The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the M Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: This study analyzed all metastatic categories of the current TNM classification of NSCLC to propose modifications of the M component in the next edition (ninth) of the classification. METHODS: A database of 124,581 patients diagnosed between 2011 and 2019 was established; of these, 14,937 with NSCLC in stages IVA to IVB were available for this analysis. Overall survival was calculated using the Kaplan-Meier method, and prognosis was assessed using multivariable-adjusted Cox proportional hazards regression. RESULTS: The eighth edition M categories revealed good discrimination in the ninth edition data set. Assessments revealed that an increasing number of metastatic lesions were associated with decreasing prognosis; because this seems to be a continuum and adjustment for confounders was not possible, no specific lesion number was deemed appropriate for stage classification. Among tumors involving multiple metastases, decreasing prognosis was found with an increasing number of organ systems involved. Multiple assessments, including after adjustment for potential confounders, revealed that M1c patients who had metastases to a single extrathoracic organ system were prognostically distinct from M1c patients who had involvement of multiple extrathoracic organ systems. CONCLUSIONS: These data validate the eighth edition M1a and M1b categories, which are recommended to be maintained. We propose the M1c category be divided into M1c1 (involvement of a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems).

Discordance in clinical versus pathological staging in breast cancer: Are we undermining the significance of accurate preoperative staging in the present era?

BACKGROUND: The present era of individualized treatment for breast cancer is influenced by the initial disease status including the anatomical extent, grade, and receptor status. An accurate preoperative staging is the basis of treatment planning and prognostication. Our study aims to determine the discordance between the preoperative clinical and the postoperative pathological stages of breast cancer patients. METHODOLOGY: The medical records of all non-metastatic breast cancer patients from January 2017 to December 2018 who underwent upfront surgery were reviewed. They were staged as per the eighth AJCC and the concordance between the clinical (c) and pathological T (tumor), N (nodal), and final AJCC stage was studied. A Chi-square test was used to determine factors that significantly correlate with disease discordance. RESULTS: A total of 307 breast cancer patients were analyzed. Among these, 43.3% were hormone receptor-positive, 30.6% were Her2 positive and 26% were triple-negative. Overall stage discordance was seen in 48.5% (n = 149) patients (upstaging in 22.1%, downstaging in 26.4%). The discordance rate was 48.9% for T stage (cT versus pT) and 57.4% for N stage (cN versus pN). Among patients with clinically node-negative disease, 53.4% were found to have positive nodes on histopathology, while 27.2% had vice versa. Overall, the factors associated with upstaging were ER-positive, Her2 positive and triple-negative status (all p < 0.05), while none of the factors showed significant association with downstaging. CONCLUSIONS: About half of breast cancer patients had discordance between clinical and pathological staging with higher discordance in the nodal stage. This changes the disease prognosis, and may also affect the offered surgical treatment and radiotherapy. Thus highlighting the need for a precise pre-operative staging. Also, this information will aid clinicians in discussions with patients, keeping in mind the likelihood of change in disease staging and management.

Verification of the eighth edition of the UICC-TNM classification on surgically resected lung adenocarcinoma: Comparison with previous classification in a local center.

BACKGROUND: The UICC 8th TNM classification of lung cancer has been changed dramatically, especially in measuring methods of T-desriptors. Different from squamous- or small-cell carcinomas, in which the solid- and the invasive-diameter mostly agree with each other, the diameter of the radiological solid part and that of pathological invasive part in adenocarcinomas often does not match. AIM: We aimed to determine radiological and pathological tumor diameters of pulmonary adenocarcinomas with clinicopathological factors and evaluate the validity of the 8th edition in comparison with the 7th edition. METHODS AND RESULTS: We retrospectively analyzed clinicopathological factors of 429 patients with surgically resected pulmonary adenocarcinomas. The maximum tumor and their solid-part diameters were measured using thin-sectioned computed tomography and compared with pathological tumor and invasive diameters. Overall survival (OS) rate was determined using the Kaplan-Meier method for different subgroups of clinicopathological factors. Akaike's information criteria (AIC) was used as a discriminative measure for the univariate Cox model for the 7th and 8th editions. Multivariate Cox regression analysis was performed to explore independent prognostic factors. Correlation coefficients between radiological and pathological diameters in the 7th and 8th editions were 0.911 and 0.888, respectively, without a significant difference. The major reasons for the difference in the 8th edition were the presence of intratumoral fibrosis and papillary growth pattern. The weighted kappa coefficients in the 8th edition were superior those in the 7th edition for both the T and Stage classifications. In the univariate Cox model, AIC levels were the lowest in the 8th edition. Multivariate analysis revealed that age, lymphovascular invasion, pT(8th), and stage were the most important determinants for OS. CONCLUSION: The UICC 8th edition is a more discriminative classification than the 7th edition. For subsolid nodules, continuous efforts are necessary to increase the universality of the measurement of solid and invasive diameters.

