Progestin treatment types included megestrol acetate (MA) (n = 24), MA with levonorgestrel intrauterine device (LngIUD) (n = 10), MA followed by LngIUD (n = 3), and LngIUD alone (n = 6). Mean number of D&Cs was 3.9 ± 0.9. Overall, 53 subjects underwent hysteroscopy; 10 (19 %) had IS. When D&Cs were grouped into 0-2, 3-4 and ≥5, each increase in D&C group had a 2.9 higher odds of IS (OR: 2.91, p = 0.04, CI: 1.05-10.02). LngIUD was associated with a nonsignificant 46 % decrease in the odds of IS (OR: 0.54, p = 0.66, CI: 0.08-2.87). Twenty-two women attempted pregnancy; 14 women achieved a total of 20 pregnancies and 9 women had total of 15 livebirths (41 % livebirth rate). The number of D&Cs and progestin treatment type were not associated with pregnancy outcomes., Discussion: Among 54 patients conservatively treated for EC/EIN, nearly 20 % developed IS. However, hysteroscopic and/or fertility treatments may improve pregnancy outcomes., Competing Interests: Declaration of Competing Interest The Edward E. Wallach Research Award provided statistical support for this study (awarded to C.N.C.M). The authors report no declarations of interest., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Introduction: Risk of breast cancer increases with age and very few data are available in patients older than 89., Methods: A retrospective analysis on patients aged 89 and older treated between 2008 and 2019 at our certified breast center. The aim was to analyze clinical characteristics, decision-making, treatment, outcomes and open questions regarding this subpopulation for which there is a lack of guidelines., Results: 58 patients included. Tumor characteristics were analyzed, 85% patients underwent surgery of which 44% had a mastectomy. The median follow-up and overall survival were 20 and 76 months, respectively.The median survival of metastatic and non-metastatic patients were 14 and 50 months, respectively. Most patients did not receive any adjuvant treatment and among these 14% had a relapse., Conclusions: Elderly patients should not be under or over-treated because of their age; they represent a large heterogeneous group deserving a sub-stratification for a better tailored treatment., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Basal and luminal subtypes of invasive bladder tumors have significant prognostic and predictive impacts for patients. However, it remains unclear whether tumor subtype commitment occurs in noninvasive urothelial lesions or in carcinoma in situ (CIS) and which gene pathways are important for bladder tumor progression. To understand the timing of this commitment, we used gene expression and protein analysis to create a global overview of 36 separate tissues excised from a whole bladder encompassing urothelium, noninvasive urothelial lesions, CIS, and invasive carcinomas. Additionally investigated were matched CIS, noninvasive urothelial lesions, and muscle-invasive bladder cancers (MIBC) from 22 patients. The final stage of subtype commitment to either a luminal or basal MIBC occurred at the CIS transition. For all tissues combined, hierarchical clustering of subtype gene expression revealed three subtypes: "luminal," "basal," and a "luminal p53-/extracellular matrix (ECM)-like" phenotype of ECM-related genes enriched in tumor-associated urothelium, noninvasive urothelial lesions, and CIS, but rarely invasive, carcinomas. A separate cohort of normal urothelium from noncancer patients showed significantly lower expression of ECM-related genes compared with tumor-associated urothelium, noninvasive urothelial lesions, and CIS. A PanCancer Progression Panel of 681 genes unveiled pathways specific for the luminal p53-/ECM-like cluster, for example, ECM remodeling, angiogenesis, epithelial-to-mesenchymal transition, cellular discohesion, cell motility involved in tumor progression, and cell proliferation and oncogenic ERBB2/ERBB3 signaling for invasive carcinomas. In conclusion, this study provides insights into bladder cancer subtype commitment and associated signaling pathways, which could help predict therapy response and enhance our understanding of therapy resistance. SIGNIFICANCE: This study demonstrates that CIS is the stage of commitment for determining MIBC tumor subtype, which is relevant for patient prognosis and therapy response., (©2021 American Association for Cancer Research.)

