SOX17: A Highly Sensitive and Specific Immunomarker for Ovarian and Endometrial Carcinomas.

PAX8 is the most commonly used immunomarker to link a carcinoma to the gynecologic tract; however, it lacks specificity. Through mining The Cancer Genome Atlas mRNA expression profile data, we identified SOX17 as a potential specific marker at the mRNA level for gynecologic tumors. To evaluate the utility of this marker in the identification of the gynecologic origin of a given carcinoma, we performed immunochemical staining in a large cohort of ovarian and endometrial cancer cases (n = 416), together with a large cohort of solid tumors from other organs (n = 1544) in tissue microarrays. Similar to PAX8, SOX17 was highly expressed in different subtypes of ovarian carcinoma (97.5% for SOX17 vs 97% for PAX8 in serous carcinoma, 90% vs 90% in endometrioid carcinoma, and 100% vs 100% in clear cell carcinoma), except for mucinous carcinoma (0% vs 27%), and was also highly expressed in different subtypes of endometrial carcinoma (88% vs 84% in endometrioid carcinoma, 100% vs 100% in serous and clear cell carcinoma). SOX17 was not expressed in thyroid and renal cell carcinomas, whereas PAX8 expression was high (86% and 85%, respectively). In addition, SOX17 was expressed at low levels in cervical adenocarcinoma (20%) and had no expression in cervical squamous carcinoma, mesothelioma, and carcinomas from the breast, lung, pancreas, colon, stomach, liver, bladder, and salivary gland. Our data indicate that SOX17 is not only a sensitive but also a specific marker for the origin of ovarian and endometrial carcinomas.

The role of postoperative radiation after radical hysterectomy for women with early-stage neuroendocrine carcinoma of the cervix: A meta-analysis.

INTRODUCTION: Neuroendocrine carcinoma of the cervix (NECC) is an aggressive disease with high rates of nodal disease spread even in seemingly cervix-confined disease. Many providers routinely prescribe postoperative radiation therapy in an effort to reduce recurrences despite a lack of supporting studies. The objective of this study was to determine recurrence and mortality in patients with early-stage NECC who had pelvic radiation after radical hysterectomy compared to those who did not receive radiation. METHODS: We performed a meta-analysis of 13 unique studies that reported recurrence and/or mortality for patients with early-stage NECC who underwent radical hysterectomy with or without adjuvant radiation therapy. RESULTS: In 5 studies that reported overall recurrence rates, 63 (52.5%) of 120 patients who received postoperative radiation recurred compared to 70 (37.8%) of 185 patients who did not (RR 1.21, 95% CI: 0.85-1.70, p = 0.29). In 5 studies that reported pelvic recurrence rates, there were 15 pelvic recurrences (12.5%) in the 120 patients who received postoperative radiation compared to 45 pelvic recurrences (24.3%) in the 185 patients who did not (RR 0.60, 95% CI: 0.34-1.08, p = 0.09). In 13 studies that reported mortality rate, there were 138 deaths (34.8%) in 396 patients who received postoperative radiation therapy compared to 223 (35.2%) in 632 patients who did not (RR 1.08, 95% CI: 0.75-1.56, p = 0.66). CONCLUSIONS: The addition of routine postoperative radiation therapy in all patients with early-stage NECC after radical hysterectomy may reduce pelvic recurrences but does not appear to decrease overall recurrence or death. However, there may still be a role for postoperative radiation therapy in patients with additional high-risk pathologic factors.

Social media use is associated with higher levels of anxiety and depression in patients with neuroendocrine carcinoma of the cervix: A NeCTuR study.