DNA 5-hydroxymethylcytosine in pediatric central nervous system tumors may impact tumor classification and is a positive prognostic marker.

BACKGROUND: Nucleotide-specific 5-hydroxymethylcytosine (5hmC) remains understudied in pediatric central nervous system (CNS) tumors. 5hmC is abundant in the brain, and alterations to 5hmC in adult CNS tumors have been reported. However, traditional approaches to measure DNA methylation do not distinguish between 5-methylcytosine (5mC) and its oxidized counterpart 5hmC, including those used to build CNS tumor DNA methylation classification systems. We measured 5hmC and 5mC epigenome-wide at nucleotide resolution in glioma, ependymoma, and embryonal tumors from children, as well as control pediatric brain tissues using tandem bisulfite and oxidative bisulfite treatments followed by hybridization to the Illumina Methylation EPIC Array that interrogates over 860,000 CpG loci. RESULTS: Linear mixed effects models adjusted for age and sex tested the CpG-specific differences in 5hmC between tumor and non-tumor samples, as well as between tumor subtypes. Results from model-based clustering of tumors was used to test the relation of cluster membership with patient survival through multivariable Cox proportional hazards regression. We also assessed the robustness of multiple epigenetic CNS tumor classification methods to 5mC-specific data in both pediatric and adult CNS tumors. Compared to non-tumor samples, tumors were hypohydroxymethylated across the epigenome and tumor 5hmC localized to regulatory elements crucial to cell identity, including transcription factor binding sites and super-enhancers. Differentially hydroxymethylated loci among tumor subtypes tended to be hypermethylated and disproportionally found in CTCF binding sites and genes related to posttranscriptional RNA regulation, such as DICER1. Model-based clustering results indicated that patients with low 5hmC patterns have poorer overall survival and increased risk of recurrence. Our results suggest 5mC-specific data from OxBS-treated samples impacts methylation-based tumor classification systems giving new opportunities for further refinement of classifiers for both pediatric and adult tumors. CONCLUSIONS: We identified that 5hmC localizes to super-enhancers, and genes commonly implicated in pediatric CNS tumors were differentially hypohydroxymethylated. We demonstrated that distinguishing methylation and hydroxymethylation is critical in identifying tumor-related epigenetic changes. These results have implications for patient prognostication, considerations of epigenetic therapy in CNS tumors, and for emerging molecular neuropathology classification approaches.

A Prognostic Model of Gastrointestinal Diffuse Large B Cell Lymphoma.

BACKGROUND The digestive tract is the most common site of extranodal involvement in diffuse large B cell lymphoma (DLBCL) and its prognostic evaluation is different from that of ordinary DLBCL. Currently, for gastrointestinal lymphoma, in addition to the Ann Arbor staging system, the Lugano and the TNM staging systems are commonly used. However, there is no effective prognostic model to identify poor prognosis in patients with localized gastrointestinal diffuse large B cell lymphoma (GI-DLBCL). MATERIAL AND METHODS This study included 82 patients with GI-DLBCL that had a median follow-up of 75 months, and developed a model (HLAMA) with 5 variables: hemoglobin, age, lactate dehydrogenase (LDH), serum albumin, and the maximum intra-abdominal lesion diameter (MIALD). The specific indicators are: HGB <105 g/L (2 points); LDH ≥300 U/L; age ≥75 years, ALB <38 g/L, MIALD ≥4 cm (each scoring 1 point). We also developed a simplified model, which includes only 3 variables (HGB, LDH, and age). RESULTS HLAMA model and the simplified model both demonstrated good ability to predict prognosis of patients with GI-DLBCL (P<0.001), performing better than the IPI score as it could distinguish low-risk groups in relatively elderly patients (60-75 years old). CONCLUSIONS This study established a prognostic model for diffuse large B cell lymphoma of the gastrointestinal tract. Both the HLAMA model and its simplified version are similar to the IPI score, but could be considered better as they can provide a simpler and more accurate prognostic assessment in patients with GI-DLBCL. For patients with localized GI-DLBCL, our model could distinguish high-risk patients.

