Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Protein kinase RNA-activated controls mitotic progression and determines paclitaxel chemosensitivity through B-cell lymphoma 2 in ovarian cancer.

Anti-tubulin agents, such as paclitaxel, have been used extensively for treatment of several types of cancer, including ovarian, lung, breast, and pancreatic cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. Protein kinase RNA-activated (PKR) plays a critical role in immune response to viral infection. We identified PKR as a phospho-protein in response to anti-tubulin agents and this phosphorylation occurs independent of its own kinase activity. PKR is phosphorylated by cyclin-dependent kinase 1 (CDK1) during anti-tubulin treatment and unperturbed mitosis and that PKR regulates mitotic progression in a phosphorylation-dependent manner. Furthermore, inactivation of PKR confers resistance to paclitaxel in ovarian and breast cancer cells in vitro and in vivo. PKR expression levels and activity are decreased in chemotherapeutic recurrent ovarian cancer patients. Mechanistically, our findings suggest that PKR controls paclitaxel chemosensitivity through repressing Bcl2 expression. Pharmacological inhibition of Bcl2 with FDA-approved agent venetoclax overcomes paclitaxel resistance in preclinical animal models of ovarian cancer. Our results suggest that PKR is a critical determinant of paclitaxel cytotoxicity and that PKR-Bcl2 axis as a potential therapeutic target for the treatment of recurrent drug-resistant ovarian tumors.

The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.

The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.

Instituting a robot-assisted surgery programme at a tertiary care cancer centre.

BACKGROUND: The initial experience of a gynaecological oncology robotic surgery programme at a tertiary care cancer centre is described. METHODS: A retrospective study was performed to evaluate the perioperative outcomes of 76 patients offered robot-assisted surgery. RESULTS: Seventy-three patients underwent robot-assisted surgery; three cases were converted to laparotomy; 51% of patients underwent treatment for endometrial cancer; 18% had ovarian cancer risk reduction surgery; and 8% were treated for uterine leiomyomata. Median body mass index (BMI) was 30. Median estimated blood loss, operative time, and length of stay were 150 ml, 195 min and 1 day, respectively. The total major complication rate was 6.8% and the total minor complication rate was 15.1%. CONCLUSION: Robot-assisted surgery is safe and appropriate for gynaecological patients undergoing surgical management. A gynaecological oncology robot-assisted programme can be easily established in a tertiary care cancer centre.

Adjuvant vaginal brachytherapy alone for high risk localized endometrial cancer as defined by the three major randomized trials of adjuvant pelvic radiation.

OBJECTIVE: Controversy exists regarding optimal management of high risk localized endometrial cancer. Given that vaginal brachytherapy (VB) alone is used routinely at our institution, we retrospectively reviewed our outcomes among high risk patients defined according to the PORTEC, GOG 99, and/or Aalders randomized trials of pelvic radiation versus observation to determine if acceptable rates of locoregional control could be achieved with vaginal brachytherapy alone in this highest risk patient population. METHODS: The Roswell Park Cancer Institute hospital tumor registry was used to identify all patients with Stage I or IIA endometrial cancer treated between January 1992 and June 2006. A total of 464 patients were identified. Of 261 patients who received post-operative RT, 225 received VB alone. Of those 225, 87 met the high risk criteria as designated by PORTEC (at least 2 of the following high risk features: age>60, Grade 3, and/or myometrial invasion >or=Occurrences of the mathematical operator' (='were changed to 'OE'. Please check.-->50%), GOG 99 (any age with 3 high risk features: Grade 2-3, >66% myometrial invasion, and/or LVSI; age >or=50 with 2 high risk features; or age >or=70 with 1 high risk feature), and/or Aalders (Stage IC, Grade 3). Descriptive recurrence statistics are provided. RESULTS: Among 87 high risk patients treated with VB alone, 36, 77, and 14 were high risk per PORTEC, GOG 99, and Aalders respectively. Forty (46%) underwent pelvic lymph node dissection. With a median follow-up of 52 months, 3 (3.4%) pelvic recurrences were observed including 1 vaginal recurrence, 1 pelvic recurrence, and 1 local recurrence involving both the vagina and pelvis. All 3 local recurrences were successfully salvaged with pelvic RT+/-surgery. CONCLUSIONS: This represents one of the largest known series of high risk localized endometrial cancer treated with VB alone. The observed 3.4% locoregional recurrence compares favorably with the 5% locoregional recurrence noted among the highest risk patients receiving pelvic RT in the PORTEC, GOG 99, and Aalders randomized trials. In this single institution experience, the 3 local recurrences were salvaged. Based on these findings, we will continue to use VB alone in the adjuvant setting for patients with high risk localized endometrial cancer.

A medical-legal partnership as a component of a palliative care model.

