Current American Joint Committee Research Articles

Abstract PO3-05-13: A Multi-Institutional Review of Contralateral Axillary Metastases: Time for Reclassification as Local-Regional Event?

Abstract Background Current American Joint Committee on Cancer (AJCC) breast cancer staging considers contralateral axillary metastasis (CAM) stage IV disease (M1). Retrospective studies suggest that women with CAM have improved overall survival (OS) compared to those with distant metastasis (M1) and/or comparable OS to locally advanced breast cancer (LABC). These studies support consideration of curative intent treatment; however, they contain heterogeneous cohorts with highly variable treatment strategies. We sought to evaluate treatment and outcomes in a well-defined CAM cohort treated with contemporary systemic and locoregional therapy. Methods We performed a retrospective multi-institution cohort study to compare OS of patients with CAM matched 1:3 on age +/- 5 years to LABC (defined as cN2-3 and/or pN2-3), and to non-CAM M1. CAM patients classified as type 1) de novo CAM, synchronous with the contralateral primary, 2) metachronous isolated CAM in the setting of prior surgical and/or radiation treatment to primary index cancer, 3) synchronous with, or 4) metachronous after an in-breast or axillary nodal recurrence of the primary index cancer. The M1 cohort included de novo and recurrent metastasis with varied sites and number of metastasis. OS was defined as time from CAM diagnosis to death or last follow-up for CAM patients; time from primary diagnosis to death or last follow-up for LABC; and time from metastatic diagnosis to death or last follow-up for M1. Unadjusted OS was estimated with the Kaplan-Meier method, and Cox proportional hazards models were used to estimate the association of group with OS after adjustment for covariates Results We identified 57 CAM and 155 LABC from 8 institutions (2016-2022), and 632 M1 from a single institution. The median age was similar between groups (CAM=59 years, LABC=58, M1=57, p=0.44), and there were no statistically significant differences in hormone receptor status (p=0.25). There were more Non-Hispanic Black patients in the M1 cohort compared to CAM or LABC (p< 0.001). The majority of CAM cases were delayed metachronous from the index cancer (type 2, 35.1%), or synchronous with a recurrence (type 3, 33.3%). Type 1 (de novo, 14%) and type 4 (delayed metachronous after breast cancer recurrence, 17.5%) were less frequent. Among CAM patients, 49.1% were hormone receptor positive (HR+)/HER2-negative (HER2-), 22.8% HR-/HER2-, 10.5% HR+/HER2+, and 5.3% HR-/HER2+. Comparing CAM versus LABC, invasive ductal carcinoma (IDC) was more commonly seen in CAM (82.5% vs 66.5%), as was grade 3 (45.6% vs 35.5%), and triple negative (22.8% vs 13.5%). Conversely, in LABC, treatment of the primary index cancer more frequently included chemotherapy (CAM=71.9%, LABC=92.3%), mastectomy (CAM=54.4%, LABC 74.2%), and adjuvant radiation (CAM=73.7%, LABC=90.3%). On multivariable analysis adjusting for age, race/ethnicity, and hormone receptor status, both CAM and M1 had inferior survival to LABC (Table 1), but with a 2.4-fold difference for CAM (95% CI 1.42-4.07, p=0.001) versus a 6.3-fold difference for M1 (95% CI 4.29-9.23, p=< 0.001). Discussion In this contemporary, multi-institution study, we demonstrated that CAM patients selected for presumed curative intent treatment experienced improved OS when compared to stage IV (M1) patients. Our data adds additional support for re-evaluating the current stage IV designation, in favor of N3, and consideration of curative intent treatment in this disease. Table. Adjusted* Overall Survival Comparing Patients with Breast Cancer Contralateral Axillary Metastasis (CAM) to those with Locally Advanced Breast Cancer (LABC) and Metastatic Disease (M1) *Adjusted for age, race/ethnicity, hormone receptors. Citation Format: Meghan R. Flanagan, Stephanie Downs-Canner, Samantha Thomas, Astrid Botty van de bruele, Margaret Lillie, Kristalyn Gallagher, Tammeza Gibson, James Jakub, Alexandra Verosky, Sarah Tevis, Malia Brennan, Francys Verdial, Jennifer Q. Zhang, Leisha Elmore, Jennifer Plichta, Laura Rosenberger. A Multi-Institutional Review of Contralateral Axillary Metastases: Time for Reclassification as Local-Regional Event? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-13.

Prognostic impact of prostate-specific membrane antigen positron emission tomography (PSMA PET) staging for clinically node-positive prostate cancer.

