Joyce N. Barlin

Pathologic ultrastaging improves micrometastasis detection in sentinel lymph nodes during endometrial cancer staging.

Objective To describe the incidence of low-volume ultrastage-detected metastases in sentinel lymph nodes (SLNs) identified at surgical staging for endometrial carcinoma and to correlate it with depth of myoinvasion and tumor grade. Methods We reviewed all patients who underwent primary surgery for endometrial carcinoma with successful mapping of at least one SLN at our institution from September 2005 to December 2011. All patients underwent a cervical injection for mapping. The SLN ultrastaging protocol involved cutting an additional 2 adjacent 5-μm sections at each of 2 levels, 50-μm apart, from each paraffin block lacking metastatic carcinoma on routine hematoxylin and eosin (H&E) staining. At each level, one slide was stained with H&E and with immunohistochemistry (IHC) using anticytokeratin AE1:AE3. Micrometastases (tumor deposits >0.2 mm and ≤2 mm) and isolated tumor cells (≤0.2 mm) were classified as low-volume ultrastage-detected metastases if pathologic ultrastaging was the only method allowing detection of such nodal disease. Results Of 508 patients with successful mapping, 413 patients (81.3%) had endometrioid carcinoma. Sixty-four (12.6%) of the 508 patients had positive nodes: routine H&E detected 35 patients (6.9%), ultrastaging detected an additional 23 patients (4.5%) who would have otherwise been missed (4 micrometastases and 19 isolated tumor cells), and 6 patients (1.2%) had metastatic disease in their non-SLNs. The incidence rates of low-volume ultrastage-detected nodal metastases in patients with grades 1, 2, and 3 tumors were 3.8%, 3.4%, and 6.9%, respectively. The frequency rates of low-volume ultrastage-detected metastases in patients with a depth of myoinvasion of 0, less than 50%, and 50% or more were 0.8%, 8.0%, and 7.4%, respectively. Lymphovascular invasion was present in 20 (87%) of the cases containing low-volume ultrastage-detected metastases in the lymph nodes. Conclusions Sentinel lymph node mapping with pathologic ultrastaging in endometrial carcinoma detects additional low-volume metastases (4.5%) that would otherwise go undetected with routine evaluations. Our data support the incorporation of pathologic ultrastaging of SLNs in endometrial carcinoma with any degree of myoinvasion. The oncologic significance of low-volume nodal metastases requires long-term follow-up.

Cytoreductive surgery for advanced or recurrent endometrial cancer: A meta-analysis

OBJECTIVE To determine the relative effect and quantify the impact of multiple prognostic variables on median overall survival time among cohorts of patients with advanced or recurrent endometrial cancer undergoing cytoreductive surgery. METHODS Fourteen retrospective cohorts with advanced or recurrent endometrial cancer (672 patients) meeting study inclusion criteria were identified. Univariate analysis was used to assess the effect on median overall survival time of multiple variables. The limited number of studies available made multivariate analysis impractical. RESULTS Statistically significant clinical variables associated with median overall survival time were the proportion of patients undergoing complete surgical cytoreduction, adjuvant radiation, or receiving adjuvant chemotherapy. Cohort median overall survival time was positively associated with increasing proportion of patients undergoing complete surgical cytoreduction (each 10% increase improving survival by 9.3 months, p=0.04) and receiving post-operative radiation therapy (each 10% increase improving survival by 11.0 months, p=0.004), while an increasing proportion of patients receiving chemotherapy was negatively associated with survival (each 10% increase decreasing survival by 10.4 months, p=0.007). CONCLUSIONS The current analysis suggests that among patients with advanced or recurrent endometrial cancer, complete cytoreduction to no gross residual disease is associated with superior overall survival outcome. The unexpected correlation between treatment modality and survival may be a surrogate marker for more precise factors such as location of disease, performance status, or cytoreductive status post-operatively, which may have influenced the decision to administer adjuvant radiation versus chemotherapy and were not able to be controlled for given the limitations of the extracted data.