Establishment of a nomogram prediction model for long diameter 10-15 mm gallbladder polyps with malignant tendency.

BACKGROUND: Surgical indications for the treatment of gallbladder polyps are controversial. Evaluation of gallbladder polyps with malignant tendency and indications for cholecystectomy in patients with long diameter polyps of 10 to 15 mm require further analysis and discussion. In this study, our objective was to re-evaluate indications for the surgical resection of gallbladder polyps and construct a nomogram model for the prediction of gallbladder polyps with malignant tendency. METHODS: Clinicopathologic data of 2,272 patients who had undergone cholecystectomy for gallbladder polyps were collected from 11 medical centers in China. Risk factor analyses and nomogram prediction model for gallbladder polyps with malignant tendency were conducted. RESULTS: Excluding 311 patients with cholelithiasis and 488 patients with long diameter polyps ≤5 and >15 mm, factors that differed significantly among patients with gallbladder polyps having a long diameter of 6 to 9 mm (885 cases) and 10 to 15 mm (588 cases) were polyp detection time, CEA and CA19-9 levels, number of polyps, fundus, echogenicity, gallbladder wall thickness and postoperative pathologic features (P < .05). Among 588 patients with gallbladder polyps with a long diameter of 10 of 15 mm, multivariate analysis indicated the following independent risk factors of gallbladder polyps with malignant tendency: single polyps (OR = 0.286/P < .001), polyps with broad base (OR = 2.644/P = .001), polyps with medium/low echogenicity (OR = 2.387/P = .003), and polyps with short diameter of 7 to 9 or 10 to 15 mm (OR = 3.820/P = .005; OR = 2.220/P = .048, respectively). The C-index of the nomogram model and internal validation were .778 and .768, respectively. In addition, a sample online calculator for the nomogram prediction model had been created (https://docliqi.shinyapps.io/dynnom/). CONCLUSION: Indications for cholecystectomy in patients with gallbladder polyps with a long diameter of 10 to 15 mm should be assessed by combining the information on short diameter, number of polyps, fundus, and echogenicity. The nomogram model can be used to predict the risk for the development of gallbladder polyps with malignant tendency.

The new (Version 9) American Joint Committee on Cancer tumor, node, metastasis staging for cervical cancer.

The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging for all cancer sites has been periodically updated as a published manual for many years. The last update, the eighth edition AJCC Cancer Staging Manual went into use on January 1, 2018. The AJCC has since restructured and updated its processes, and all AJCC staging-related data are now housed on its new application programming interface. Consequently, the next AJCC TNM staging update, AJCC version 9 TNM staging, will be published electronically and will be released chapter by chapter. The first chapter of version 9 AJCC TNM staging is the updated cervical cancer staging, which is now published. This article highlights the changes to the AJCC TNM cervical cancer staging; these changes align with the International Federation of Gynecology and Obstetrics staging. The most important of the changes are: 1) the incorporation of imaging and surgical findings, 2) the elimination of lateral spread from T1a, 3) the addition of a subcategory to T1b (T1b3), and 4) histopathology is updated to reflect human papillomavirus-associated and human papillomavirus-independent carcinomas.

Validation of the American Joint Committee on Cancer Eighth Edition Staging of Patients With Metastatic Cutaneous Melanoma Treated With Immune Checkpoint Inhibitors.