OBJECTIVE: Neuroendocrine cervical carcinoma (NECC) is rare. Educational resources are limited for NECC patients, leading many to seek information online through patient-led social networks. We sought to characterize the relationships between anxiety and depression levels and social media use among NECC patients. METHODS: Seven surveys assessing social media use, anxiety, and depression were distributed to living NECC patients enrolled in our NECC registry. The primary outcomes were associations between Social Network Time Use Scale (SONTUS) global score and Generalized Anxiety Disorder (GAD-7) and Center for Epidemiologic Studies Depression Scale (CESD) total scores. RESULTS: Eighty-eight patients enrolled; 81 who completed at least 1 survey were included. Ninety-seven percent (70/72) of patients completing SONTUS were low-to-average social media users. Seventy-four percent (53/72) of patients visited a patient-led NECC support-group page on Facebook within the past 4 weeks, and of those, 79% (42/53) reported receiving useful information. Among the patients who did not visit the page, 47% (9/19) reported that the page elicited anxiety and/or sadness. The mean GAD-7 and CES-D scores for the entire cohort were 7.3 and 18.1, respectively. The Spearman correlations between social media use and these scores were significant (GAD-7: 0.23 [p = 0.05]; CESD: 0.25 [p = 0.04]). The estimated odds ratios for moderate/severe anxiety and depression as a function of SONTUS global score were 1.26 (95% CI 1.03-1.55; p = 0.03) and 1.23 (95% CI 1.01-1.49; p = 0.04), respectively. CONCLUSIONS: NECC patients demonstrated low-to-average social media use and relatively high anxiety and depression. Increased social media use was associated with elevated anxiety and depression.

Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in patients with recurrent high-grade neuroendocrine cervical cancer: a Neuroendocrine Cervical Tumor Registry (NeCTuR) study.

BACKGROUND: Recurrent high-grade neuroendocrine cervical cancer has a very poor prognosis and limited active treatment options. OBJECTIVE: This study aimed to evaluate the efficacy of the 3-drug regimen of topotecan, paclitaxel, and bevacizumab in women with recurrent high-grade neuroendocrine cervical cancer. STUDY DESIGN: This retrospective cohort study used data from the Neuroendocrine Cervical Tumor Registry (NeCTuR), which include data abstracted directly from medical records of women diagnosed with high-grade neuroendocrine carcinoma of the cervix from English- and Spanish-speaking countries. The study compared women with recurrent high-grade neuroendocrine cervical cancer who received the topotecan, paclitaxel, and bevacizumab regimen as first- or second-line therapy for recurrence and women with recurrent high-grade neuroendocrine cervical cancer who received chemotherapy but not the topotecan, paclitaxel, and bevacizumab regimen. Patients continued chemotherapy until disease progression or the development of unacceptable toxic effects. Progression-free survival from the start of therapy for recurrence to the next recurrence or death, overall survival from the first recurrence, and response rates were evaluated. RESULTS: The study included 62 patients who received the topotecan, paclitaxel, and bevacizumab regimen as first- or second-line therapy for recurrence and 56 patients who received chemotherapy but not the topotecan, paclitaxel, and bevacizumab regimen for recurrence. The median progression-free survival rates were 8.7 months in the topotecan, paclitaxel, and bevacizumab regimen group and 3.7 months in the non-topotecan, paclitaxel, and bevacizumab regimen group, with a hazard ratio for disease progression of 0.27 (95% confidence interval, 0.17-0.48; P<.0001). In the topotecan, paclitaxel, and bevacizumab regimen group, 15% of patients had stable disease, 39% of patients had a partial response, and 18% of patients had a complete response. Compared with patients in the non-topotecan, paclitaxel, and bevacizumab regimen group, significantly more patients in the topotecan, paclitaxel, and bevacizumab regimen group remained on treatment at 6 months (31% vs 67%, respectively; P=.0004) and 1 year (9% vs 24%, respectively; P=.02). The median overall survival rates were 16.8 months in the topotecan, paclitaxel, and bevacizumab regimen group and 14.0 months in the non-topotecan, paclitaxel, and bevacizumab regimen group, with a hazard ratio for death of 0.87 (95% confidence interval, 0.55-1.37). CONCLUSION: Combination therapy with topotecan, paclitaxel, and bevacizumab was an active regimen in women with recurrent high-grade neuroendocrine cervical cancer and improved progression-free survival while decreasing the hazard ratio for disease progression.

Clinicopathologic characteristics, oncologic outcomes, and prognostic factors in neuroendocrine cervical carcinoma: a Neuroendocrine Cervical Tumor Registry study.