INTRODUCTION: A medical-legal partnership (MLP) incorporated as part of a comprehensive palliative care model addresses unmet social and material needs for patients. This study retrospectively reviews the experience of one MLP and quantifies the benefits of the program for both patients and the host health care institution. METHODS: The Legal Services Program, an MLP, reviewed their program referral and outcomes from April 1, 2004 to December 31, 2007 to document legal needs resolved. The patient accounts manager in the host health care institution reported on the revenue reimbursed to date on a subset of benefits advocacy cases. RESULTS: The Legal Services Program received 297 referrals from April 1, 2004 to December 31, 2007 and resolved multiple legal issues. Seventeen benefits advocacy cases successfully overturned benefit denials, with the institution receiving $923,188 for current and past health services rendered. Two patient-client case studies are described in-depth. CONCLUSION: This MLP demonstrates the ability to help both patients and health care institutions effectively address the needs of patients with cancer and is an important component of a comprehensive palliative care model.

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers.

BACKGROUND: Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC-related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations. METHODS: Seventy-seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC-associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative. RESULTS: None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious. CONCLUSIONS: HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing.

Higher regular coffee and tea consumption is associated with reduced endometrial cancer risk.

Several studies have investigated the associations between diet and endometrial cancer, but few have focused specifically on coffee and tea. In a hospital-based case-control study, we examined the associations between endometrial cancer risk and usual consumption of coffee, decaffeinated coffee, and black tea among 541 women with endometrial cancer and 541 women with an intact uterus but without a cancer diagnosis seen at Roswell Park Cancer Institute (Buffalo, New York) between 1982 and 1998. Daily frequency of consumption of coffee, decaffeinated coffee, and black tea in the few years prior to diagnosis in cases and questionnaire completion in controls was assessed with a self-administered epidemiologic questionnaire and categorized as none, 0.5 cups/d, 1-2 cups/d and >2 cups/d. Odds ratios (OR) and 95% confidence intervals (CI) for each category referent to nondrinkers were estimated with unconditional logistic regression adjusting for age, endometrial cancer risk factors and each beverage mutually adjusted for other beverages. Compared to nondrinkers, we observed a nonsignificant negative association with endometrial cancer risk among women who reported >2 cups/d regular coffee (OR 0.71, 95% CI 0.49-1.03), a significant inverse association with >2 cups/d black tea (OR 0.56, 95% CI 0.35-0.90) and a significant inverse association with >4 cups/d combined coffee and tea consumption (OR 0.47, 95% CI 0.28-0.80). These findings suggest coffee and tea may be important in reducing endometrial cancer risk.

Higher intakes of vegetables and vegetable-related nutrients are associated with lower endometrial cancer risks.

A limited number of studies have investigated diet in association with endometrial cancer (EC). We examined the association between intakes of selected food groups and nutrients with EC risk among 541 women with histologically confirmed EC and 541 women with an intact uterus and noncancer diagnoses seen at Roswell Park Cancer Institute between 1982 and 1998. Self-reported dietary and other epidemiologic data were collected by questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% CI, adjusting for age, BMI, hormone replacement therapy use, cigarette smoking, lifetime duration of menstruation, and total energy intake. We observed significant inverse associations for women in the highest vs. lowest quartiles of intake of total vegetables (OR, 0.51; 95% CI, 0.34-0.75), vitamin E (OR, 0.44; 95% CI, 0.27-0.70), dietary fiber (OR, 0.60; 95% CI, 0.39-0.94), beta-carotene (OR, 0.55; 95% CI, 0.37-0.82), lutein (OR, 0.52; 95% CI, 0.34-0.78), and folate (OR, 0.57; 95% CI, 0.36-0.91). Our results support that vegetables and related nutrients are associated with decreased risk of EC.

Intraobserver and interobserver variability in distinguishing between endocervical and endometrial adenocarcinoma on problematic cases of cervical curettings.

We conducted a prospective study where 4 pathologists examined patients' problematic cases of cervical curetting for adenocarcinoma to determine whether it is of endocervical or endometrial origin based on 3 parameters: age, morphology, and immunohistochemistry (IHC) panel. Our aims were to evaluate the intraobserver and interobserver variability and to compare the results using those parameters to the final hysterectomy specimens. The value of morphology, morphology+age, and the combined parameters (morphology+age+IHC) in predicting the correct origin of the tumor was evaluated. The intraobserver agreements ranged from fair to almost perfect for each of morphology, morphology+age, and the combined parameters. The interobserver agreements were fair in the first review and ranged from slight to fair in the second review. The agreements between the diagnosis based on morphology, morphology+age, and the combined parameters compared with the final diagnosis on the hysterectomy specimen were slight (kappa=0.137), fair (kappa=0.290), and moderate (kappa=0.497), respectively. We concluded that (i) discriminating between endocervical and endometrial carcinoma is highly subject to intraobserver and interobserver variability. (ii) Surprisingly, this variability is not affected by pathologists' experience. (iii) An IHC panel adds a useful piece of information to predict the tumor origin. Lastly, even though the combination of morphology, age, and IHC is far from perfect in predicting the correct origin of the tumor, it is still the best available method.

Desmoplastic small round cell tumor (DSRCT) with ovarian involvement in 2 young women.

