Mohs surgery for female genital Paget's disease: a prospective observational trial.

BACKGROUND: Extramammary Paget's disease recurs often after traditional surgical excision. Margin-controlled surgery improves the recurrence rate for male genital disease but is less studied for female anatomy. OBJECTIVE: This study aimed to compare surgical and oncologic outcomes of margin-controlled surgery vs traditional surgical excision for female genital Paget's disease. STUDY DESIGN: We conducted a prospective observational trial of patients with vulvar or perianal Paget's disease treated with surgical excision guided by Mohs micrographic surgery between 2018 and 2022. The multidisciplinary protocol consisted of office-based scouting biopsies and modified Mohs surgery followed by surgical excision with wound closure under general anesthesia. Modified Mohs surgery cleared peripheral disease margins using a moat technique with cytokeratin 7 staining. Medial disease margins (the clitoris, urethra, vagina, and anus) were assessed using a hybrid of Mohs surgery and intraoperative frozen sections. Surgical and oncologic outcomes were compared with the outcomes of a retrospective cohort of patients who underwent traditional surgical excision. The primary outcome was 3-year recurrence-free survival. RESULTS: Three-year recurrence-free survival was 93.3% for Mohs-guided excision (n=24; 95% confidence interval, 81.5%-100.0%) compared to 65.9% for traditional excision (n=63; 95% confidence interval, 54.2%-80.0%) (P=.04). The maximum diameter of the excisional specimen was similar between groups (median, 11.3 vs 9.5 cm; P=.17), but complex reconstructive procedures were more common with the Mohs-guided approach (66.7% vs 30.2%; P<.01). Peripheral margin clearance was universally achieved with modified Mohs surgery, but positive medial margins were noted in 9 patients. Reasons included intentional organ sparing and poor performance of intraoperative hematoxylin and eosin frozen sections without cytokeratin 7. Grade 3 or higher postoperative complications were rare (0.0% for Mohs-guided excision vs 2.4% for traditional excision; P=.99). CONCLUSION: Margin control with modified Mohs surgery significantly improved short-term recurrence-free survival after surgical excision for female genital Paget's disease. Use on medial anatomic structures (the clitoris, urethra, vagina, and anus) is challenging, and further optimization is needed for margin control in these areas. Mohs-guided surgical excision requires specialized, collaborative care and may be best accomplished at designated referral centers.

Into the future: A pilot study combining imaging with molecular profiling to predict resectability in ovarian cancer.

OBJECTIVE: We sought to determine the predictive value of combining tumor molecular subtype and computerized tomography (CT) imaging for surgical outcomes after primary cytoreductive surgery in advanced stage high-grade serous ovarian cancer (HGSOC) patients. METHODS: We identified 129 HGSOC patients who underwent pre-operative CT imaging and post-operative tumor mRNA profiling. A continuous CT-score indicative of overall disease burden was defined based on six imaging measurements of anatomic involvement. Molecular subtypes were derived from mRNA profiling of chemo-naïve tumors and classified as mesenchymal (MES) subtype (36%) or non-MES subtype (64%). Fischer exact tests and multivariate logistic regression examined residual disease and surgical complexity. RESULTS: Women with higher CT-scores were more likely to have MES subtype tumors (p = 0.014). MES subtypes and a high CT-score were independently predictive of macroscopic disease and high surgical complexity. In multivariate models adjusting for age, stage and American Society of Anesthesiologists (ASA) score, patients with a MES subtype and high CT-score had significantly elevated risk of macroscopic disease (OR = 26.7, 95% CI = [6.42, 187]) and were more likely to undergo high complexity surgery (OR = 9.53, 95% CI = [2.76, 40.6], compared to patients with non-MES tumor and low CT-score. CONCLUSION: Preoperative CT imaging combined with tumor molecular subtyping can identify a subset of women unlikely to have resectable disease and likely to require high complexity surgery. Along with other clinical factors, these may refine predictive scores for resection and assist treatment planning. Investigating methods for pre-surgical molecular subtyping is an important next step.

Ultrastaging of 'negative' pelvic lymph nodes in patients with low- and intermediate-risk endometrioid endometrial cancer who developed non-vaginal recurrences.