OBJECTIVE: To evaluate clinicopathologic features and oncologic outcomes of patients with neuroendocrine cervical carcinoma in an institutional neuroendocrine cervical tumor registry. METHODS: Retrospective study including patients with neuroendocrine cervical carcinomas diagnosed between 1986 and 2022. Patients were categorized into International Federation of Gynecology and Obstetrics 2018 stage groups: early-stage (IA1-IB2, IIA1); locally advanced (IB3, IIA2-IVA); and advanced (IVB). Clinicopathologic characteristics and oncologic outcomes were evaluated by stage. Survival was compared between patients diagnosed in 1986-2003 and those diagnosed in 2004-2016. Progression-free and overall survival were estimated using the Kaplan-Meier product-limit estimator. RESULTS: A total of 453 patients was included, 133 (29%) with early-stage, 226 (50%) with locally advanced, and 94 (21%) with advanced disease. Median age was 38 years (range 21-93). Sixty-nine percent (306/453) had pure and 32% (146/453) had mixed histology. The node positivity rate (surgical or radiological detection) was 19% (21/108) for tumors ≤2 cm, 37% (39/105) for tumors >2 to ≤4 cm, and 61% (138/226) for tumors >4 cm (p<0.0001). After primary treatment, rates of complete response were 86% (115/133) for early-stage, 65% (147/226) for locally advanced, and 19% (18/94) for advanced disease (p<0.0001). The recurrence/progression rate was 43% for early-stage, 69% for locally advanced, and 80% for advanced disease (p<0.0001). Five-year progression-free and overall survival rates were 59% (95% CI 50% to 68%) and 71% (95% CI 62% to 80%), respectively, for early-stage, 28% (95% CI 22% to 35%) and 36% (95% CI 29% to 43%), respectively, for locally advanced, and 6% (95% CI 0% to 11%) and 12% (95% CI 5% to 19%), respectively, for advanced disease. For early-stage disease, the 5-year progression-free survival rate was 68% for tumors ≤2 cm and 43% for tumors >2 to ≤4 cm (p=0.0013). Receiving cisplatin/carboplatin plus etoposide (HR=0.33, 95% CI 0.17 to 0.63, p=0.0008) and receiving curative radiotherapy (HR=0.32, 95% CI 0.17 to 0.6, p=0.0004) were positive predictors of survival for patients with advanced disease. CONCLUSION: Among patients with neuroendocrine cervical carcinomas, overall survival is favorable for patients with early-stage disease. However, most patients present with locally advanced disease, and overall survival remains poor in this subgroup. For patients with advanced disease, receiving cisplatin/carboplatin plus etoposide and curative radiation therapy is associated with improved overall survival.

PET/CT scan improves detection of metastatic disease compared with CT scan alone in women with high-grade neuroendocrine cervical cancer: a NeCTuR study.

OBJECTIVE: To determine the optimal imaging modality for women with high-grade neuroendocrine carcinoma of the cervix. METHODS: Women with high-grade neuroendocrine carcinoma of the cervix who had undergone a computed tomography (CT) scan and combined positron emission tomography with computed tomography (PET/CT) scan within 4 weeks of each other were identified from the NeCTuR Cervical Tumor Registry. One radiologist reviewed all CT scans, and another radiologist reviewed all PET/CT scans. The radiologists denoted the presence or absence of disease at multiple sites. Each radiologist was blinded to prior reports, patient outcomes, and the readings of the other radiologist. With findings on PET/CT used as the gold standard, sensitivity, specificity, and accuracy were calculated for CT scans. RESULTS: Fifty matched CT and PET/CT scans were performed in 41 patients. For detecting primary disease in the cervix, CT scan had a sensitivity of 85%, a specificity of 46%, and an accuracy of 74%. For detecting disease spread to the liver, CT scan had a sensitivity of 80%, a specificity of 89%, and an accuracy of 86%. For detecting disease spread to the lung, CT had a sensitivity of 89%, a specificity of 68%, and an accuracy of 77%. Of the 14 patients who had scans for primary disease work-up, 4 (29%) had a change in their treatment plan due to the PET/CT scan. Had treatment been prescribed on the basis of the CT scan alone, 2 patients would have been undertreated, and 2 would have been overtreated. CONCLUSION: A CT scan is inferior to a PET/CT scan in assessment of metastatic disease in women with high-grade neuroendocrine carcinoma of the cervix. Almost one-third of patients with newly diagnosed high-grade neuroendocrine cervical cancer would have received incorrect therapy had treatment planning been based solely on a CT scan. We recommend a PET/CT scan for both initial work-up and surveillance in women with high-grade neuroendocrine carcinoma of the cervix.

Impact of pelvic radiation therapy in patients with early neuroendocrine cervical carcinoma and no residual disease in the radical hysterectomy specimen: a NeCTuR study.