In the current American Joint Committee on Cancer staging system, patients with pelvic nodal metastases are considered stage IV prostate cancer. This study aims to investigate whether men with prostate-specific membrane antigen positron emission tomography (PSMA PET)-detected pelvic node-positive prostate cancer at diagnosis have a better outcome compared to men with node-positive disease identified on conventional imaging. This is a retrospective cohort study comparing the outcomes of men with node-positive prostate cancer and disease confined to the pelvis, staged with conventional versus PSMA PET imaging. Men had to be treated definitively with a combination of androgen deprivation therapy and radiation treatment to the prostate and pelvic lymph nodes. Kaplan-Meier and Cox regression analysis was used to compare biochemical failure-free survival (BFFS) and overall survival (OS). Seventy-six men with nodal metastases confined to the pelvis were identified. Fifty-one were detected with PSMA PET while 25 were staged with conventional imaging. PSMA PET staged patients had a lower proportion of Gleason 8-10 disease (78% vs. 96%) as well as a lower median prostate-specific antigen (11 ng/mL vs. 26 ng/mL). BFFS at 4 years was 72% with PSMA PET-detected node-positive disease vs. 38% with conventionally detected node-positive disease. Four-year OS was 93% with PSMA PET staged patients vs. 76% with conventionally staged patients. On multivariate analysis, the PSMA PET staged group was associated with improved BFFS (Adjusted HR = 3.00, 95% CI 1.43, 6.29, P = 0.004) and OS (Adjusted HR = 5.81, 95% CI 1.43, 23.7, P = 0.007). Men with PSMA PET-detected node-positive prostate cancer confined to the pelvis have significantly better biochemical control and survival compared to those with node-positive pelvic disease identified through conventional staging.

A nomogram incorporating treatment data for predicting overall survival in gastroenteropancreatic neuroendocrine tumors: a population-based cohort study.

Over the last few decades, the annual global incidence of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) has steadily increased. Because of the complex and inconsistent treatment of GEP-NETs, the prognosis of patients with GEP-NETs is still difficult to assess. The study aimed to construct and validate the nomograms included treatment data for prediction overall survival (OS) in GEP-NETs patients. GEP-NETs patients determined from the Surveillance, Epidemiology, and End Results (SEER)-13 registry database (1992-2018) and with additional treatment data from the SEER-18 registry database (1975-2016). In order to select independent prognostic factors that contribute significantly to patient survival and can be included in the nomogram, multivariate Cox regression analysis was performed using the minimum value of Akaike information criterion (AIC) and we analyzed the relationship of variables with OS by calculating hazard ratios (HRs) and 95% CIs. In addition, we also comprehensively compared the nomogram using to predict OS with the current 7th American Joint Committee on Cancer (AJCC) staging system. From 2004 to 2015, a total of 42662 patients at diagnosis years with GEP-NETs were determined from the SEER database. The results indicated that the increasing incidence of GEP-NETs per year and the highest incidence is in patients aged 50-54. After removing cases lacking adequate clinicopathologic characteristics, the remaining eligible patients ( n =7564) were randomly divided into training (3782 patients) and testing sets (3782 patients). In the univariate analysis, sex, age, race, tumour location, SEER historic stage, pathology type, TNM, stage, surgery, radiation, chemotherapy, and CS tumour size were found to be significantly related to OS. Ultimately, the key factors for predicting OS were determined, involving sex, age, race, tumour location, SEER historic stage, M, N, grade, surgery, radiation, and chemotherapy. For internal validation, the C-index of the nomogram used to estimate OS in the training set was 0.816 (0.804-0.828). For external validation, the concordance index (C-index) of the nomogram used to predict OS was 0.822 (0.812-0.832). In the training and testing sets, our nomogram produced minimum AIC values and C-index of OS compared with AJCC stage. Decision curve analysis (DCA) indicated that the nomogram was better than the AJCC staging system because more clinical net benefits were obtained within a wider threshold probability range. A nomogram combined treatment data may be better discrimination in predicting overall survival than AJCC staging system. The authors highly recommend to use their nomogram to evaluate individual risks based on different clinical features of GEP-NETs, which can improve the diagnosis and treatment outcomes of GEP-NETs patients and improve their quality of life.

Real-World Evidence Confirms Risk Stratification of the 31-GEP and i31-GEP in Prospectively Tested Patients with Stage I-III Cutaneous Melanoma

Introduction: Current American Joint Committee on Cancer (AJCC 8th edition) guidelines in patients with cutaneous melanoma (CM) separate them into risk categories based on the pathological tumor data of Breslow thickness, ulceration status, and sentinel lymph node status. The 31-gene expression profile was developed and prospectively validated to identify patients considered high or low risk by AJCC with low or high-risk tumor biology who may be over- or under-treated by current guidelines. To further advance personalized patient care, the 31-GEP result was integrated with clinical and pathological factors (i31-GEP for risk of recurrence, ROR) to provide a personalized, precise risk of tumor recurrence. 
 
 Methods: Patients with stage I-III CM enrolled in the CONNECTION study were prospectively tested with the 31-GEP between 2013 and 2017 (n=1,831). Kaplan-Meier analysis with the log-rank test was used to estimate survival differences between low (Class 1A), intermediate (Class 1B/2A), and high (Class 2) risk groups and the i31-GEP risk groups. The i31-GEP ROR combines Breslow thickness, ulceration, SLN status, mitotic rate, tumor location, age, and the 31-GEP result to provide a personalized estimate of recurrence-free survival (RFS). While guidelines have not established a ROR threshold for determining when to escalate or de-escalate care, the NCCN uses stage IIA versus IIB as the cut-point. This cut-point translates to a 5-year RFS rate of 69.8% and was used for the present analysis. Cox multivariable regression analysis was used to identify predictors of recurrence. 
 