Purpose: To describe the regional burden of AIN and rate of progression to cancer in patients managed in specialist and non-specialist clinic settings., Methods: Patients with a histopathological diagnosis of AIN between 1994 and 2018 were retrospectively identified. Clinicopathological characteristics including high-risk status (chronic immunosuppressant use or HIV positive), number and type of biopsy (punch/excision) and histopathological findings were recorded. The relationship between clinicopathological characteristics and progression to cancer was assessed using logistic regression., Results: Of 250 patients identified, 207 were eligible for inclusion: 144 from the specialist and 63 from the non-specialist clinic. Patients in the specialist clinic were younger (<40 years 31% vs 19%, p = 0.007), more likely to be male (34% vs 16%, p = 0.008) and HIV positive (15% vs 2%, p = 0.012). Patients in the non-specialist clinic were less likely to have AIN3 on initial pathology (68% vs 79%, p = 0.074) and were more often followed up for less than 36 months (46% vs 28%, p = 0.134). The rate of progression to cancer was 17% in the whole cohort (20% vs 10%, p = 0.061). On multivariate analysis, increasing age (OR 3.02, 95%CI 1.58-5.78, p < 0.001), high risk status (OR 3.53, 95% CI 1.43-8.74, p = 0.006) and increasing number of excisions (OR 4.88, 95%CI 2.15-11.07, p < 0.001) were related to progression to cancer., Conclusion: The specialist clinic provides a structured approach to the follow up of high-risk status patients with AIN. Frequent monitoring with specialist assessments including high resolution anoscopy in a higher volume clinic are required due to the increased risk of progression to anal cancer., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Immunohistochemical stains have been suggested to aid in diagnostically challenging cases of urothelial carcinoma in-situ (CIS). Although full thickness immunostaining for CK20 is supportive of CIS, a subset of CIS cases is CK20(-), the clinical significance of which was unknown. This study included 43 patients with primary diagnosis of bladder CIS including 32 with only CIS, 5 with CIS and separate noninvasive high-grade papillary urothelial carcinoma, and 6 with CIS and separate high-grade urothelial carcinoma with lamina propria invasion. Digital morphometric image analysis showed that the average nuclear areas of enlarged nuclei were similar in CK20(+) and CK20(-) CIS (26.9 vs. 24.5 µM2; P=0.31). Average Ki67 index for CK20(+) CIS was higher than CK20(-) CIS (31.1% vs. 18.3%; P=0.03). Patients with CK20(+) CIS [28 (65%)] and patients with CK20(-) CIS [15 (35%)] had the same rates of Bacillus Calmete-Guerin (BCG) failure but patients with CK20(-) CIS had higher stage progression [3 CK20(+) (11%) vs. 6 CK20(-) (40%); P=0.02]. Given recent approval of immune checkpoint inhibitors in patients with CIS refractory to BCG, programmed death ligand-1 expression and colocalization with CD8(+) lymphocytes was investigated as signature of adaptive immune response and was seen in 8 patients regardless of CK20 status and exclusively among patients who failed BCG. Our results confirm that negative CK20 IHC does not exclude CIS and that those patients have similar clinical outcomes as patients with CK20(+) CIS. Programmed death ligand-1 and CD8 colocalization seen among patients who failed BCG therapy is an easy assay to perform to identify patients who could potentially benefit from combined BCG therapy and immune checkpoint inhibition., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Vulvar cancers, although rare, are becoming an increasingly serious threat to women's health. Cancer of the vulva accounted for 0.3% of all new cancers in the United States in 2019, with 6,070 newly diagnosed cases. This review details the epidemiology, pathogenesis, diagnosis, staging, and treatment of vulvar malignancies., Objective: To review cancer entities of the vulva, including vulvar intraepithelial neoplasms, squamous cell carcinoma (SCC), malignant melanoma, basal cell carcinoma, neuroendocrine tumors, and adenocarcinomas., Materials and Methods: Literature review using PubMed search for articles related to cancer of the vulva., Results: Vulvar intraepithelial neoplasms represent premalignant precursors to SCC of the vulva. There are several different histopathologic subtypes of SCC, and treatment is dependent on characteristics of primary tumor and lymph node involvement. Melanoma is the second most common cancer to affect the vulva, and staging is based on tumor, node, and