OBJECTIVE: The impact of adjuvant pelvic radiation therapy on the rate and location of recurrences was evaluated in patients with early-stage (IA1-IB2) neuroendocrine cervical carcinoma who underwent prior conization or polypectomy with no residual disease and negative nodes in the subsequent upfront radical hysterectomy specimen. As a secondary objective, disease-free and overall survival were analyzed. METHODS: We searched the Neuroendocrine Cervical Tumor Registry (NeCTuR) to identify patients with clinical early-stage neuroendocrine cervical carcinoma with no residual disease in the specimen from upfront radical surgery and negative nodes. Patients who received pelvic radiation therapy were compared with those who did not, regardless of whether they received adjuvant chemotherapy. RESULTS: Twenty-seven patients met the inclusion criteria, representing 17% of all patients with clinical early-stage disease who underwent upfront radical hysterectomy included in the NeCTuR registry. The median age was 36.0 years (range 26.0-51.0). Six (22%) patients had stage IA, 20 (74%) had stage IB1, and one (4%) had stage IB2 disease. Seven (26%) patients received adjuvant radiation therapy and 20 (74%) did not. All seven patients in the radiation group and 14 (70%) in the no-radiation group received adjuvant chemotherapy (p=0.16). Fifteen percent (4/27) of patients had a recurrence, 14% (1/7) in the radiation group and 15% (3/20) in the no-radiation group (p=0.99). In the radiation group the recurrence was outside the pelvis, and in the no-radiation group, 67% (2/3) recurred outside the pelvis and 33% (1/3) recurred both inside and outside the pelvis (p=0.99). In the radiation group the 5-year disease-free and overall survival rates were 100% while, in the no-radiation group, the 5-year disease-free and overall survival rates were 81% (95% CI 61% to 100%) (p=0.99) and 80% (95% CI 58% to 100%) (p=0.95), respectively. CONCLUSIONS: For patients with no residual disease and negative nodes in the upfront radical hysterectomy specimen, our study did not find that pelvic radiation therapy improves survival.

Germ Cell Tumors of the Ovary: A Review.

Ovarian germ cell tumors are a diverse group of benign and malignant neoplasms that occur in a wide age range, but with a predilection for younger age group. The majority are represented by the frequently encountered mature cystic teratomas. Malignant germ cell tumors are uncommon, and in some cases have a characteristic clinical presentation. However, from a histologic standpoint these tumors can sometimes be challenging to diagnose due to overlapping morphology with epithelial, and in some cases sex cord tumors. In these cases, a panel of immunohistochemical stains often facilitates the correct diagnosis. This review article discusses the clinicopathologic findings and pertinent ancillary studies of both common and uncommon germ cell tumors of the ovary.

Definitive pelvic radiation therapy improves survival in stage IVB neuroendocrine cervical carcinoma: A NeCTuR study.

OBJECTIVE: To evaluate the survival impact of adding definitive pelvic radiation therapy (RT) to chemotherapy among patients with stage IVB neuroendocrine cervical carcinoma (NECC). METHODS: We retrospectively studied patients with FIGO 2018 stage IVB NECC diagnosed during 1998-2020 who received chemotherapy with or without definitive whole pelvic RT (concurrent or sequential). Demographic, oncologic, and treatment characteristics were summarized. Progression-free (PFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using Cox regression. RESULTS: The study included 71 patients. Median age was 43 years (range, 24-75). Fifty-nine patients (83%) had pure neuroendocrine histology, and 57 (80%) had pretreatment tumor size >4 cm. Fifty-six patients (79%) received chemotherapy alone with (n = 15) or without (n = 41) palliative pelvic RT, and 15 (21%) received chemotherapy and definitive pelvic RT (chemo+RT). Median follow-up time was 20.1 months (range, 11.3-170.3) for the chemo+RT group and 13.5 months (range, 0.9-73.6) for the chemotherapy-alone group. Median PFS was 10.3 months (95% CI, 7.5-∞) for the chemo+RT group vs 6.6 months (95% CI, 6.1-8.7) for the chemotherapy-alone group (p = 0.0097). At 24 months, the PFS rate was 24% for chemo+RT vs 7.8% for chemotherapy alone. Median OS was 20.3 months (95% CI, 18.5-∞) for the chemo+RT group vs 13.6 months (95% CI, 11.3-19.2) for the chemotherapy-alone group (p = 0.0013). At 24 months, the OS rate was 49.2% for chemo+RT vs 21.5% for chemotherapy alone. In a Cox regression model, definitive RT was associated with improved PFS (HR, 0.44; 95% CI, 0.23-0.83; p = 0.0119) and OS (HR, 0.31; 95% CI, 0.14-0.65; p = 0.0022). CONCLUSIONS: Addition of definitive pelvic RT to chemotherapy may improve survival in patients with stage IVB NECC.