We report 2 cases of desmoplastic small round cell tumor (DSRCT) involving the ovaries in young women. The first patient presented with symptoms of acute appendicitis and the second patient presented with a mass in the lower abdomen and slightly elevated CA-125 level. In both patients, the tumor was widely metastatic at presentation. The ovarian involvement was unilateral in the first patient and bilateral in the second with tumor size ranging from 9 to 11 cm. Morphology, immunohistochemistry, and molecular cytogenetics were consistent with DSRCT. Despite tumor debulking and multiple chemotherapy regimens, the first patient died at 20 months after initial diagnosis and the second is still undergoing chemotherapy at 7 months after initial presentation. To gain additional insight on DSRCT with ovarian involvement, the literature was reviewed and summarized.

Prospective determination of prevalence of lynch syndrome in young women with endometrial cancer.

PURPOSE: Age younger than 50 years at the time of colon cancer diagnosis is often used as a screening criterion for Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). The purpose of this study was to determine the prevalence of MLH1, MSH2, and MSH6 mutations in an unselected cohort of women diagnosed with endometrial cancer at age younger than 50 years. METHODS: A prospective, multicenter study was performed at three institutions. After written consent was obtained, germline mutation testing by full sequencing and large deletion analysis of the MLH1, MSH2, and MSH6 genes was performed. Tumor studies included immunohistochemistry of MLH1, MSH2, and MSH6; microsatellite instability analysis; and hypermethylation of the MLH1 promoter. RESULTS: Of the 100 women, nine (9%; 95% CI, 4.2 to 16.4) carried a deleterious germline mutation: seven women with mutations in MSH2, one woman with a mutation in MLH1, and one woman with a mutation in MSH6. Two additional women had molecular studies consistent with the diagnosis of Lynch syndrome. The mean body mass index (BMI) for the entire cohort was 34.4, which is significantly higher than 29.2, the mean BMI for the mutation carriers. Predictors of finding a germline mutation included having a first-degree relative with a Lynch syndrome-associated cancer, endometrial tumor with loss of MSH2 expression, tumors with high microsatellite instability, and lower BMI. CONCLUSION: In this prospective study of endometrial cancer patients younger than age 50 years, 9% were found to carry germline Lynch syndrome-associated mutations. In addition to young age of onset, family history, BMI, and molecular tumor studies can improve the likelihood of identifying a Lynch syndrome-associated germline mutation in MLH1, MSH2, and MSH6.

Uterine carcinosarcoma associated with hereditary nonpolyposis colorectal cancer.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) was originally described as a genetic disorder predominantly involving colorectal cancer. Numerous neoplasms are known to be associated with this condition. Sarcomas have also been reported within families with HNPCC. The challenge is determining if these cancers are sporadic or hereditary. CASE: We report on a 46-year-old woman with uterine carcinosarcoma and a family history suspicious for HNPCC. Genetic testing identified a germline MLH1 mutation. Immunohistochemistry testing of the carcinosarcoma revealed loss of MLH1 expression with preservation of MSH2 expression. CONCLUSION: The loss of MLH1 protein expression suggests the germline mutation contributed to the development of the carcinosarcoma. Hereditary nonpolyposis colorectal cancer should be included in the differential diagnosis of persons with uterine carcinosarcoma when noted within a family history suspicious for HNPCC.

Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer.

NY-ESO-1 is a "cancer-testis" antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO(157-170), is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO(157-170) mixed with incomplete Freund's adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO(157-170) epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC.

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression.

The purpose of this study was to understand the characteristics of prostate-derived Ets factor (PDEF) protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal, and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays, including benign prostate, prostate intraepithelial neoplasias (PINs), and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46%, and 51% of benign breast tissues, intraductal, invasive ductal, and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast vs tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu overexpression. Increased expression of PDEF was also found in 27%, 33%, and 40% of benign prostate tissues, PIN samples, and prostate adenocarcinomas, respectively. Again, in matching samples of cancer vs benign and cancer vs PIN, 68% and 70%, respectively, showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared with low-grade tumors (P < .01). In addition, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.

Medically related legal needs and quality of life in cancer care: a structural analysis.

BACKGROUND: This study investigated the interface of medical and legal systems by empirically identifying and evaluating the relation of medically related legal needs and patient quality of life and by assessing the degree to which these needs were addressed in standard patient care. METHODS: Medically related legal needs were identified in a focus group setting. These needs were subsequently sorted and rated by a sample of 50 mixed-site cancer patients (22 men and 28 women; mean age, 52 years) and subjected to multidimensional scaling and cluster analyses. Participants also rated each need in terms of the extent to which it was met in their medical care and the impact on their quality of life. RESULTS: Participants identified 30 medically related legal needs. Multivariate analyses identified 4 distinct medical-legal domains: Health Care Related, Estate Related, Financial, and Employment Related. Participants rated these domains as exerting a significant impact on quality of life. Patients reported that that these needs were not met by their current medical or supportive care. CONCLUSIONS: The present study identified a range of medically related legal needs of cancer patients. Despite their importance to patient quality of life, these needs were not met by standard medical and supportive care. Findings underscored the need to integrate legal resources into cancer care as an important component of interventions that enhance patient quality of life.