Importance: Immune checkpoint inhibitors (ICIs) have transformed the survival of patients with metastatic melanoma. Patient prognosis is reflected by the American Joint Committee on Cancer (AJCC) staging system; however, it is unknown whether the metastatic (M) stage categories for cutaneous melanoma remain informative of prognosis in patients who have received ICIs. Objectives: To evaluate the outcomes of patients with metastatic cutaneous melanoma based on the M stage category from the AJCC eighth edition and to determine whether these designations continue to inform the prognosis of patients who have received ICIs. Design, Setting, and Participants: This cohort study included patients with metastatic cutaneous melanoma who were treated between August 2006 and August 2019 at the University of Michigan. The estimated median follow-up time was 35.5 months. Patient data were collected via the electronic medical record system. Critical findings were externally validated in a multicenter nationwide cohort of patients treated within the Veterans Affairs health care system. Data analysis was conducted from February 2020 to January 2021. Exposures: All patients were treated with dual-agent concurrent ipilimumab and nivolumab followed by maintenance nivolumab or single-agent ipilimumab, nivolumab, or pembrolizumab therapy. Patients were staged using the AJCC eighth edition. Main Outcomes and Measures: Univariable and multivariable analyses were used to assess the prognostic value of predefined clinicopathologic baseline factors on survival. Results: In a discovery cohort of 357 patients (mean [SD] age, 62.6 [14.2] years; 254 [71.1%] men) with metastatic cutaneous melanoma treated with ICIs, the M category in the AJCC eighth edition showed limited prognostic stratification by both univariable and multivariable analyses. The presence of liver metastases and elevated levels of serum lactate dehydrogenase (LDH) offered superior prognostic separation compared with the M category (liver metastases: hazard ratio, 2.22; 95% CI, 1.48-3.33; P < .001; elevated serum LDH: hazard ratio, 1.73; 95% CI, 1.16-2.58; P = .007). An updated staging system based on these factors was externally validated in a cohort of 652 patients (mean [SD] age, 67.9 [11.6] years; 630 [96.6%] men), with patients without liver metastases or elevated LDH levels having the longest survival (median overall survival, 30.7 months). Conclusions and Relevance: This study found that the AJCC eighth edition M category was poorly reflective of prognosis in patients receiving ICIs. Future staging systems could consider emphasizing the presence of liver metastases and elevated LDH levels. Additional studies are needed to confirm the importance of these and other prognostic biomarkers.

Risk of preoperative understaging of duodenal neuroendocrine neoplasms: a plea for caution in the treatment strategy.

PURPOSE: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. METHODS: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. RESULTS: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. CONCLUSIONS: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.

Interobserver Variation in Evaluating Perineural Invasion for Oral Squamous Cell Carcinoma: Phase 2 Survey Study.

In a previous study, we found interobserver agreement among 88 board-certified pathologists evaluating perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) was fair, and participants most often used the following criteria: (1) tumor invading the perineurium, (2) tumor surrounding a nerve. In this study, we aimed to determine whether application of these most commonly used criteria may improve interobserver agreement. 512 pathologists were invited to participate in a web-based survey. Participants were asked to assess the presence/absence of PNI in a set of OSCC photomicrographs by applying each of the two criteria above. The survey was completed by 84 board-certified pathologists [mean age: 52 years (range 31-81), mean years in practice: 19 (range 1-56)]. Interobserver agreement was moderate (k = 0.46, 95% CI 0.45-0.46) when using definition #1 (tumor invading the perineurium) and fair (k = 0.24, 95% CI 0.23-0.25) when using definition #2 (tumor surrounding a nerve). By comparison, interobserver agreement was fair (k = 0.36, 95% CI 0.35-0.37) among phase 1 participants asked to evaluate these photomicrographs as they would in their pathology practice. Differences in kappa between definition #1 and phase 1, definition #2 and phase 2, and definition #1 and #2 were statistically significant (p < 0.001). Compared to our prior study based on pathologists' personal views, the current study shows improved interobserver agreement with application of the criterion, "tumor invading the perineurium." However, further work is needed to delineate concise, objective, and more reproducible criteria for histopathologic assessment of PNI.

Fourier Transform Infrared Spectroscopy in Oral Cancer Diagnosis.

Oral cancer is one of the most common cancers worldwide. Despite easy access to the oral cavity and significant advances in treatment, the morbidity and mortality rates for oral cancer patients are still very high, mainly due to late-stage diagnosis when treatment is less successful. Oral cancer has also been found to be the most expensive cancer to treat in the United States. Early diagnosis of oral cancer can significantly improve patient survival rate and reduce medical costs. There is an urgent unmet need for an accurate and sensitive molecular-based diagnostic tool for early oral cancer detection. Fourier transform infrared spectroscopy has gained increasing attention in cancer research due to its ability to elucidate qualitative and quantitative information of biochemical content and molecular-level structural changes in complex biological systems. The diagnosis of a disease is based on biochemical changes underlying the disease pathology rather than morphological changes of the tissue. It is a versatile method that can work with tissues, cells, or body fluids. In this review article, we aim to summarize the studies of infrared spectroscopy in oral cancer research and detection. It provides early evidence to support the potential application of infrared spectroscopy as a diagnostic tool for oral potentially malignant and malignant lesions. The challenges and opportunities in clinical translation are also discussed.