Nomogram for predicting 5-year disease-specific mortality after primary surgery for epithelial ovarian cancer

OBJECTIVE To develop a nomogram based on established prognostic factors to predict the probability of 5-year disease-specific mortality after primary surgery for patients with all stages of epithelial ovarian cancer (EOC) and compare the predictive accuracy with the currently used International Federation of Gynecology and Obstetrics (FIGO) staging system. METHODS Using a prospectively kept database, we identified all patients with EOC who had their primary surgery at our institution between January 1996 and December 2004. Disease-specific mortality was estimated using the Kaplan-Meier method. Twenty-eight clinical and pathologic factors were analyzed. Significant factors on univariate analysis were included in the Cox proportional hazards regression model, which identified factors utilized in the nomogram. The concordance index (CI) was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed. RESULTS A total of 478 patients with EOC were included. The most predictive nomogram was constructed using seven variables: age, FIGO stage, residual disease status, preoperative albumin level, histology, family history suggestive of hereditary breast/ovarian cancer (HBOC) syndrome, and American Society of Anesthesiologists (ASA) status. This nomogram was internally validated using bootstrapping and shown to have excellent calibration with a bootstrap-corrected CI of 0.714. The CI for FIGO staging alone was significantly less at 0.62 (P=0.002). CONCLUSION We have developed an all-stage nomogram to predict 5-year disease-specific mortality after primary surgery for epithelial ovarian cancer. This tool is more accurate than FIGO staging and should be useful for patient counseling, clinical trial eligibility, postoperative management, and follow-up.

Progression-free and overall survival of a modified outpatient regimen of primary intravenous/intraperitoneal paclitaxel and intraperitoneal cisplatin in ovarian, fallopian tube, and primary peritoneal cancer

OBJECTIVE GOG study 172 demonstrated improved progression-free (PFS) and overall (OS) survival for patients with stage III optimally debulked ovarian and peritoneal carcinoma treated with IV/IP paclitaxel and IP cisplatin compared to standard IV therapy. The inpatient administration, toxicity profile, and limited completion rate have been blamed for the lack of acceptance and widespread use of this regimen. We sought to evaluate the PFS, OS, toxicity, and completion rate of a modified outpatient IP regimen. METHODS Using a prospectively maintained database, we evaluated the outcomes of patients who underwent primary optimal cytoreduction for stage III ovarian, tubal, or peritoneal carcinoma followed by IV/IP chemotherapy from 1/05-3/09. Our modified regimen was as follows: IV paclitaxel (135 mg/m(2)) over 3h on day 1, IP cisplatin (75 mg/m(2)) on day 2, and IP paclitaxel (60 mg/m(2)) on day 8, given every 21 days for 6 cycles. RESULTS We identified 102 patients who initiated the modified IV/IP regimen and completed chemotherapy. The median follow-up was 43 months. The median age at diagnosis was 57 years (range, 23-76). Primary disease site was: ovary, 77 (75%); fallopian tube, 13 (13%); peritoneum, 12 (12%). FIGO stage was: IIIA, 8 (8%); IIIB, 4 (4%); IIIC, 90 (88%). Residual disease after cytoreduction was: none, 58 (57%); ≤ 1 cm, 44 (43%). The most frequent grade 3/4 toxicities were: neutropenia, 12 (12%); gastrointestinal, 8 (8%); neurologic, 6 (6%). Eighty-two (80%) of 102 patients completed 4 or more cycles of IV/IP therapy; 56 (55%) completed all 6 cycles. The median PFS and OS were 29 and 67 months, respectively. CONCLUSIONS By modifying the GOG 172 treatment regimen, convenience, toxicity, and tolerability appear improved, with survival outcomes similar to those of GOG 172. This modified IV/IP regimen warrants further study.

Classification and regression tree (CART) analysis of endometrial carcinoma: Seeing the forest for the trees

OBJECTIVE The objectives of the study are to evaluate which clinicopathologic factors influenced overall survival (OS) in endometrial carcinoma and to determine if the surgical effort to assess para-aortic (PA) lymph nodes (LNs) at initial staging surgery impacts OS. METHODS All patients diagnosed with endometrial cancer from 1/1993-12/2011 who had LNs excised were included. PALN assessment was defined by the identification of one or more PALNs on final pathology. A multivariate analysis was performed to assess the effect of PALNs on OS. A form of recursive partitioning called classification and regression tree (CART) analysis was implemented. Variables included: age, stage, tumor subtype, grade, myometrial invasion, total LNs removed, evaluation of PALNs, and adjuvant chemotherapy. RESULTS The cohort included 1920 patients, with a median age of 62 years. The median number of LNs removed was 16 (range, 1-99). The removal of PALNs was not associated with OS (P=0.450). Using the CART hierarchically, stage I vs. stages II-IV and grades 1-2 vs. grade 3 emerged as predictors of OS. If the tree was allowed to grow, further branching was based on age and myometrial invasion. Total number of LNs removed and assessment of PALNs as defined in this study were not predictive of OS. CONCLUSION This innovative CART analysis emphasized the importance of proper stage assignment and a binary grading system in impacting OS. Notably, the total number of LNs removed and specific evaluation of PALNs as defined in this study were not important predictors of OS.