 Results: Patients with a Class 1A result had higher 5-year RFS than those with a Class 1B/2A or Class 2B result (94.4% vs. 78.6% vs. 65.5%, p<0.001). The following were significant predictors of recurrence in multivariable analysis: Class 1B/2A (HR=2.07, p<0.001), Class 2B (HR=2.40, p<0.001), positive SLN (HR=4.54, p<0.001), Breslow thickness (HR=1.09, p=0.028), presence of ulceration (HR=1.57, p=0.005), mitotic rate >2/mm2 (HR=1.47, p=0.016), and age (HR=1.02, p<0.001). Patients with a low-risk i31-GEP result had significantly higher 5-year RFS than those considered high risk by the i31-GEP (92.4% vs. 49.7%, p<0.001). 
 
 Conclusions: The i31-GEP is validated in a real-world group of prospectively tested patients. The independent i31-GEP ROR test result improves identification of patients whose management should be escalated or de-escalated within current guidelines.

Development and Methodological Validation of a Modified Staging System for de Novo Metastatic Breast Cancer

Validation of a new method for prognostication of de novo metastatic breast cancer (dnMBC) to better reflect the heterogenecity of the disease. To perform external methodological validation of the Plichta staging system, a novel prognostic system for de novo metastatic breast cancer (dnMBC). This retrospective cohort study used a multicenter, nationwide, population-based Danish Breast Cancer Group database to validate the new method. Participants were patients with dnMBC diagnosed between 2010 and 2019. Data were analyzed from April to June 2023. A recursive partitioning analysis (RPA) was performed, as demonstrated by Plichta and colleagues, to group patients with similar overall survival (OS) based on clinical factors. The main outcome was to group patients into 4 prognostic groups based on 3-year OS as stage IVa, greater than 70%; stage IVb, 50% to 70%; stage IVc, 25% to less than 50%; or stage IVd, less than 25%. Bootstrapping was applied for 1000 iterations, with final stage assignments based on the most commonly occurring assignment. A total of 1859 women were included with a median (IQR) age of 69 (57-77) years. With a median potential follow-up of 89.9 (95% CI, 86.4-95.1) months and a median OS of 31.7 (95% CI, 29.5-34.1) months, the RPA stratified patients into 10 groups, with organ sites, estrogen receptor status, and human epidermal growth factor receptor 2 status as the key clinical factors. Three-year survival rates ranged from 62% (95% CI, 56%-69%) to 8% (95% CI, 3%-21%), which were further combined into 3 stage groups: IVb, 59.4% (95% CI, 56.2%-62.8%); IVc, 39.4% (95% CI, 36.2%-43.0%); and IVd, 15.4% (95% CI, 11.2%-21.3%) (P < .001). Following bootstrapping, an IVa group emerged, resulting in 4 stage groups with separate 3-year OS rates identified as IVa, 75.8% (95% CI, 67.8%-84.7%); IVb, 58.8% (95% CI, 55.5%-62.3%); IVc, 39.2% (95% CI, 35.8%-43.0%); and IVd, 14.4% (95% CI, 10.8%-19.4%) (P < .001). These findings provide external and independent validation of the methods applied in the novel Plichta staging system for dnMBC. This could guide future revisions of the current American Joint Committee on Cancer staging guidelines and may be incorporated as a stratification factor in clinical trials.

Predicting Recurrence-Free and Overall Survival for Patients With Stage II Melanoma: The MIA Calculator.

Improvements in recurrence-free survival (RFS) were demonstrated in two recent randomized trials for patients with sentinel node (SN)-negative stage IIB or IIC melanoma receiving adjuvant systemic therapy (pembrolizumab/nivolumab). However, adverse events also occurred. Accurate individualized prognostic estimates of RFS and overall survival (OS) would allow patients to more accurately weigh the risks and benefits of adjuvant therapy. Since the current American Joint Committee on Cancer eighth edition (AJCC-8) melanoma staging system focuses on melanoma-specific survival, we developed a multivariable risk prediction calculator that provides estimates of 5- and 10-year RFS and OS for these patients. Data were extracted from the Melanoma Institute Australia (MIA) database for patients diagnosed with stage II (clinical or pathological) melanoma (n = 3,220). Survival prediction models were developed using multivariable Cox regression analyses (MIA models) and externally validated twice using data sets from the United States and the Netherlands. Each model's performance was assessed using C-statistics and calibration plots and compared with Cox models on the basis of AJCC-8 staging (stage models). The 5-year and 10-year RFS C-statistics were 0.70 and 0.73 (MIA-model) versus 0.61 and 0.60 (stage-model), respectively. For OS, the 5-year and 10-year C-statistics were 0.71 and 0.75 (MIA-model) compared with 0.62 and 0.61 (stage-model), respectively. The MIA models were well calibrated and externally validated. The MIA models offer accurate and personalized estimates of both RFS and OS in patients with stage II melanoma even in the absence of pathological staging with SN biopsy. These models were robust on external validations and may be used in everyday practice both with (ideally) and without performing SN biopsy to identify high-risk patients for further management strategies. An online tool will be available at the MIA website (Risk Prediction Tools).

