Risks and benefits of sentinel lymph node evaluation in the management of endometrial intraepithelial neoplasia.

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.

Endometroid intraepithelial neoplasia (EIN) is a premalignant lesion to endometrial cancer, the most common gynecologic cancer in the United States. The definitive treatment for EIN is hysterectomy. An increasing number of gynecologic oncologists are performing sentinel lymph node (SLN) assessment during surgery for EIN since 30­40% of patients with EIN will have underlying carcinoma. For those patients, lymph node evaluation is important for cancer staging, especially if high-risk or advanced stage disease is found on the pathologic specimen. The SLN procedure cannot be performed post-hysterectomy, so an improperly staged patient may require a second operation for lymphadenectomy; this has a greater chance of morbidity compared to an SLN biopsy. However, an SLN evaluation still confers perioperative risk and comes at an additional monetary cost, especially when most patients diagnosed with endometrial cancer after EIN will ultimately have low-risk, stage IA disease. We propose an algorithm for clinicians to help determine which patients with EIN would best benefit from the SLN procedure; this includes maximizing preoperative endometrial sampling and considering selective criterion with risk factors for concurrent endometrial carcinoma including age, endometrial thickness, obesity, and molecular classification.

Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial.

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 .

Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial.

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 × 1011 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.

Oncologic Outcomes for Squamous Cell Carcinoma In Situ With a Clinically Resolved Biopsy Site Managed by Watchful Waiting.

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%.

Comparing the effects of argon plasma coagulation and interferon therapy in patients with vaginal intraepithelial neoplasia: a single-center retrospective study.

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.

Condyloma and Anal Dysplasia.

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.

Radiotherapy Combined with a Radiosensitizer for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Carcinoma In Situ Bladder Cancer: An Open-label, Single-arm, Multicenter, Phase 2 European Organisation for Research and Treatment of Cancer Trial.

Radical cystectomy with pelvic lymph node dissection and urinary diversion is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). However, many patients are unwilling or unable to undergo such major surgery associated with high morbidity and a negative impact on quality of life. Chemoradiotherapy is an established treatment option for muscle-invasive bladder cancer. However, it has not been investigated adequately in NMIBC until now. The European Organisation for Research and Treatment of Cancer (EORTC) 2235 study (NCT06310369) is designed as a multicenter, prospective, international, phase 2 trial of moderate hypofractionated radiotherapy combined with a radiosensitizer in BCG-unresponsive NMIBC patients with carcinoma in situ (CIS) who are not eligible for or declined to undergo radical cystectomy. Patients who have received nadofaragene firadenovec or TAR-200 are eligible. The primary endpoint is the 6-mo complete response (CR) rate defined by the absence of CIS proven by a control biopsy of the bladder. The secondary endpoints include overall survival, progression-free survival, durability of CR, grade 3-4 adverse events rate, patients' quality of life, and organ preservation rate. PATIENT SUMMARY: Intravesical instillation of bacillus Calmette-Guérin is the standard treatment of non-muscle-invasive, also coined as superficial, bladder cancer. In case the cancer recurs, even superficially, there is no other proven treatment than a radical cystectomy-the surgical removal of the bladder. Although the surgical technique has improved dramatically over the past few years, it remains contraindicated in patients with severe comorbidities. In addition, because it affects the quality of life, patients may reject this option. This study will assess the efficacy of external beam radiotherapy, a robust alternative to surgery in muscle-invasive bladder cancer. Radiotherapy will be administered 5 d a week for 4 wk. It will be associated with a "radiosensitizer," an intravenous or oral drug, during the radiotherapy treatment. The study will measure the proportion of patients remaining recurrence free at 6 mo and thereafter. It will also evaluate the safety of the treatment and its impact on quality of life.

Differentiated vulvar intraepithelial neoplasia long-term follow up and prognostic factors: An analysis of a large historical cohort.

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.

Fertility After Endometrial Intraepithelial Neoplasia and Early Endometrial Cancer: Ovulation Induction May Shorten Time to Conception.

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.

Seminal papers in urology: maintenance Bacillus Calmette-Guerin (BCG) immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized southwest oncology group study (SWOG-8507).

The South West Oncology Group's 2000 randomised-control trial investigated the addition of maintenance intravesical bacillus Calmette-Guerin (BCG) to non-muscle invasive urothelial carcinoma (NMIUC) treatment. The results were published when the efficacy of BCG immunotherapy maintenance was unclear.Randomisation produced two arms, each containing 192 patients assessed to be at high risk of recurrence following induction BCG therapy for NMIUC. The treatment arm went on to receive three successive weekly intravesical and percutaneous BCG administrations at three months, six months and then six monthly for three years from the start of induction therapy.Recurrence free-survival (RFS), was higher in the maintenance arm with 41% (95%CI 35-49) RFS at five years in the control arm and 60% RFS (53-67 95% CI) in the maintenance arm (p < 0.0001). Only 16% of patients in the treatment arm received all of the scheduled maintenance courses of BCG.The study's seminal results correlate with contemporary systematic review and have guided international guidelines.

Serous endometrial intraepithelial carcinoma: a case report.

Serous endometrial intraepithelial carcinoma (SEIC) is a rare but highly aggressive form of uterine endometrial cancer. We report two cases of post-menopausal, 58-year-old patients with abundant vaginal bleeding and pelvic pain. The first patient had a history of surgical hysteroscopy in 2019 for an endocervical polyp. The second patient had a history of breast resection, axillary lymph node dissection, chemotherapy, radiation therapy, and tamoxifen therapy for breast carcinoma 6 years ago. An abdominal hysterectomy was performed in both patients. The pathological assessment showed serous endometrial intraepithelial carcinoma. Diagnosis of a serous proliferation of the uterus implies the exploration of other genital tract organs as well as distant locations in search of metastatic disease.

Current monitoring and treatment for anal intraepithelial neoplasms.

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.

Anal Intraepithelial Neoplasia and Anal Squamous Cell Carcinoma: Updates From the Last 3 Years.

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.

Extramammary Paget's Disease of the Vulva and Concomitant Premalignant/Malignant Vulvar Lesions: A Potential Challenge in Diagnosis and Treatment.

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.

Anal intraepithelial neoplasia: a review of terminology, differential diagnoses, and patient management.

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.

Prognosis of local invasive relapses after carcinoma in situ of the breast: a retrospective study from a population-based registry.

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.

Active surveillance for non-muscle-invasive bladder cancer: fallacy or opportunity?

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.

Atypical Ductal Hyperplasia-Ductal Carcinoma In Situ Spectrum: Diagnostic Considerations and Treatment Impact in the Era of Deescalation.

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.