OBJECTIVE: Evidence on micrometastases and isolated tumor cells as factors associated with non-vaginal recurrence in low- and intermediate-risk endometrial cancer is limited. The goal of our study was to investigate risk factors for non-vaginal recurrence in low- and intermediate-risk endometrial cancer. METHODS: Records of all patients with endometrial cancer surgically managed at the Mayo Clinic before sentinel lymph node implementation (1999-2008) were reviewed. We identified all patients with endometrioid low-risk (International Federation of Gynecology and Obstetrics (FIGO) stage I, grade 1 or 2 with myometrial invasion <50% and negative peritoneal cytology) or intermediate-risk (FIGO stage I, grade 1 or 2 with myometrial invasion ≥50% or grade 3 with myometrial invasion <50% and negative peritoneal cytology) endometrial cancer at definitive pathology after pelvic and para-aortic lymph node assessment. All pelvic lymph nodes of patients with non-vaginal recurrence (any recurrence excluding isolated vaginal cuff recurrences) underwent ultrastaging. RESULTS: Among 1303 women, we identified 321 patients with low-risk (n=236) or intermediate-risk (n=85) endometrial cancer (median age 65.4 years; 266 (82.9%) stage IA; 55 (17.1%) stage IB). Of the total of 321, 13 patients developed non-vaginal recurrence (Kaplan-Meier rate 4.7% by 60 months; 95% CI 2.1% to 7.2%): 11 hematogenous/peritoneal and two para-aortic and distant lymphatic. Myometrial invasion and lymphovascular space invasion were univariately associated with non-vaginal recurrence. In these patients, the original hematoxylin/eosin slides review confirmed all 646 pelvic and para-aortic removed lymph nodes as negative. The ultrastaging of 463 pelvic lymph nodes did not identify any occult metastases (prevalence 0%; 95% CI 0% to 22.8% considering 13 patients; 95% CI 0% to 0.8% considering 463 pelvic lymph nodes). CONCLUSION: There were no occult metastases in pelvic lymph nodes of patients with low- or intermediate-risk endometrial cancer with non-vaginal recurrence. Myometrial invasion and lymphovascular space invasion appear to be associated with non-vaginal recurrence.

Adjuvant brachytherapy for FIGO stage I serous or clear cell endometrial cancer.

OBJECTIVES: Optimal adjuvant treatment for early-stage clear cell and serous endometrial cancer remains unclear. We report outcomes for women with surgically staged International Federation of Gynecology and Obstetrics (FIGO) stage I clear cell, serous, and mixed endometrial cancers following adjuvant vaginal cuff brachytherapy with or without chemotherapy. METHODS: From April 1998 to January 2020, women with FIGO stage IA-IB clear cell, serous, and mixed endometrial cancer underwent surgery and adjuvant vaginal cuff brachytherapy. Seventy-six patients received chemotherapy. High-dose rate vaginal cuff brachytherapy was planned to a total dose of 21 gray in three fractions using a multichannel vaginal cylinder. The primary objective was to determine the effectiveness of adjuvant vaginal cuff brachytherapy and to identify surgicopathological risk factors that could portend towards worse oncological outcomes. RESULTS: A total of 182 patients were included in the analysis. Median follow-up was 5.3 years (2.3-12.2). Ten-year survival was 73.3%. Five-year cumulative incidence (CI) of vaginal, pelvic, and para-aortic relapse was 1.4%, 2.1%, and 0.9%, respectively. Five-year locoregional failure, any recurrence, peritoneal relapse, and other distant recurrence was 4.4%, 11.6%, 5.3%, and 6.7%, respectively. On univariate analysis, locoregional failure was worse for larger tumors (per 1 cm) (HR 1.9, 95% CI 1.2 to 3.0, p≤0.01). Any recurrence was worse for tumors of at least 3.5 cm (HR 3.8, 95% CI 1.3 to 11.7, p=0.02) and patients with positive/suspicious cytology (HR 4.4, 95% CI 1.5 to 12.4, p≤0.01). Ten-year survival for tumors of at least 3.5 cm was 56.9% versus 86.6% for those with smaller tumors (HR 2.9, 95% CI 1.4 to 5.8, p≤0.01). Ten-year survival for positive/suspicious cytology was 50.9% versus 77.4% (HR 2.2, 95% CI 0.9 to 5.4, p=0.09). Multivariate modeling demonstrated worse locoregional failure, any recurrence, and survival with larger tumors, as well as any recurrence with positive/suspicious cytology. Subgroup analysis demonstrated improved outcomes with the use of adjuvant chemotherapy in patients with large tumors or positive/suspicious cytology. CONCLUSION: Adjuvant vaginal cuff brachytherapy alone without chemotherapy is an appropriate treatment for women with negative peritoneal cytology and small, early-stage clear cell, serous, and mixed endometrial cancer. Larger tumors or positive/suspicious cytology are at increased risk for relapse and worse survival, and should be considered for additional upfront adjuvant treatments, such as platinum-based chemotherapy.