ESGO/ESTRO/ESP Guidelines for the management of patients with endometrial carcinoma.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

A Survey of Breast Pathologists' Practice in Staging Multiple Foci of Invasive Carcinoma.

BACKGROUND: The American Joint Committee on Cancer (AJCC) staging system is the reference standard for describing the extent of neoplastic disease on the basis of the size of primary tumor (T), and the presence of regional lymph node (N) involvement and distant metastasis (M). Multiple foci of invasive breast carcinoma may pose staging challenges to the reporting pathologist. We set out to evaluate the practice of local breast pathologists with regard to staging of multiple foci of invasive carcinoma. PATIENTS AND METHODS: Breast pathologists were surveyed at a Community of Interest in Breast Pathology meeting. The live voting survey contained 6 case-based scenarios of multiple foci of invasive mammary carcinoma of the same or different histologic type and with unilateral or bilateral involvement. A supporting illustration was provided for each case. RESULTS: There was poor interobserver agreement with no consensus reached among the respondents in any of the cases. Staging choices varied from staging tumors together irrespective of histology or procedure type to staging tumors of the same histologic type together, or staging each tumor focus separately. Confusion was particularly evident when tumor foci with different histologic types were present. CONCLUSION: Inconsistencies exist in the reporting of AJCC pathologic TNM stage for multiple foci of invasive carcinoma. The results serve as a reminder that education and strict adherence to the AJCC guidelines is essential for establishing standard practice in order to provide accurate cancer staging and ensure optimal clinical management.

The prognostic value of tumor deposits and the impact on the TNM classification system in esophageal cancer patients.

OBJECTIVE: To explore the prognostic significance of tumor deposits (TDs), isolated tumor foci lacking residual lymph nodes, in esophageal cancer (EC). METHODS: A retrospective review of patients with EC undergoing esophagectomy between 2005 and 2017 was conducted. The prognostic value of TD was evaluated using a Cox regression model. Patients from different sources and periods were split into discovery and validation sets. A propensity score matching model was used in the validation set to reduce the confounding bias. The impact of TD on the TNM classification system was evaluated. RESULTS: The discovery and validation sets included 179 and 2875 patients, respectively. Propensity-matched patients with and without TDs were constructed in the validation set with 132 patients in each group. Overall survival (p < .001 and p = .004, respectively) and disease-free survival (p < .001 and p = .019, respectively) were both decreased in TD positive patients in the discovery set and propensity-matched groups of validation set. Classifying patients with TDs into pN3 stage improved the discriminative power of the current TNM staging system. CONCLUSIONS: TD is an independent prognostic factor for EC. The inclusion of TD in the TNM staging system may upstage appropriate patients to help guide therapy, and future studies are warranted.

Which Staging System Is More Suitable for Gastric Neuroendocrine Cancer and Mixed Adenoneuroendocrine Carcinomas? A Multicenter Cohort Study.

PURPOSE: To evaluate whether the European Neuroendocrine Tumor Society (ENETS) system or the 8th American Joint Committee on Cancer (AJCC) staging manual are suitable for gastric neuroendocrine carcinomas and/or mixed adenoneuroendocrine carcinomas (G-NECs/MANECs). METHODS: Patients in a multicentric series with G-NEC/MANEC who underwent curative-intent surgical resection for a primary tumor were included. An optimal staging system was proposed base on analysis of the T and N status and validated by the SEER database. RESULTS: Compared with the ENETS system, the survival curves of the T category and N category in the 8th AJCC system were better separated and distributed in a more balanced way, but the survival curves of T2 vs. T3, N0 vs. N1, and N3a vs. N3b overlapped. For the T category, the 8th AJCC T category was modified by combining T2 and T3, which was consistent with the T category in the 6th AJCC manual for GC. For the N category, the optimal cut-off values of metastatic lymph nodes using X-tile were also similar to those of the N category in the 6th AJCC system. The Kaplan-Meier plots of the 6th AJCC system showed statistically significant differences between individual substages. Compared with the other 2 classifications, the 6th AJCC system also showed superior prognostic stratification. Similar results were obtained in both multicentric and SEER validation sets. CONCLUSIONS: Compared to the 8th AJCC and ENETS systems, the 6th AJCC staging system for GC is more suitable for G-NEC/MANEC and can be adopted in clinical practice.