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Ulceration represents a key feature in cutaneous melanoma, contributing to staging according to the current American Joint Committee on Cancer (AJCC) system. However, cases with incipient ulceration do not quite fulfill the AJCC definition of ulceration and are consequently classified as nonulcerated, presenting interpretive difficulty for pathologists. The prognostic implication of incipient ulceration is uncertain. To evaluate the prognostic significance of incipient ulceration in cutaneous melanoma. This case-control study consisted of resected primary cutaneous melanomas diagnosed between 2005 and 2015, identified from the Melanoma Institute Australia research database and with slides available for review at Royal Prince Alfred Hospital. Slides were reviewed by pathologists experienced in the diagnosis of melanocytic lesions to identify cases (incipient ulceration) and controls (ulcerated or nonulcerated). Incipient ulceration cases were matched at a 1:2 ratio with nonulcerated and ulcerated controls, respectively. Study analysis was conducted from March to June 2023. Clinicopathological factors and clinical outcomes: overall survival (OS), melanoma-specific survival (MSS), and recurrence-free survival (RFS) were compared between cases and controls. Of 2284 patients with melanoma identified, 340 patients (median [IQR] age, 69 [24-94] years; 136 [68%] men; median follow-up, 7.2 years) met the criteria. The matched cohort consisted of 40 cases of incipiently ulcerated melanoma matched 1:2 with 80 nonulcerated controls, and 80 ulcerated controls. The median (IQR) Breslow thickness differed significantly between cases and controls; 2.8 (1.7-4.1) mm for incipient cases compared with 1.0 (0.6-2.1) mm and 5.3 (3.5-8.0) mm for nonulcerated and ulcerated melanomas, respectively. Median (IQR) tumor mitotic rate was 5.0 (3.0-9.0) per mm2 in incipiently ulcerated cases compared with 1 (0-3.0) per mm2 in nonulcerated controls and 9 (5.0-14.0) per mm2 in ulcerated controls. Based on the matched cohorts, patients with nonulcerated tumors had significantly better OS (hazard ratio [HR], 0.49; 95% CI, 0.27-0.88; P = .02) and RFS (HR, 0.37; 95% CI, 0.22-0.64; P < .001) than patients with incipient ulceration. The RFS was significantly worse in ulcerated tumors compared with incipiently ulcerated cases (HR, 1.67; 95% CI, 1.07-2.60; P = .03). After adjusting for pathological factors, no statistically significant differences in clinical outcomes were observed between cases and either control group. The findings of this case-control study indicate that incipient ulceration in a primary melanoma represents an adverse prognostic feature that should be noted by pathologists in their reports and considered in future guidelines.

The impact of multifocal perineural invasion in predicting survival in patients with oral squamous cell carcinoma: A multicenter investigation.

Perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) does not contribute to the current American Joint Committee on Cancer 8th edition (AJCC8) staging manual. This study seeks to validate the effect of multifocal PNI in a large cohort of patients. Patients undergoing primary surgical treatment of OSCC with curative intent between 1995 and 2022 was retrieved from two Australian head and neck databases. PNI was categorized as a single focus or multiple foci. Study end points included disease-specific survival (DSS) and overall survival (OS). Complete data for survival analysis was available in 993 patients. Multifocal PNI was associated with a 61% increased risk of death due to OSCC (HR 1.61, 95% CI 1.11-2.33, p = 0.014) and a 32% increased risk of death from any cause (HR 1.32, 95% CI 1.01-1.73, p = 0.045). Multifocal PNI is a significant predictor of survival in OSCC.

Early Stage Melanoma of the Vermillion with Mucosal Melanoma in Situ: A Clinical Conundrum

BackgroundMelanoma is a predominantly cutaneous malignancy associated with sun exposure. Mucosal melanoma is rare and carries a distinct pathogenesis from cutaneous tumors. The vermillion of the lip is a unique site that divides cutaneous from mucosal tissues. Tumors arising on the dry aspect are classified as cutaneous and those of the wet aspect are mucosal. The distinction is importation in tumor staging as all mucosal melanomas are classified as T3-T4b under the current 8th edition American Joint Committee of Cancer (AJCC) guidelines.MethodsWe describe a case of early stage melanoma of the vermillion with associated mucosal melanoma in situ. We discuss nuances of management at this site and the distinctions between cutaneous versus mucosal melanomas with a review of the literature.ResultsOur patient was treated surgically with 2-3 cm margins. Residual melanoma in situ was present at the mucosal margin on final pathology which required a second surgery for margin revision. The case was discussed at tumor board with recommendation for no further treatment.ConclusionsThe nuances between the vermillion and mucosal lip must be understood for appropriate staging and treatment of melanomas. The paucity of literature on melanomas affecting this site render management decisions challenging. Multidisciplinary discussion is essential for guiding care.