Malignant Peritoneal Mesothelioma Associated With Endometriosis: A Clinicopathologic Study of 15 Cases.

Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation.

Cervical cancer prevention in El Salvador: A prospective evaluation of screening and triage strategies incorporating high-resolution microendoscopy to detect cervical precancer.

Cervical cancer remains a leading cause of cancer death for women in low- and middle-income countries. The goal of our study was to evaluate screening and triage strategies, including high-resolution microendoscopy (HRME), to detect cervical abnormalities concerning for precancer at the point of care. Women (n = 1824) were enrolled at the Instituto de Cáncer de El Salvador. All underwent screening by both human papillomavirus (HPV) testing using careHPV and visual inspection with acetic acid (VIA). Screen-positives, along with 10% of screen-negatives, were invited to return for a follow-up examination that included triage with VIA, colposcopy and HRME imaging. Biopsies were taken of any abnormalities identified. If no abnormalities were identified, then the worst scoring site by HRME was biopsied. The sensitivities of HPV testing and VIA to screen for cervical intraepithelial neoplasia Grade 2 or more severe diagnoses (CIN2+) were 82.1% and 75% (P = .77), while the specificities were 90.4% and 80.9% (P < .001), respectively. The sensitivities of VIA, colposcopy and HRME as triage tests for CIN2+ were 82.1%, 82.1% and 71.4%, respectively (P ≥ .38). HRME had a significantly higher specificity (66.7%) than VIA (51.9%) (P < .001) and colposcopy (53.3%) (P < .001). When evaluating different theoretical screening and triage strategies, screening with HPV testing followed by triage with HRME would result in more women receiving appropriate care (97%) compared to screening with VIA (75%) or HPV alone (90%). Our findings demonstrate that screening with HPV is superior to VIA, and that triage with HRME imaging increases the specificity of detecting CIN2+ at the point of care in a low-resource setting.

Immunohistochemical Loss of DPC4 in Tumors With Mucinous Differentiation Arising in or Involving the Gynecologic Tract.

DPC4 immunohistochemistry (IHC) is usually part of the work-up of mucinous neoplasms in the ovary where the distinction between an ovarian primary and metastatic pancreaticobiliary adenocarcinoma (PanACa) must be made. Although DPC4 IHC is lost in about 55% (46%-61%) of PanACas and typically retained in most primary ovarian mucinous neoplasms, no study has evaluated the expression of this marker in a large cohort of neoplasms arising in or involving gynecologic (GYN) organs. In this study, we retrospectively analyzed the expression of DPC4 IHC in a total of 251 tumors and lesions related to the GYN tract in which DPC4 IHC stain was performed during the initial pathology evaluation. Of these, 138 were primary GYN tumors and lesions, 31 were metastatic GYN tumors involving non-GYN sites, and 83 were metastatic non-GYN tumors involving the GYN tract. We identified 27 cases with loss of DPC4 IHC expression of which 20 cases met the inclusion criteria (i.e. clinical information was available to determine the site of tumor origin). We observed that loss of DPC4 nuclear expression was most commonly seen in tumors of endocervical origin (n=7), of which 5 were gastric-type cervical adenocarcinomas (GCxACa) and 2 were usual-type cervical adenocarcinomas, either primary or metastatic. This was followed by tumors of the pancreaticobiliary tract (n=5), ovary (n=2), and appendix (n=1). In addition, 1 gastric-type vaginal adenocarcinoma (GVaACa) also showed loss of DPC4. Our findings indicate that in female patients with mucinous neoplasms involving the ovary or other sites, with loss of DPC4 by IHC, and negative pancreaticobiliary imaging, the possibility of an occult GCx/GVaACa, and rarely an ovarian primary must be considered.

Role of radical hysterectomy in patients with early-stage high-grade neuroendocrine cervical carcinoma: a NeCTuR study.