Intraoperative Pathologic Margin Analysis and Re-Excision to Minimize Reoperation for Patients Undergoing Breast-Conserving Surgery.

BACKGROUND: Reoperation rates following breast-conserving surgery (BCS) range from 10 to 40%, with marked surgeon and institutional variation. OBJECTIVE: The aim of this study was to identify factors associated with intraoperative margin re-excision, evaluate for any differences in local recurrence based on margin re-excision and determine reoperation rates with use of intraoperative margin analysis. PATIENTS AND METHODS: We analyzed consecutive patients with ductal carcinoma in situ (DCIS) or invasive breast cancer who underwent BCS at our institution between 1 January 2005 and 31 December 2016. Routine intraoperative frozen section margin analysis was performed and positive or close margins were re-excised intraoperatively. Univariate analysis was used to compare margin status and the Kaplan-Meier method was used to compare recurrence. Multivariable logistic regression was utilized to analyze factors associated with re-excision. RESULTS: We identified 3201 patients who underwent BCS-688 for DCIS and 2513 for invasive carcinoma. Overall, 1513 (60.2%) patients with invasive cancer and 434 (63.1%) patients with DCIS had close or positive margins that underwent intraoperative re-excision. Margin re-excision was associated with larger tumor size in both groups. The permanent pathology positive margin rate among all patients was 1.2%, and the 30-day reoperation rate for positive margins was 1.1%. Five-year local recurrence rates were 0.6% and 1.2% for patients with DCIS and invasive cancer, respectively. There was no difference in recurrence between patients with and without intraoperative margin re-excision (p = 0.92). CONCLUSION: Both DCIS and invasive carcinoma had similar rates of intraoperative margin re-excision. Although intraoperative margin re-excision was common, the reoperation rate was extremely low and there was no difference in recurrence between those with or without intraoperative re-excision.

Role of adjuvant therapy in stage IIIC2 endometrial cancer.

OBJECTIVE: The role of the different types of adjuvant treatments in endometrial cancer with para-aortic node metastases is unclear. The aim of this study was to report oncologic outcomes after adjuvant therapy in patients with stage IIIC2 endometrial cancer. METHODS: This retrospective single-institution study assessed patients with stage IIIC2 endometrial cancer who underwent primary surgery from January 1984 to December 2014. All patients had hysterectomy (±salpingo-oophorectomy) plus lymphadenectomy (para-aortic nodes, ±pelvic nodes). We included all patients with stage III endometrial cancer and documented para-aortic lymph node metastases (International Federation of Obstetrics and Gynecologists stage IIIC2). We excluded patients who did not provide consent, who had synchronous cancer, or who underwent neoadjuvant chemotherapy. Follow-up was restricted to the first 5 years post-operatively. Cox proportional hazards models, with age as the time scale, was used to evaluate associations of risk factors with disease-free survival and overall survival. RESULTS: Among 105 patients with documented adjuvant therapy, external beam radiotherapy was administered to 25 patients (24%), chemotherapy to 24 (23%), and a combination (chemotherapy and external beam radiotherapy) to 56 (53%) patients. Most patients receiving chemotherapy and external beam radiotherapy (80%) had chemotherapy first. The majority of relapses had a distant component (31/46, 67%) and only one patient had an isolated para-aortic recurrence. Non-endometrioid subtypes had poorer disease-free survival (HR 2.57; 95% CI 1.38 to 4.78) and poorer overall survival (HR 2.00; 95% CI 1.09 to 3.65) compared with endometrioid. Among patients with endometrioid histology (n=60), chemotherapy and external beam radiotherapy improved disease-free survival (HR 0.22; 95% CI 0.07 to 0.71) and overall survival (HR 0.28; 95% CI 0.09 to 0.89) compared with chemotherapy or external beam radiotherapy alone. Combination therapy did not improve prognosis for patients with non-endometrioid histology (n=45). CONCLUSIONS: In our cohort of patients with stage IIIC2 endometrioid endometrial cancer, those receiving chemotherapy and external beam radiotherapy had improved survival compared with patients receiving chemotherapy or external beam radiotherapy alone. However, the prognosis of patients with non-endometrioid endometrial cancer remained poor, regardless of the adjuvant therapy administered. Distant recurrences were the most common sites of failure.