Abstract #1400120: A Case Report of Papillary Thyroid Carcinoma with Thymic Metastasis

Papillary thyroid carcinomas (PTCA) are one of the most treatable cancers. Distant metastasis may occur, commonly to lungs and bones and is often associated with poorer prognosis. Metastasis to the thymus is extremely rare in any cancer and has only been reported in few case reports. We report a case of young Filipino patient presenting with papillary thyroid carcinoma metastasizing to the thymus. This is a case of a 32-year old Filipino female presenting with an incidental finding of a mediastinal mass with a palpable thyroid nodule. On neck ultrasound, multiple calcified nodules with increased vascularity over the right thyroid lobe and pretracheal lymphadenopathies were visualized. Fine-needle biopsy was performed and cytology was suspicious for PTCA. Chest CT showed non-enhancing hypodense cystic mediastinal mass while F18-FDG PET revealed a hypermetabolic thyroid nodule with a non-hypermetabolic right paratracheal mass. Total thyroidectomy with mediastinal mass excision was performed with histopathology showing PTCA metastasizing to perithyroidal and right thymic lymph nodes, left thymus and mediastinum. Radioactive iodine at a dose of 150 mCi was subsequently administered, followed by a post-therapy whole body scan showing no pathologic uptake. She was then maintained on TSH-suppressive dose of levothyroxine. On six months follow-up, TSH and thyroglobulin levels remained suppressed and a repeat neck ultrasound showed no evidence of recurrence. While PTCA is generally associated with a favorable prognosis, certain risk factors have been associated with worse clinical outcomes including advanced age, presence of distant metastasis and extent and size of the primary tumor. Age greatly affects the prognosis among PTCA patients as mortality was observed to be higher among patients aged 55 years above with distant metastasis compared to their younger counterparts. This provided the rationale for the current American Joint Committee on Cancer (AJCC) staging system which applies an age cut-off. In the recent years, it was also observed that while a younger age would lead to a better outcome in PTCA patients, certain young patients with distant metastasis still experienced poor survival outcomes compared to those without distant metastasis. Among these patients, male sex has been linked with poorer survival. Thymic metastasis in PTCA may be considered a distant metastasis. However, due to the scarcity of cases, the long-term clinical outcomes among PTCA patients with thymic metastasis is still uncertain. Few cases of thyroid malignancies with thymic metastasis have been reported and showed favorable prognosis with surgery alone. Nevertheless, due to an increased incidence of PTCA recurrence among Filipino patients, radioactive iodine therapy postoperatively was still performed for our patient in accordance to the American Thyroid Association (ATA) guidelines recommendation and led to favorable response. This highlights the importance of individualized management.

Novel Prognostic Staging System for Patients With De Novo Metastatic Breast Cancer.

Given the heterogeneity and improvement in outcomes for metastatic breast cancer (MBC), we developed a staging system that refines prognostic estimates for patients with metastatic cancer at the time of initial diagnosis, de novo MBC (dnMBC), on the basis of survival outcomes and disease-related variables. Patients with dnMBC (2010-2016) were selected from the National Cancer Database (NCDB). Recursive partitioning analysis (RPA) was used to group patients with similar overall survival (OS) on the basis of clinical T category, grade, estrogen receptor (ER), progesterone receptor, human epidermal growth factor receptor 2, histology, organ system site of metastases (bone-only, brain-only, visceral), and number of organ systems involved. Three-year OS rates were used to assign a final stage: IVA: >70%, IVB: 50%-70%, IVC: 25 to <50%, and IVD: <25%. Bootstrapping was applied with 1,000 iterations, and final stage assignments were made based on the most commonly occurring assignment. Unadjusted OS was estimated. Validation analyses were conducted using SEER and NCDB. At a median follow-up of 52.9 months, the median OS of the original cohort (N = 42,467) was 35.4 months (95% CI, 34.8 to 35.9). RPA stratified patients into 53 groups with 3-year OS rates ranging from 73.5% to 5.7%; these groups were amalgamated into four stage groups: 3-year OS, A = 73.2%, B = 61.9%, C = 40.1%, and D = 17% (log-rank P < .001). After bootstrapping, the survival outcomes for the four stages remained significantly different (log-rank P < .001). This staging system was then validated using SEER data (N = 20,469) and a separate cohort from the NCDB (N = 7,645) (both log-rank P < .001). Our findings regarding the heterogeneity in outcomes for patients with dnMBC could guide future revisions of the current American Joint Committee on Cancer staging guidelines for patients with newly diagnosed stage IV disease. Our findings should be independently confirmed.

Survival Contradiction in Stage II, IIIA, And IIIB Colon Cancer: A Surveillance, Epidemiology, and End Result-Based Analysis.

There exists an inconsistency between stage and survival in the current American Joint Committee on Cancer (AJCC) staging system for colon cancer. In this study, we compared the clinicopathological characteristics and prognosis of colon cancer patients with stage II, IIIA, and IIIB disease based on the surveillance, epidemiology, and end results (SEER) database. Kaplan-Meier analysis was used to generate overall survival (OS) and cancer-specific survival (CSS) curves. The Cox regression was employed to identify risk factors. The competing risk model was completed by the cumulative incidence function and Gray's test. In the final population of 31,361 colon cancer patients, Kaplan-Meier curve analysis showed that stage IIIA had the highest OS and CSS, followed by stage IIA and IIIB, and IIB and IIC showed the worst OS and CSS. In the Cox model, the stage was proven to be an independent prognostic factor. In the competing risk model, stage IIIA colon cancer patients had the lowest 5-year cancer-specific death rate in stages II, IIIA, and IIIB. In conclusion, the prognosis of colon cancer patients in stage IIA was worse than that of patients in stage IIIA, while the survival rate of stage IIB and IIC was lower than that of stage IIIB.