Validated gene targets associated with curatively treated advanced serous ovarian carcinoma

OBJECTIVES High-grade serous ovarian cancer (HGSOC) mostly presents at an advanced stage and has a low overall survival rate. However, a subgroup of patients are seemingly cured after standard initial therapy. We hypothesize that the molecular profiles of these patients vary from long-term survivors who recur. METHODS Patients with advanced HGSOC who underwent primary cytoreductive surgery and platinum-based chemotherapy were identified from The Cancer Genome Atlas (TCGA) and institutional (MSKCC) samples. A curative-intent group was defined by recurrence-free survival of >5years. A long-term recurrent group was composed of patients who recurred but survived >5years. RNA was hybridized to Affymetrix U133A transcription microarrays. The NanoString nCounter gene expression system was used for validation in an independent patient population. RESULTS In 30 curative and 84 recurrent patients, class comparison identified twice as many differentially expressed probes between the groups than expected by chance alone. TCGA and MSKCC data sets had 19 overlapping genes. Pathway analyses identified over-represented networks that included nuclear factor kappa B (NFkB) transcription and extracellular signal-regulated kinase (ERK) signaling. External validation was performed in an independent population of 28 curative and 38 recurrent patients. Three genes (CYP4B1, CEPT1, CHMP4A) in common between our original data sets remained differentially expressed in the external validation data. CONCLUSIONS There are distinct transcriptional elements in HGSOC from patients likely to be cured by standard primary therapy. Three genes have withstood rigorous validation and are plausible targets for further study, which may provide insight into molecular features associated with long-term survival and chemotherapy resistance mechanisms.

Optimal (≤1 cm) but visible residual disease: Is extensive debulking warranted?

OBJECTIVES To determine if extensive upper abdominal surgery (UAS) affected overall survival (OS) in patients left with ≤ 1 cm but visible residual disease after undergoing primary cytoreductive surgery for ovarian cancer. Our secondary objective was to determine if leaving ≤ 1cm but visible residual throughout the small bowel (SB) conferred a worse prognosis. METHODS All stage IIIB-IV ovarian cancer patients who had visible but ≤ 1 cm residual disease at time of primary cytoreductive surgery from 2001 to 2010 were identified. Extensive UAS procedures and residual SB involvement were recorded. RESULTS The 219 patients identified with ≤1 cm but visible residual disease had a median OS of 51 months. In this cohort, 127 had extensive UAS performed, and 87 had residual disease involving the SB. Univariate OS analysis was performed. There was no significant difference in OS between patients who did or did not have extensive UAS (45 vs. 52 months, P=0.56), or between patients with or without residual SB disease (45 vs. 51 months, P=0.84). Factors that were significantly associated with OS were age, ASA score, family history, and stage. CONCLUSIONS Patients cytoreduced to ≤ 1 cm but visible residual disease who required UAS did not have a worse OS than those who did not require UAS. OS was similar if residual disease involved the SB or not. For ovarian cancer patients with disease not amenable to complete gross resection, extensive surgery should still be considered to achieve ≤ 1 cm but visible residual disease status, including cases where the residual disease involves the SB.

Molecular Subtypes of Uterine Leiomyosarcoma and Correlation with Clinical Outcome

The molecular etiology of uterine leiomyosarcoma (ULMS) is poorly understood, which accounts for the wide disparity in outcomes among women with this disease. We examined and compared the molecular profiles of ULMS and normal myometrium (NL) to identify clinically relevant molecular subtypes. Discovery cases included 29 NL and 23 ULMS specimens. RNA was hybridized to Affymetrix U133A 2.0 transcription microarrays. Differentially expressed genes and pathways were identified using standard methods. Fourteen NL and 44 ULMS independent archival samples were used for external validation. Molecular subgroups were correlated with clinical outcome. Pathway analyses of differentially expressed genes between ULMS and NL samples identified overrepresentation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes (P < 4.4 × 10− 4, Bonferroni corrected), with 84% of the overexpressed genes, including CDC7, CDC20, GTSE1, CCNA2, CCNB1, and CCNB2, participating in cell cycle regulation. Unsupervised clustering of ULMS identified two clades that were reproducibly associated with progression-free (median, 4.0 vs 26.0 months; P = .02; HR, 0.33) and overall (median, 18.2 vs 77.2 months; P = .04; HR, 0.33) survival. Cell cycle genes play a key role in ULMS sarcomagenesis, providing opportunities for therapeutic targeting. Reproducible molecular subtypes associated with clinical outcome may permit individualized adjuvant treatment after clinical trial validation.