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases.

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

Ultrastaging of negative pelvic lymph nodes to decrease the true prevalence of isolated paraaortic dissemination in endometrial cancer.

OBJECTIVE: This study aimed to determine the prevalence of occult pelvic lymph node metastasis in patients with endometrial cancer (EC) with isolated paraaortic dissemination who underwent pelvic and paraaortic lymphadenectomy. METHODS: From 2004 to 2008, patients undergoing surgery for EC at our institution were prospectively treated according to a validated surgical algorithm relying on intraoperative frozen section. For the current study, we re-reviewed pathologic slides obtained at the time of diagnosis and performed ultrastaging of all negative pelvic lymph nodes to assess the prevalence of occult pelvic lymph node metastasis. RESULTS: Of 466 patients at risk for lymphatic dissemination, 394 (84.5%) underwent both pelvic and paraaortic lymphadenectomy. Of them, 10 (2.5%) had isolated paraaortic metastasis. Pathologic review of hematoxylin-eosin-stained slides identified 1 patient with micrometastasis in 1 of 18 pelvic lymph nodes removed. Ultrastaging of 296 pelvic lymph nodes removed from the 9 other patients (median [range], 32 [20-50] nodes per patient) identified 2 additional cases (1 with micrometastasis and 1 with isolated tumor cells), for a total of 3/10 patients (30%) having occult pelvic dissemination. CONCLUSIONS: Ultrastaging and pathologic review of negative pelvic lymph nodes of patients with presumed isolated paraaortic metastasis can identify occult pelvic dissemination and reduce the prevalence of true isolated paraaortic disease. In the era of the sentinel lymph node (SLN) algorithm for EC staging, which incorporates ultrastaging of the SLNs removed, these findings demonstrate that use of the SLN algorithm can further mitigate the concern of missing cases of isolated paraaortic dissemination.

Role of lymphadenectomy in endometrial cancer with nonbulky lymph node metastasis: Comparison of comprehensive surgical staging and sentinel lymph node algorithm.

OBJECTIVES: To compare survival and progression outcomes between 2 nodal assessment approaches in patients with nonbulky stage IIIC endometrial cancer (EC). METHODS: Patients with stage IIIC EC treated at 2 institutions were retrospectively identified. At 1 institution, a historical series (2004-2008) was treated with systematic pelvic and para-aortic lymphadenectomy (LND cohort). At the other institution, more contemporary patients (2006-2013) were treated using a sentinel lymph node algorithm (SLN cohort). Outcomes (hazard ratios [HRs]) within the first 5 years after surgery were compared between cohorts using Cox models adjusted for type of adjuvant therapy. RESULTS: The study included 104 patients (48 LND, 56 SLN). The use of chemoradiotherapy was similar in the 2 cohorts (46% LND vs 50% SLN), but the use of chemotherapy alone (19% vs 36%) or radiotherapy alone (15% vs 2%) differed. Although there was evidence of higher risk of cause-specific death (HR, 2.10; 95% CI, 0.79-5.58; P = 0.14) and lower risk of para-aortic progression (HR, 0.27; 95% CI, 0.05-1.42; P = 0.12) for the LND group, the associations did not meet statistical significance. The risk of progression was not significantly different between the groups (HR, 1.27; 95% CI, 0.60-2.67; P =0 .53). In parsimonious multivariable models, high-risk tumor characteristics and nonendometrioid type were independently associated with lower cause-specific survival and progression-free survival. CONCLUSIONS: In EC patients with nonbulky positive lymph nodes, use of the SLN algorithm with limited nodal dissection does not compromise survival compared with LND. Aggressive pathologic features of the primary tumor are the strongest determinants of prognosis.