Derivation of a Modified Novel Pathologic Nodal Classification System for Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> For decades, nodal staging for non-small cell lung cancer (NSCLC) has been based predominantly on location. Given increasing evidence of the prognostic power of quantitative nodal burden across solid tumors, it is possible that positive lymph node (LN+) count is a primary driver of survival among surgically staged patients with NSCLC. <h3>Materials/Methods</h3> Retrospective cohort analysis was performed on patients with NSCLC undergoing upfront surgery and nodal evaluation, excluding those receiving neoadjuvant chemotherapy in the National Cancer Database (NCDB). Tumor stage was recoded to conform to the current American Joint Committee on Cancer, 8^th Edition (AJCC 8E) based on size and tumor extension. The association between number of positive LNs and survival was modeled with restricted cubic splines in multivariable Cox regression analysis. Recursive partitioning analysis (RPA) was used to develop a modified nodal classification system based on nodal factors independently associated with survival. The proposed nodal classification system was independently validated in patients with NSCLC, now allowing for patients who received neoadjuvant chemotherapy ± radiation, from Surveillance, Epidemiology, and End Results-18 (SEER-18). <h3>Results</h3> Overall, 126,473 patients (62,428 men [49.4%]; mean [SD] age, 67.1 [9.9] years; 32,958 node-positive patients) were included in the NCDB discovery cohort. Mortality risk increased continuously with increasing number of positive LNs in multivariable analysis, with the greatest correlation with the first 3 LN+ (0-3 LN+: HR per LN, 1.38; 95% CI, 1.36-1.41; P<0.001; ≥4 LN+: HR per LN, 1.06; 95% CI, 1.05-1.07; P<0.001). Location of LN (ipsilateral mediastinum) was also a predictor of survival (HR, 1.30; 95% CI, 1.24-1.36; P<0.001). Univariate RPA identified six clusters of patients stratified only by nodal count and not by LN location. On multivariable analysis, these groups demonstrated continuously increasing and non-overlapping mortality risk: N0 (0 LN; reference); N1a (1 LN+; HR, 1.68; 95% CI, 1.61-1.75); N1b (2-3 LN+; HR 1.90; 95% CI, 1.82-1.99); N2a (4 LN+; HR, 2.19; 95% CI, 2.03-2.37); N2b (5-8 LN+; HR, 2.51; 95% CI, 2.35-2.68); N3 (≥9 LN+; HR, 3.35; 95% CI, 3.04-3.70). By contrast, the AJCC 8E nodal classification system spanned a more limited range of mortality risk: N0 (0 LN; reference); N1 (HR, 1.24; 95% CI, 1.09-1.42); N2 (HR, 1.62; 95% CI, 1.41-1.86); N3 (HR, 1.11; 95% CI, 0.75-1.64). The proposed nodal system was validated for overall survival (log-rank P<0.001) and cause-specific survival (k-sample P<0.001) among 112,153 patients with or without neoadjuvant treatment from the SEER-18 validation cohort. <h3>Conclusion</h3> Number of positive LNs is a dominant predictor of outcomes in patients with NSCLC undergoing surgical resection and nodal evaluation, whereas LN location has more limited independent prognostic information in this context. Thus, nodal count should serve as a backbone for pathologic nodal staging in patients with NSCLC.

A Novel Tumor Staging System Incorporating Tumor Regression Grade (TRG) With Lymph Node Status (ypN-Category) Results in Better Prognostication Than ypTNM Stage Groups After Neoadjuvant Therapy for Esophageal Squamous Cell Carcinoma.

This study aims at constructing a staging system incorporating tumor regression grade and ypN-category (TRG-N) in patients with neoadjuvant therapy before esophagectomy. It is hypothesized that this would prognosticate better than the current American Joint Committee on Cancer (AJCC) postneoadjuvant therapy (ypTNM) stage groups. Conventional pathological T-category is defined by the depth of invasion, and may lose prognostic relevance after neoadjuvant therapy. TRG defines treatment response by the degree of tumor regression, and when combined with ypN-category may be more prognostic than AJCC postneoadjuvant therapy (ypTNM) stage groups. A training cohort of 210 patients with esophageal squamous cell carcinoma and who had had neoadjuvant therapy before esophagectomy were studied. A validation cohort comprised 107 patients from another hospital. Resected esophagi were assessed by ypT-category and TRG, the latter assigned according to the Becker 4-tier system. These categories were grouped with ypN-category into a TRG-N system. Patients' survival was compared between the current AJCC postneoadjuvant therapy (ypTNM) stage groups and this TRG-N system. In the training cohort, 5-year survival rates according to ypTNM stage I, II, IIIA, IIIB, and IVA were 53%, 39.4%, 47%, 18.3%, and 0%, respectively. For TRG-N stages I, II, III, and IV, the respective figures were 59.6%, 43.5%, 23.8%, and 15.6%. TRG-N stage showed better fit in survival than ypTNM stage groups, indicated by lower Akaike Information Criteria (AIC) and Bayesian Information Criterion values. Similar results were found in the validation cohort. Multivariate analysis showed that TRG-N stage ( P =0.02), age ( P =0.006), and sex ( P =0.005) were independent prognostic factors. TRG-N stage shows better prognostication than the AJCC postneoadjuvant therapy (ypTNM) stage groups.