OBJECTIVE: Patients with early-stage, high-grade neuroendocrine cervical carcinoma typically undergo radical hysterectomy with pelvic lymphadenectomy followed by adjuvant radiotherapy and/or chemotherapy. To explore the role of radical surgery in patients with this disease, who have a high likelihood of undergoing postoperative adjuvant therapy, we aimed to determine the rate of parametrial involvement and the rate of parametrial involvement without other indications for adjuvant treatment in these patients. METHODS: We retrospectively studied patients in the Neuroendocrine Cervical Tumor Registry (NeCTuR) at our institution to identify those with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA1-IB2, high-grade neuroendocrine cervical carcinoma who underwent up-front radical surgery with or without adjuvant therapy. RESULTS: One hundred patients met the inclusion criteria. The median age was 35 years (range 22-65), and 51% (51/100) had pure high-grade neuroendocrine carcinoma. No patient had a tumor >4 cm or suspected parametrial or nodal disease before surgery. Ten patients (10%) had microscopic parametrial compromise in the final surgical specimens. Ninety-four (94%) patients underwent nodal assessment, and 19 (19%) had positive nodes. Ten patients underwent both sentinel lymph node biopsy and pelvic lymphadenectomy, and none had false-negative findings. Patients with parametrial compromise were more likely to have positive pelvic nodes (80% vs 12%, p<0.0001), and a positive vaginal margin (20% vs 1%, p=0.03). All patients with parametrial compromise had lymphovascular space invasion (100% vs 73%, p=0.10). Of the 100 patients, 95 (95%) were recommended adjuvant therapy and 89 (89%) were known to have received it. Adjuvant pelvic radiotherapy reduced the likelihood of local recurrence by 62%. CONCLUSIONS: In carefully selected patients with high-grade neuroendocrine cervical carcinoma, the rate of microscopic parametrial involvement is 10%. As most patients receive adjuvant treatment, we hypothesize that simple hysterectomy may be adequate when followed by adjuvant radiotherapy with concurrent cisplatin and etoposide followed by additional chemotherapy.

ConCerv: a prospective trial of conservative surgery for low-risk early-stage cervical cancer.

OBJECTIVE: The objective of the ConCerv Trial was to prospectively evaluate the feasibility of conservative surgery in women with early-stage, low-risk cervical cancer. METHODS: From April 2010 to March 2019, a prospective, single-arm, multicenter study evaluated conservative surgery in participants from 16 sites in nine countries. Eligibility criteria included: (1) FIGO 2009 stage IA2-IB1 cervical carcinoma; (2) squamous cell (any grade) or adenocarcinoma (grade 1 or 2 only) histology; (3) tumor size <2 cm; (4) no lymphovascular space invasion; (5) depth of invasion <10 mm; (6) negative imaging for metastatic disease; and (7) negative conization margins. Cervical conization was performed to determine eligibility, with one repeat cone permitted. Eligible women desiring fertility preservation underwent a second surgery with pelvic lymph node assessment, consisting of sentinel lymph node biopsy and/or full pelvic lymph node dissection. Those not desiring fertility preservation underwent simple hysterectomy with lymph node assessment. Women who had undergone an 'inadvertent' simple hysterectomy with an unexpected post-operative diagnosis of cancer were also eligible if they met the above inclusion criteria and underwent a second surgery with pelvic lymph node dissection only. RESULTS: 100 evaluable patients were enrolled. Median age at surgery was 38 years (range 23-67). Stage was IA2 (33%) and IB1 (67%). Surgery included conization followed by lymph node assessment in 44 women, conization followed by simple hysterectomy with lymph node assessment in 40 women, and inadvertent simple hysterectomy followed by lymph node dissection in 16 women. Positive lymph nodes were noted in 5 patients (5%). Residual disease in the post-conization hysterectomy specimen was noted in 1/40 patients-that is, an immediate failure rate of 2.5%. Median follow-up was 36.3 months (range 0.0-68.3). Three patients developed recurrent disease within 2 years of surgery-that is, a cumulative incidence of 3.5% (95% CI 0.9% to 9.0%). DISCUSSION: Our prospective data show that select patients with early-stage, low-risk cervical carcinoma may be offered conservative surgery.

Prophylactic Risk-reducing Hysterectomies and Bilateral Salpingo-oophorectomies in Patients With Lynch Syndrome: A Clinicopathologic Study of 29 Cases and Review of the Literature.