Sentinel lymph node biopsy with cervical injection of indocyanine green in apparent early-stage endometrial cancer: predictors of unsuccessful mapping.

OBJECTIVE: To identify predictors of unsuccessful sentinel lymph node (SLN) mapping in patients with apparent early-stage endometrial cancer (EC) undergoing surgical staging with cervical injection of indocyanine green and SLN biopsy. METHODS: We retrospectively identified consecutive patients with EC with attempted SLN biopsy between June 2014 and June 2016 at our institution. Patients were grouped according to whether they had a successful procedure, defined as the bilateral identification of SLNs, or an unsuccessful procedure, defined as unilateral or no SLN mapping. Logistic regression was used to evaluate predictors of an unsuccessful procedure. RESULTS: Among 327 patients included in the analysis, 256 (78.3%) had a successful procedure and 71 (21.7%) had an unsuccessful procedure (15.0% unilateral SLN mapping, 6.7% no mapping). The rate of successful procedure increased from 57.7% to 83.3% between the first and last quarters of the 2-year study period, which represented the learning curve for the technique. The mean (SD) operative time decreased from 164 (55) to 137 (37) minutes. By multivariable analysis, lysis of adhesions at the beginning of surgery (odds ratio, 3.07; 95% CI, 1.56-6.07) and the presence of enlarged lymph nodes (odds ratio, 4.69; 95% CI, 1.82-12.11) were independently associated with an unsuccessful procedure. CONCLUSIONS: Lysis of adhesions at the beginning of surgery and the presence of enlarged lymph nodes independently affect the bilateral detection of SLNs.

Uterine serous carcinoma: Reassessing effectiveness of platinum-based adjuvant therapy.

OBJECTIVE: Two randomized trials failed to demonstrate efficacy of platinum-based chemotherapy (PbCT) for uterine serous carcinoma (USC). Our objective was to reassess the value of PbCT for patients with microscopic residuum (R0). METHODS: Progression-free survival (PFS) after surgery was analyzed for 409 patients and correlated with adjuvant therapies: vaginal brachytherapy (VBRT), external beam radiotherapy (EBRT), PbCT, or combinations. RESULTS: The estimated 5-year PFS for stage I (n=209) USC was 65.1% for observation only; 90.7%, VBRT only; and 91.1%, PbCT±VBRT (85% received VBRT); VBRT significantly (P=.004) impacted PFS, but the added value of PbCT remains uncertain. Of 58 stage IIIC, PbCT-treated patients (±EBRT), 5-year PFS was 33.9%; most failures had a vascular disseminated component. Median PFS for 72 stage IV, PbCT-treated patients was 18.6months for R0; 8.0, R1≤1cm residual disease; and 4.6, R2>1cm (P=.008). The progression rate (PR) during 1 to 2year follow-up for R0 was similar to PR during 0-1year follow-up for R1 (P=.31), suggesting recurrences in patients with R0 disease before 2years are likely platinum resistant. PRs during follow-up were nearly identical for R0≥2years and R1≥1year (P=.95), presumably showing limited numbers of platinum-sensitive tumors. CONCLUSIONS: A comparison of PR for patients treated with PbCT for stage IV R0 and R1 disease suggested that a 1-year lag interval precedes clinical recognition of PbCT refractory/resistant R0 disease. Most patients treated with PbCT who had microscopic residuum had recurrences within 2years (across stages), emphasizing the need for more effective therapy.

Genital Rhabdomyoma of the Lower Female Genital Tract: A Study of 12 Cases With Molecular Cytogenetic Findings.