The Prognostic Prediction Value of Positive Lymph Nodes Numbers for the Hypopharyngeal Squamous Cell Carcinoma.

BackgroundThe current American Joint Committee on Cancer (AJCC) system only considered the importance of the size and laterality of lymph nodes while not the positive lymph node number (PLNN) for hypopharyngeal squamous cell carcinoma (HPSCC).MethodsA total of 973 patients with HPSCC from the Surveillance, Epidemiology, and End Results database (2004–2015) were identified. Univariate and multivariate Cox regression analyses were used to evaluate the prognostic effects. We applied six Cox regression models to compare the survival prognostic values of PLNN and AJCC systems.ResultsPositive lymph node number showed a significant association with overall survival (OS) and cancer-specific survival (CSS) (P < 0.001) in univariate and multivariable analyses. The increased PLNN of HPSCC gave rise to poor OS and CSS. The survival model incorporating a composite of PLNN and TNM classification (C-index for OS:0.682, C-index for CSS:0.702) performed better than other models.ConclusionsA positive lymph node number could serve as a survival predictor for patients with HPSCC and a complement to enhance the prognostic assessment effects of TNM cancer staging systems.

Inclusion of the Number of Metastatic Lymph Nodes in the Staging System for Medullary Thyroid Cancer: Validating a Modified American Joint Committee on Cancer Tumor-Node-Metastasis Staging System.

Background: The current American Joint Committee on Cancer (AJCC) staging system (8th edition) for medullary thyroid cancer (MTC) was originally extrapolated from the staging system for differentiated thyroid cancer. However, the current staging system does not accurately predict the prognosis of patients with MTC. Patients and Methods: The present study was based on data from the Surveillance, Epidemiology, and End Results (SEER) database and validated by multicenter data from the Shanghai Tenth People's Hospital, Tongji University School of Medicine, Xuzhou City Central Hospital, and Suzhou Ninth People's Hospital. Hazard ratio with its 95% confidence interval [CI] was estimated by Cox proportional hazards regression analysis. The concordance index (C-index) was used to evaluate the discrimination accuracy of the current AJCC tumor-node-metastasis (TNM) staging system and the modified AJCC (mAJCC) TNM staging system. Results: A total of 1175 MTC patients were selected from the SEER database and 312 from the three hospitals in China. We redefined the N category according to the number of metastatic lymph nodes (LNs) as follows: N'0 category (0 metastatic LNs), N'1 category (1-9 metastatic LNs), and N'2 category (≥10 metastatic LNs). The four distinct tumor stages were reclassified in the mAJCC staging system as follows: stage I (T1-4N'0M0, T1N'1M0), stage II (T2-3N'1M0, T1N'2M0), stage III (T4N'1M0, T2-4N'2M0), and stage IV (TanyN'anyM1). The C-index of the current AJCC staging system and the mAJCC staging system was 0.72 [CI, 0.67-0.78] and 0.78 [CI, 0.73-0.84], respectively. Similar results were observed in the survival analysis of the multicenter data set. Conclusions: The mAJCC staging system could discriminate the prognosis of MTC patients more effectively than the current AJCC staging system, indicating that it is feasible and appropriate to modify the current AJCC staging system by introducing the number of metastatic LNs instead of the location of LNs. These findings might be adopted in the next edition of the AJCC staging system and be used to guide clinical practice.

Proposed Models for Prediction of Mortality in Stage-I and Stage-II Gastric Cancer and 5 Years after Radical Gastrectomy.

The current American Joint Committee on Cancer (AJCC) staging system provides limited information for patients with early death from stage-I and stage-II gastric cancer (GC) and death at >5 years after radical gastrectomy. The aim of this study was to construct nomogram models to predict the mortality risk of these patients. In this study, clinical and pathological data on patients who underwent curative gastrectomy at Harbin Medical University Cancer Hospital between 2000 and 2014 were retrospectively collected. Receiver operating characteristic analysis was used to screen for sensitive serum immune biomarkers to predict the risk of mortality death >5 years after radical gastrectomy (Group A) and risk of early death in stage-I and stage-II GC (Group B). The prediction model was constructed by combining serum immune markers with clinicopathological features by R Studio. We found that serum fibrinogen (F), systemic immune inflammation (SII), and pTNM stage were independent risk factors for prognosis in Group A (P < 0.05). F, SII, age, Borrmann type, and scope of gastrectomy were independent risk factors for prognosis in Group B (P < 0.05). The area under the curve of the predictive model in Groups A and B was 0.726 and 0.848, respectively. In conclusion, the predictive models of F and SII combined with clinicopathological features can predict high mortality risk in patients with stage-I and stage-II GC and >5 years after radical gastrectomy, which will contribute to the supplement of the traditional AJCC system and to individual survival prediction.