metastatic spread., Conclusion: Vulvar malignancies are rare, and diagnosis is dependent on biopsy and pathologic evaluation. Treatment for vulvar malignancies depends on histopathologic diagnosis but ranges from wide local excision with or without lymph node biopsy or dissection to radiation therapy with chemo- or immunotherapy. Overall survival varies by diagnosis., (Copyright © 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Vulvar squamous cell carcinomas (VSCC), which constitute over 90% of vulvar malignancies in adults, are classifiable into 2 subgroups that are mostly clinicopathologically distinct, a classification that is fundamentally based whether or not the tumors are HPV-mediated. In this review, we aim to summarize the recent advances in the understanding of molecular events in the pathogenesis of VSCC, including common and targetable mutations, copy number alterations, epigenetics, noncoding RNAs, and tumor immune microenvironment, which may provide insight into the future management of the disease. These events show substantial differences between the 2 subgroups, although significant areas of overlap exist. Recurrent, driver mutations appear to be substantially more prevalent in HPV(-) VSCC. TP53 mutations are the most common somatic mutations in VSCC overall, and are notably predominant in the HPV(-) VSCC, where 30-88% show a mutation. TP53 mutations are associated with worse patient outcomes, and co-mutations between TP53 and either HRAS, PIK3CA or CDKN2A appear to define subsets with even worse outcomes. A wide variety of other somatic mutations have been identified, including a subset with different mutational frequencies between HPV(+) and HPV(-) VSCC. CDKN2A mutations are common, and have been identified in 21 to 55% of HPV(-) VSCC, and in 2 to 25% of HPV(+) VSCC. Hypermethylation of CDKN2A is the most frequently reported epigenetic alteration in VSCC and the expression of some microRNAs may be associated with patient outcomes. The PTEN/PI3K/AKT/mTOR pathway is commonly altered in HPV(+) VSCC, and is accordingly potentially targetable. HPV-positivity/p16 block expression by immunohistochemistry has been found to be an independent prognostic marker for improved survival in VSCC, and may have some predictive value in VSCC patients treated with definitive radiotherapy. 22-39.3% and 68% of VSCC show EGFR amplification and protein overexpression respectively, although the prognostic and predictive value of an EGFR alteration requires additional study. Recurrent chromosomal gains in VSCCs have been found at 1q, 2q, 3q, 4p, 5p, 7p, 8p, 8q, and 12q, and there may be differential patterns of alterations depending on HPV-status. At least one-third of VSCC patients may potentially benefit from immune checkpoint inhibition therapy, based on a high frequency of PD-L1 expression or amplification, or a high tumor mutational burden. Additional studies are ultimately required to better understand the global landscape of genetic and epigenetic alterations in VSCC, and to identify and test potential targets for clinical application., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: Vulvar intraepithelial neoplasia (VIN) represents an increasingly common, yet challenging diagnosis that shares many common risk factors with cervical intraepithelial neoplasia. However, unlike cervical intraepithelial neoplasia, effective screening and treatment strategies are much less defined for patients with VIN., Objective: The objective of this article is to review the underlying risk factors leading to the development of VIN, identify special populations at risk for VIN, and outline acceptable treatment strategies., Evidence Acquisition: This literature review was performed primarily using PubMed., Results: Vulvar intraepithelial neoplasia can be separated into usual VIN (uVIN) and differentiated VIN (dVIN). The more common uVIN is related to underlying human papillomavirus infection, whereas dVIN occurs in the setting of other vulvar inflammatory conditions such as lichen sclerosis. Differentiated VIN carries a higher risk of progression to invasive malignancy. Extramammary Paget disease is a rare intraepithelial adenocarcinoma unrelated to uVIN and dVIN, although management is similar., Conclusions and Relevance: Vulvar intraepithelial neoplasia is a preinvasive neoplasia of the vulva with few robust strategies for surveillance or management. Careful examination with targeted biopsy is warranted for suspicious lesions, and a combination of surgical and medical management can be tailored for individual patient needs.