Of the subtypes of extracardiac rhabdomyoma, genital rhabdomyoma is most uncommon and is occasionally classified as fetal rhabdomyoma due to morphologic similarities. In contrast to other forms of rhabdomyoma, the genetic alterations of genital rhabdomyoma are unknown. The clinical and pathologic findings in 12 cases were reviewed and 2 cases were processed for whole genome copy number analysis by single nucleotide polymorphism microarray. Twelve patients ranged in age from 43 to 65 yr (mean: 50.2 yr). Nine tumors arose in the vagina and 3 in the cervix, with their greatest dimension spanning 0.9 to 1.7 cm (mean: 1.4 cm). Follow-up was available for 7 patients and none had evidence of recurrence (67-263 mo, mean: 153.7 mo). No somatic copy number alterations, particularly involving genes in Hedgehog signaling, were identified by microarray. Although genital rhabdomyoma has sufficiently unique clinicopathologic characteristics including age of onset and organs of involvement to distinguish it from fetal rhabdomyoma, the genetic mechanisms underlying its development are unclear given the lack of copy number variation and loss of heterozygosity by single nucleotide polymorphism microarray.

PDGFB Rearrangements in Dermatofibrosarcoma Protuberans of the Vulva: A Study of 11 Cases Including Myxoid and Fibrosarcomatous Variants.

Dermatofibrosarcoma protuberans (DFSP) is a low-grade fibroblastic sarcoma that tends to arise in young to middle age adults and involve the trunk and proximal extremities. Rare examples of vulvar DFSP have been reported, including myxoid, myoid, and fibrosarcomatous variants, but detection of the characteristic t(17;22)(q22;q13) that produces COL1A1-PDGFB gene fusion has not been evaluated in a large series of primary vulvar tumors. The clinical, morphologic, immunohistochemical, and molecular cytogenetic features of 11 cases were examined. Patient age ranged from 29 to 75 yr (mean, 46 yr; median, 43 yr). Seven tumors were purely classic DFSP, 1 was purely myxoid DFSP and the remaining 3 had varying quantities of fibrosarcomatous DFSP. All cases of classic DFSP had diffuse expression of CD34 and low-level p53 immunoreactivity. Myxoid variants had strong, but reduced expression of CD34. Fibrosarcomatous DFSP showed focal CD34 expression and increased p53 reactivity. Nine of 11 tumors (82%) had rearrangement of PDGFB by fluorescence in situ hybridization. The 2 nonrearranged tumors were a classic DFSP and a myxoid DFSP with fibrosarcomatous transformation. Follow-up was available for 9 patients (82%) and ranged from 1 to 108 mo (mean, 30 mo; median, 21 mo). Eight patients had tumors with positive margins, one of which developed local recurrence after no further therapy. No patient developed metastasis. The high frequency of PDGFB rearrangement in vulvar DFSP provides a useful exploit in diagnostically challenging cases and genetic evidence of probable clinical response to targeted therapeutics in cases of locally advanced or metastatic tumors.

Selective Use of Sentinel Lymph Node Surgery in Patients Undergoing Prophylactic Mastectomy Using Intraoperative Pathology.

BACKGROUND: Routine sentinel lymph node (SLN) surgery during prophylactic mastectomy (PM) is unnecessary, because most PMs do not contain cancer. Our institution utilizes intraoperative pathology to guide the surgical decision for resection of SLNs in PM. The purpose of this study was to review the effectiveness of this approach. METHODS: We identified all women aged ≥18 years who underwent bilateral PM (BPM) or contralateral PM (CPM) at our institution from January 2008 to July 2016. We evaluated the frequency of SLN resection and rate of occult breast cancer (DCIS or invasive disease) in the PM. We used the following definitions: over-treatment-SLN surgery in patients without cancer; under-treatment-no SLN surgery in patients with cancer; appropriate treatment-no SLN in patients without cancer or SLN surgery in patients with cancer. RESULTS: PM was performed on 1900 breasts: 1410 (74.2%) CPMs and 490 (25.8%) BPMs. Cancer was identified in 58 (3.0%) cases (32 invasive disease and 26 DCIS) and concurrent SLN surgery was performed in 44 (75.9%) of those cases. Overall, SLN surgery guided by intraoperative pathology resulted in appropriate treatment of 1787 (94.1%) cases: 1319 (93.5%) CPMs and 468 (95.5%) BPMs, by avoiding SLN in 1743/1842 cases without cancer (94.6%), and performing SLN surgery in 44/58 cases with cancer (75.9%). CONCLUSIONS: Use of intraoperative pathology to direct SLN surgery in patients undergoing PM minimizes over-treatment from routine SLN in PM and minimizes under-treatment from avoiding SLN in PM, demonstrating the value of intraoperative pathology in this era of focus on appropriateness of care.