Lynch syndrome (LS) is associated with an increased risk for colorectal, endometrial, and ovarian carcinomas in women. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy (RRHSO) has been shown to be a cost-effective form of management and prevention of gynecological malignancies in patients with LS. Studies of incidental gynecologic malignancies identified in RRHSO are limited. In addition, recommendations on optimal handling of this type of specimen have ranged from submitting for microscopic examination the entire endometrium, fallopian tubes and ovaries to submitting only routine representative sections of these organs. In this study, we present the clinicopathologic findings of 29 cases of LS patients that underwent risk-reducing gynecologic surgery at our institution over a period of 13 yr. Clinical-pathologic information was obtained from the patients' charts and pathology reports. Significant pathologic abnormalities were identified in 17% (5/29) of cases, all showing endometrial hyperplasia. Four of them with atypical and 1 without atypical. All of our cases with endometrial pathology had significant findings on preoperative endometrial sampling. To further study the recommendation of in toto submission of the endometrium, ovaries and fallopian tubes and the utility of preoperative endometrial sampling, we undertook a literature review of all the reported cases of incidental pathologic findings identified in RRHSO. The findings of our cohort and the literature reviewed support in toto submission of endometrium, and adnexal structures in the absence of gross lesions. In addition, our findings show a definite benefit for preoperative endometrial sampling as part of the workup for LS patients undergoing RRHSO.

Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix.

OBJECTIVES: Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease. METHODS: Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40-100 moderate, and ≥100 high. RESULTS: Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%). CONCLUSIONS: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

Perineural invasion (PNI) in vulvar carcinoma: A review of 421 cases.

OBJECTIVES: To evaluate the prevalence and associated prognostic indicators in patients with vulvar carcinoma with and without evidence of perineural invasion (PNI). METHODS: A retrospective review identified 421 patients with invasive vulvar carcinoma evaluated at a single institution between 1993 and 2011. Medical records were reviewed for demographic data, pathologic information and presence or absence of PNI, treatment type, and recurrence/outcome information. Variables were compared between patients with PNI to those without PNI. RESULTS: Of the 421 patients included in the study, 32 (7.6%) had tumors with PNI. There were no significant differences in age, race/ethnicity, smoking history, histologic subtype, or grade between the group of patients with PNI and the group without PNI. The group with PNI was more likely to have lichen sclerosus (25.0% vs. 15.4%, p = 0.024), stage III/IV disease (59.4% vs. 36.0%, p = 0.007), lymph node involvement (50.0% vs. 21.6%, p = 0.002), and lymphovascular space invasion (LVSI) (53.1% vs. 15.9%, p < 0.001). A higher proportion of patients in the PNI group underwent primary or adjuvant radiation therapy (68.8% vs. 45.0%, p = 0.016). The median follow-up was 67.1 months (range < 1.0 to 284.3). Patients with PNI had significantly shorter overall survival (OS), median 25.5 vs. 94.3 months (p < 0.001), and progression-free survival (PFS), median 17.5 vs. 29.0 months (p = 0.004). After adjusting for stage, patients with PNI had a greater risk for death and progression (OS: hazard ratio, 2.71; p < 0.001; PFS: hazard ratio, 1.64; p-value = 0.020). CONCLUSION: PNI should be considered an independent poor prognostic factor for patients with vulvar carcinoma, and should be included as part of the pathologic analysis.

Accuracy of Intraoperative Frozen Section Diagnosis of Borderline Ovarian Tumors by Hospital Type.