Follow-up study of the correlation between postoperative computed tomographic scan and primary surgeon assessment in patients with advanced ovarian, tubal, or peritoneal carcinoma reported to have undergone primary surgical cytoreduction to residual disease of 1 cm or smaller

Introduction: We previously reported a 52% correlation between the primary surgeons assessment and the postoperative computed tomographic (CT) scan findings of residual disease in patients reported to have undergone cytoreduction to residual disease of 1 cm or smaller. This is a follow-up analysis of survival and prognostic factors for patients who had concordant and discordant postoperative CT scan findings. Methods: Patients scheduled for primary cytoreductive surgery for presumed advanced ovarian carcinoma were offered enrollment in a prospective study evaluating the ability of preoperative CT scan to predict cytoreductive outcome. If cytoreduction to residual disease of 1 cm or smaller was reported, a CT scan was done 7 to 35 days postoperatively. The CT scan findings were graded by protocol radiologists using a qualitative analysis scale from 1 (normal) to 5 (definitely malignant). Results: From January 2001 to September 2006, 285 patients were enrolled; 67 patients were eligible. Postoperative CT scans confirmed the primary surgeons assessment of no residual disease larger than 1 cm in 38 cases (57%). In 29 cases (43%), the radiologist found residual disease larger than 1 cm and reported it as probably or definitely malignant. Comparing concordant versus discordant findings, there was no significant difference in median progression-free survival (21 vs 17 months; P = 0.365) or overall survival (60 vs 43 months; P = 0.146). Age (P = 0.040), stage (P = 0.038), and residual disease of 0.5 mm or smaller versus 0.6 to 1.0 cm (P = 0.018) were significant for overall survival on multivariate analysis. Conclusions: On this follow-up analysis, only age, stage, and residual disease were significant prognostic factors for overall survival. Discordant findings between the primary surgeons assessment and the postoperative CT scan findings of residual disease was not an independent prognostic factor.

Redefining stage I endometrial cancer: incorporating histology, a binary grading system, myometrial invasion, and lymph node assessment.

Objective We propose a new staging system for stage I endometrial cancer and compare its performance to the 1988 and 2009 International Federation of Gynecology and Obstetrics (FIGO) systems. Methods We analyzed patients with 1988 FIGO stage I endometrial cancer from January 1993 to August 2011. Low-grade carcinoma consisted of endometrioid grade 1 to grade 2 lesions. High-grade carcinoma consisted of endometrioid grade 3 or nonendometrioid carcinomas (serous, clear cell, and carcinosarcoma). The proposed system is as follows: IA. Low-grade carcinoma with less than half myometrial invasion IA1: Negative nodes IA2: No nodes removed IB. High-grade carcinoma with no myometrial invasion IB1: Negative nodes IB2: No nodes removed IC. Low-grade carcinoma with half or greater myometrial invasion IC1: Negative nodes IC2: No nodes removed ID. High-grade carcinoma with any myometrial invasion ID1: Negative nodes ID2: No nodes removed Results Data from 1843 patients were analyzed. When patients were restaged with our proposed system, the 5-year overall survival significantly differed (P < 0.001): IA1, 96.7%; IA2, 92.2%; IB1, 92.2%; IB2, 76.4%; IC1, 83.9%; IC2, 78.6%; ID1, 81.1%; and ID2, 68.8%. The bootstrap-corrected concordance probability estimate for the proposed system was 0.627 (95% confidence interval, 0.590–0.664) and was superior to the concordance probability estimate of 0.530 (95% confidence interval, 0.516–0.544) for the 2009 FIGO system. Conclusions By incorporating histological subtype, grade, myometrial invasion, and whether lymph nodes were removed, our proposed system for stage I endometrial cancer has a superior predictive ability over the 2009 FIGO staging system and provides a novel binary grading system (low-grade including endometrioid grade 1–2 lesions; high-grade carcinoma consisting of endometrioid grade 3 carcinomas and nonendometrioid carcinomas).