Comparison of a sentinel lymph node mapping algorithm and comprehensive lymphadenectomy in the detection of stage IIIC endometrial carcinoma at higher risk for nodal disease.

OBJECTIVE: To determine if a sentinel lymph node (SLN) mapping algorithm will detect metastatic nodal disease in patients with intermediate-/high-risk endometrial carcinoma. METHODS: Patients were identified and surgically staged at two collaborating institutions. The historical cohort (2004-2008) at one institution included patients undergoing complete pelvic and paraaortic lymphadenectomy to the renal veins (LND cohort). At the second institution an SLN mapping algorithm, including pathologic ultra-staging, was performed (2006-2013) (SLN cohort). Intermediate-risk was defined as endometrioid histology (any grade), ≥50% myometrial invasion; high-risk as serous or clear cell histology (any myometrial invasion). Patients with gross peritoneal disease were excluded. Isolated tumor cells, micro-metastases, and macro-metastases were considered node-positive. RESULTS: We identified 210 patients in the LND cohort, 202 in the SLN cohort. Nodal assessment was performed for most patients. In the intermediate-risk group, stage IIIC disease was diagnosed in 30/107 (28.0%) (LND), 29/82 (35.4%) (SLN) (P=0.28). In the high-risk group, stage IIIC disease was diagnosed in 20/103 (19.4%) (LND), 26 (21.7%) (SLN) (P=0.68). Paraaortic lymph node (LN) assessment was performed significantly more often in intermediate-/high-risk groups in the LND cohort (P<0.001). In the intermediate-risk group, paraaortic LN metastases were detected in 20/96 (20.8%) (LND) vs. 3/28 (10.7%) (SLN) (P=0.23). In the high-risk group, paraaortic LN metastases were detected in 13/82 (15.9%) (LND) and 10/56 (17.9%) (SLN) (%, P=0.76). CONCLUSIONS: SLN mapping algorithm provides similar detection rates of stage IIIC endometrial cancer. The SLN algorithm does not compromise overall detection compared to standard LND.

Expression signature distinguishing two tumour transcriptome classes associated with progression-free survival among rare histological types of epithelial ovarian cancer.

BACKGROUND: The mechanisms of recurrence have been under-studied in rare histologies of invasive epithelial ovarian cancer (EOC) (endometrioid, clear cell, mucinous, and low-grade serous). We hypothesised the existence of an expression signature predictive of outcome in the rarer histologies. METHODS: In split discovery and validation analysis of 131 Mayo Clinic EOC cases, we used clustering to determine clinically relevant transcriptome classes using microarray gene expression measurements. The signature was validated in 967 EOC tumours (91 rare histological subtypes) with recurrence information. RESULTS: We found two validated transcriptome classes associated with progression-free survival (PFS) in the Mayo Clinic EOC cases (P=8.24 × 10(-3)). This signature was further validated in the public expression data sets involving the rare EOC histologies, where these two classes were also predictive of PFS (P=1.43 × 10(-3)). In contrast, the signatures were not predictive of PFS in the high-grade serous EOC cases. Moreover, genes upregulated in Class-1 (with better outcome) were showed enrichment in steroid hormone biosynthesis (false discovery rate, FDR=0.005%) and WNT signalling pathway (FDR=1.46%); genes upregulated in Class-2 were enriched in cell cycle (FDR=0.86%) and toll-like receptor pathways (FDR=2.37%). CONCLUSIONS: These findings provide important biological insights into the rarer EOC histologies that may aid in the development of targeted treatment options for the rarer histologies.

A Picture is Worth a Thousand Words: Intraoperative Photography as a Quality Metric for Axillary Dissection.