Background: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer., Methods: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10 11 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849., Findings: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths., Interpretation: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state., Funding: FKD Therapies Oy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Anal intraepithelial neoplasia (AIN) and 89-100% of anal cancers are caused by persistent infections with high-risk (HR) human papillomaviruses (HPV). In HIV-positive patients, anal HPV infection and AIN are very common and these patients have a significantly increased risk for anal cancer. However, a continuous increase in the incidence of anal cancer has also been observed in the general population in recent decades. AIN can clinically present in diverse manners. In HIV-positive patients AIN can be hidden in condylomas. Approximately 3-14% of high-grade AIN progress to anal cancer within 5 years. Therefore, screening examinations should be offered to patients with an increased risk for anal cancer. The treatment options for AIN are similar to those for condylomas. HIV-positive patients with controlled immune status and HIV-negative patients with anal cancer respond comparably well to combined radiochemotherapy. A German-language S3 guideline for anal cancer will be available in 2020. In HIV-positive patients over 26 years of age, HPV vaccination showed no effect in a controlled phase‑3 study. To prevent AIN and anal cancer in the future, HPV vaccination rates need to be increased in HPV-naïve girls and boys.

Background: Patients with esophageal squamous cell carcinoma (SCC) have a poor prognosis mostly due to the late diagnosis. A morphological method is still the main diagnostic method for SCC. The aim of the study was to find out which histological criteria, namely Western or Japanese criteria, for early stage SCC are used by pathologists in Ukraine as compared with their Japanese colleagues., Methods: 14 Ukrainian and 6 Japanese pathologists have participated in this study. Virtual slides for research were provided by National Cancer Research Center (Tokyo, Japan) in 2018. Each of the pathologists has used these slides and presented the conclusion via the Internet., Results: Essential diagnostic discrepancies were revealed: a number of biopsy specimens was diagnosed by Japanese pathologists as "noninvasive carcinoma", while Ukrainian pathologists classified the specimens as high-grade or low-grade dysplasia, indefinite for neoplasia, or reactive/regenerative lesions., Conclusion: The adoption of a unified concept of criteria for non-invasive (intraepithelial) carcinoma underlies early endoscopic/surgical treatment, which significantly increases the survival rate of patients with SCC. A solid common approach to the diagnosis between Western and Japanese pathologists, as well as endoscopists, is necessary to ensure timely treatment and increase survival rate of patients with SCC.

Background: Vaginal intraepithelial neoplasia (VaIN) is a rare disease of the lower genital tract, strongly associated with HPV infection, which may progress to vaginal carcinoma., Purpose: The aim of this review is to summarise current treatment options, evaluate their efficacy and make provide recommendations on the optimal management of the disease., Materials and Methods: A comprehensive search of the literature was performed using the PubMed database for articles referring to the treatment of VaIN. We restricted our search only in articles written in English with publication dates within the last 10 years., Results: Surgical approach included local excision, CO 2 laser ablation, CO 2 laser skinning colpectomy and laparoscopic upper vaginectomy. Medical management was based on intravaginally administered topical agents such as 5% imiquimod cream, 5-fluorouracil cream and topical oestrogens. Intracavitary radiation therapy was reported in two forms: Low-dose rate (LDR) brachytherapy and high-dose rate (HDR) brachytherapy. All treatment options were well tolerated, with satisfactory cure rates and acceptable recurrence rates., Conclusion: The choice of treatment depends upon many factors. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Topical agents are useful for persistent, multifocal lesions or for women that cannot undergo surgical treatment. Brachytherapy is associated with high morbidity rates and should be reserved for women who have multifocal disease, are poor surgical candidates and/or have failed other treatments. CO 2 laser ablation achieves minimal scarring and sexual dysfunction; however, invasive disease should be ruled out with biopsies before the initiation of the treatment., (© 2020 John Wiley & Sons Ltd.)