Oncologic Status of Obturator Lymph Node Metastases in Locally Advanced Low Rectal Cancer: A Japanese Multi-Institutional Study of 3487 Patients.

The American Joint Committee on Cancer tumor-node-metastasis staging system for rectal cancer defines lateral pelvic lymph nodes (LPLNs) only in the internal iliac region as regional. However, the Japanese Society for Cancer of the Colon and Rectum (JSCCR) staging system, also considers obturator lymph nodes (LNs) as regional. This retrospective cohort study evaluated the oncologic status of obturator LNs in low rectal cancer. The study identified 3487 patients with pT3-T4 low rectal cancer who had undergone curative resections without preoperative radiotherapy or chemotherapy between 2003 and 2011 in the JSCCR database and divided them into six groups. Overall survival (OS) and recurrence-free survival (RFS) were analyzed by groups. Histologic LPLN metastases were identified in 8% (279/3487) of all the patients and in 18.2% (279/1530) of the patients who underwent lateral pelvic node dissection. The 5-year OS and RFS rates of the obturator-LPLN group (P = 0.095) were worse than those of the internal-LPLN group (P = 0.075), but the difference was not significant. The OS of the obturator-LPLN group was similar to that of the resectable liver metastasis group (P = 0.731), and the RFS of the obturator-LPLN group was significantly better than that of the other-LPLN group (P = 0.016). The prognosis for obturator LN metastases in low rectal cancer was not significantly worse than for internal iliac LN metastases, defined as regional by the current American Joint Committee on Cancer staging system, and the oncologic status of obturator LNs warrants more studies.

A novel LASSO‐derived prognostic model predicting survival for non‐small cell lung cancer patients with M1a diseases

IntroductionThe current American Joint Committee on Cancer (AJCC) M1a staging of non‐small cell lung cancer (NSCLC) encompasses a wide disease spectrum, showing diverse prognosis.MethodsPatients who diagnosed in an earlier period formed the training cohort, and those who diagnosed thereafter formed the validation cohort. Kaplan–Meier analysis was performed for the training cohort by dividing the M1a stage into three subgroups: (I) malignant pleural effusion (MPE) or malignant pericardial effusion (MPCE); (II) separate tumor nodules in contralateral lung (STCL); and (III) pleural tumor nodules on the ipsilateral lung (PTIL). Gender, age, histologic, N stage, grade, surgery for primary site, lymphadenectomy, M1a groups, and chemotherapy were selected as independent prognostic factors using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. And a nomogram was constructed using Cox hazard regression analysis. Accuracy and clinical practicability were separately tested by Harrell's concordance index, the receiver operating characteristic (ROC) curve, calibration plots, residual plot, the integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA).ResultsThe concordance index (0.661 for the training cohort and 0.688 for the validation cohort) and the area under the ROC curve (training cohort: 0.709 for 1‐year and 0.727 for 2‐year OS prediction; validation cohort: 0.737 for 1‐year and 0.734 for 2‐year OS prediction) indicated satisfactory discriminative ability of the nomogram. Calibration curve and DCA presented great prognostic accuracy, and clinical applicability. Its prognostic accuracy preceded the AJCC staging with evaluated NRI (1‐year: 0.327; 2‐year: 0.302) and IDI (1‐year: 0.138; 2‐year: 0.130).ConclusionOur study established a nomogram for the prediction of 1‐ and 2‐year OS in patients with NSCLC diagnosed with stage M1a, facilitating healthcare workers to accurately evaluate the individual survival of M1a NSCLC patients. The accuracy and clinical applicability of this nomogram were validated.

Revised Nodal Staging Integrating Tumor Deposit Counts With Positive Lymph Nodes in Patients With Stage III Colon Cancer.

We evaluated the prognostic value of tumor deposit (TD) counts and incorporated them with the number of positive lymph nodes to develop a revised nodal staging. The current American Joint Committee on Cancer (AJCC) staging on colon cancer includes the TDs only for nodenegative patients, as N1c, and their counts are not considered. We included consecutive patients with stage III colorectal cancer who underwent curative resections between January 2010 and December 2019. The patients were grouped as TD 0, TD 1, TD 2, or TD ≥3 based on their TD counts. Disease-free survival and overall survival were compared. Of 2446 eligible stage III patients, 658 (26.9%) had TDs. Among them, 500 (76.0%) patients concurrently had positive lymph nodes (LNs). TD counts were significantly related to worse disease-free survival (DFS) and overall survival regardless of pT stages or the number of positive LNs. The patients were restaged based on the integrated number of TD counts and positive LNs. The N3 stage, which had ≥10 integrated TDs and positive LNs, was newly classified. Among the patients who completed 6 months of adjuvant chemotherapy, those upstaged to N2 from an initial stage of N1 experienced significantly worse DFS than those confirmed as N1 in the revised N staging. The newly N3-staged patients showed significantly worse DFS than the patients initially staged as N2. Revised N staging using the integrated number of TD counts and positive LNs could predict DFS more accurately than current staging. It would also draw greater attention to the patients with high-risk stage III colon cancer staged as N3.