BACKGROUND: The adequacy of an axillary lymph node dissection (ALND) is frequently assessed by the number of LNs pathologically identified. We hypothesized that intraoperative photographs facilitate objective measurement of the surgical quality of an ALND. METHODS: Intraoperative photographs of the axilla were obtained prospectively following ALND by four surgeons. An objective scoring system was created based on the visibility of anatomic landmarks, with a maximum score of 7. Photographs of each case were scored independently by the other three surgeons. Factors thought to influence LN count were evaluated for correlation. Interrater variability was calculated. RESULTS: A total of 115 cases were evaluated: 98 breast and 17 melanoma. Mean LN count was 25.1 (SD 10.5): 23.2 (SD 7.9) for breast and 36.5 (SD 15.8) for melanoma. Ninety percent of cases had a LN count ≥15. Factors associated with a higher number of LNs were melanoma (p < 0.001), visualization of the axillary vein (p = 0.03), and long thoracic nerve (p = 0.04). There was no association with age, body mass index, number of positive LNs, neoadjuvant chemotherapy, or matted LNs. Mean ALND photograph score was 4.8 (SD 1.3). A 1-point change in total score increased the mean LN count by 2.4 (p = 0.002). Correlations for interrater reliability varied from 0.27 to 0.62. CONCLUSIONS: Photographic visualization of axillary anatomic structures correlates with the number of LNs identified on pathology. These findings support initiating a larger study with more surgeons to define the optimal photo metrics of an adequate ALND.

Molecular classification of high grade endometrioid and clear cell ovarian cancer using TCGA gene expression signatures.

BACKGROUND: It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs. METHODS: We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF). RESULTS: We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p<0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype. CONCLUSIONS: Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.

Primary brain metastases of endometrial cancer: A report of 18 cases and review of the literature.

OBJECTIVE: To present a series of brain metastases from endometrial cancer (EC) and describe a comprehensive review of the literature. METHODS: We retrospectively reviewed medical records of 1) patients with cerebral dissemination of EC treated at Mayo Clinic from 1984 to 2001 and 2) all patients referred for treatment of primary brain metastases after primary treatment for EC elsewhere. We also reviewed published case reports and case series describing cerebral spread of EC. RESULTS: Among the 1632 patients treated at Mayo, 14 (0.86%) had primary brain dissemination; 4 additional referral cases were identified (total, 18 patients). In 2 cases (11.1%), diagnosis of brain metastases was made at presentation of EC; in the others, median time to development of brain metastasis was 5 (range, 1-57) months. Median survival was 57 (range, 7-118) months in patients with single cerebral metastases and no extracerebral involvement (n=6); for the remaining 12 patients, median survival was 4 (range, 0-28) months. Among the 6 patients with single brain metastases, complete surgical excision was possible in 5; in that group, the overall survival was 64 (range, 12-118) months. We identified 98 cases of brain metastases of EC in the literature: 58 were primary cerebral metastases. Overall survival after brain dissemination was significantly higher in patients with a single metastasis without other localization and receiving multimodal treatment including surgery and whole-brain radiotherapy. CONCLUSIONS: Single primary brain metastases without extracerebral spread seem to have a relatively favorable prognosis. Aggressive multimodal treatment may include surgery and brain radiation.

Frozen section analysis of SLNs in trunk and extremity melanoma has a high false negative rate but can spare some patients a second operation.

OBJECTIVES: The purpose of this study was to evaluate the accuracy of frozen section (FS) analysis of sentinel lymph nodes (SLN) in melanoma. METHODS: Five hundred seventy-one patients underwent FS analysis of SLN between 1/2000 and12/2010. Surgical and pathological characteristics, recurrence, and survival were analyzed. Comparisons were made using χ2 and Fisher's exact t-test. RESULTS: One hundred thirty-three (23%) patients were SLN positive of which 63 (47.4%) were identified on FS. 16/70 SLN metastases not identified on FS (23%) were seen only on immunohistochemistry. FS analysis detected 84% of SLN metastasis >2 mm. SLN FS false negative rate was 53%, positive predictive value 100%, negative predictive value 88%, and overall accuracy 89%. Among patients with a FS positive SLN, 17/63 (27%) had additional positive nodes on CLND, versus 1 of 70 (1.4%) with a positive SLN identified only on permanent section pathology (P < 0.0001). The nodal recurrence rate following a negative SLN biopsy was 5%. CONCLUSIONS: FS analysis for SLNs spared approximately half of patients a second operation. Patients with a positive SLN detected on FS were more likely to have further nodal involvement. In our experience intraoperative pathologic analysis of melanoma SLNs does not impair our ability to detect SLN metastasis or lead to a high rate of false positive results or nodal recurrences. J. Surg. Oncol. 2016;114:879-883. © 2016 2016 Wiley Periodicals, Inc.