STUDY OBJECTIVE: To compare the accuracy of frozen section diagnosis of borderline ovarian tumors among 3 distinct types of hospital-academic hospital with gynecologic pathologists, academic hospital with nongynecologic pathologists, and community hospital with nongynecologic pathologists-and to determine if surgical staging alters patient care or outcomes for women with a frozen section diagnosis of borderline ovarian tumor. DESIGN: Retrospective study (Canadian Task Force classification II-1). SETTING: Tertiary care, academic, and community hospitals. PATIENTS: Women with an intraoperative frozen section diagnosis of borderline ovarian tumor at 1 of 3 types of hospital from April 1998 through June 2016. INTERVENTIONS: Comparison of final pathology with intraoperative frozen section diagnosis. MEASUREMENTS AND MAIN RESULTS: Two hundred twelve women met the inclusion criteria. The frozen section diagnosis of borderline ovarian tumor correlated with the final pathologic diagnosis in 192 of 212 cases (90.6%), and the rate of correlation did not differ among the 3 hospital types (p = .82). Seven tumors (3.3%) were downgraded to benign on final pathologic analysis and 13 (6.1%) upgraded to invasive carcinoma. The 3 hospital types did not differ with respect to the proportion of tumors upgraded to invasive carcinoma (p = .62). Mucinous (odds ratio, 7.1; 95% confidence interval, 2.1-23.7; p = .002) and endometrioid borderline ovarian tumors (odds ratio, 32.4; 95% confidence interval, 1.8-595.5; p = .02) were more likely than serous ovarian tumors to be upgraded to carcinoma. Only 88 patients (41.5%) underwent lymphadenectomy, and only 1 (1.1%) had invasive carcinoma in a lymph node. CONCLUSIONS: A frozen section diagnosis of borderline ovarian tumor correlates with the final pathologic diagnosis in a variety of hospital types.

Differential structured illumination microendoscopy for in vivo imaging of molecular contrast agents.

Fiber optic microendoscopy has shown promise for visualization of molecular contrast agents used to study disease in vivo. However, fiber optic microendoscopes have limited optical sectioning capability, and image contrast is limited by out-of-focus light generated in highly scattering tissue. Optical sectioning techniques have been used in microendoscopes to remove out-of-focus light but reduce imaging speed or rely on bulky optical elements that prevent in vivo imaging. Here, we present differential structured illumination microendoscopy (DSIMe), a fiber optic system that can perform structured illumination in real time for optical sectioning without any opto-mechanical components attached to the distal tip of the fiber bundle. We demonstrate the use of DSIMe during in vivo fluorescence imaging in patients undergoing surgery for cervical adenocarcinoma in situ. Images acquired using DSIMe show greater contrast than standard microendoscopy, improving the ability to detect cellular atypia associated with neoplasia.

Ultrastaging of Sentinel Lymph Nodes in Endometrial Carcinoma According to Use of 2 Different Methods.

Sentinel lymph node (SLN) sampling may provide staging information without exposing patients to risks of lymph node dissection. There is no consensus protocol for optimal pathologic handling of these specimens. This study compares 2 ultrastaging protocols of SLN in endometrial carcinoma (EC). All SLN were serially sectioned perpendicular to the long axis in 2 mm intervals and entirely submitted for routine hematoxylin and eosin (H&E) processing. SLN negative by routine processing had ultrastaging (US) by one of the following: method 1 (M1), 5 H&E levels at 250 µm intervals with 2 unstained slides at each level; pankeratin immunohistochemistry (IHC) performed on level 1 in cases with negative H&E levels or method 2 (M2), 1 H&E level + 2 unstained slides cut 250 µm into the tissue block; pankeratin IHC performed in cases with negative H&E. Histologic subtype, numbers of SLN, positive SLN, non-SLN, positive non-SLN, and metastasis size were recorded. A total of 178 patients had 527 SLNs (1-16 per case; median, 2 SLN) sampled during hysterectomy for the following EC histotypes: endometrioid International Federation of Gynecology and Obstetrics grade 1/2, 117 (66%); endometrioid International Federation of Gynecology and Obstetrics grade 3, 18 (10%); serous, 20 (11%); carcinosarcoma, 11 (6%); clear cell, 9 (5%); and undifferentiated, 3 (2%). In all, 172 patients had ultrastaging: M1=65; M2=58. In total, 33 patients were SLN positive. Twenty-seven had SLN submitted for US: M1=11; M2=16. Eleven patients had additional SLN detected by US: M1=5; M2=6. Of these, 8 were patients whose SLN were only detected by US representing an increase of 32% in number of patients with positive SLN. Six patients (M1=2; M2=4) with negative SLN had a positive non-SLN. Mean size of ultrastage-detected metastasis was 0.24 mm for M1 and 0.38 mm for M2. Statistical analysis comparing M1 and M2 detected no statistically significant associations with respect to number of positive SLN detected, size of metastasis or false-negative rate and method. The methods performed similarly for both low-grade and high-grade EC. A more comprehensive US protocol had no significant advantages over a single wide interval and IHC in this study population. A pankeratin IHC stain enhances metastasis detection. Additional studies are required to further test this limited protocol as well as to evaluate the clinical significance of the low volume disease detected by ultrastaging.