Introducing the eighth edition of the tumor-node-metastasis classification as relevant to colorectal cancer, anal cancer and appendiceal cancer: a comparison study with the seventh edition of the tumor-node-metastasis and the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma.

BACKGROUND: The eighth edition of the tumor-node-metastasis classification of malignant tumors updates cancer staging according to the evidence accumulated in the last 8 years since the release of the tumor-node-metastasis seventh edition. This review focuses on the new staging system. METHODS: The eight edition was compared with the seventh edition as well as the Japanese Classification of Colorcetal, Appendiceal, and Anal carcinoma ninth edition. RESULTS: Of colon and rectum, the tumor-node-metastasis eighth edition expands the M category. Specifically, colorectal cancer with peritoneal metastasis is newly categorized as M1c, distinguishing it from M1a (metastasis to one organ) and M1b (metastasis to more than one organ). In the ninth edition of Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma, M1c is further subdivided into M1c1 (metastasis to the peritoneum without other organ involvement) and M1c2 (metastasis to the peritoneum with other organ involvement). In the T category, the tumor-node-metastasis eighth edition excludes high-grade dysplasia (intraepithelial carcinoma) from Tis; this differs from both the tumor-node-metastasis seventh edition and the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma ninth edition. In the N category, the tumor-node-metastasis eighth edition does not add the number of tumor deposits to the number of positive regional lymph nodes, whereas this number is added in the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma ninth edition. The definition of anal cancer is also modified considerably in the tumor-node-metastasis eighth edition; specifically, tumors of perianal skin defined as within 5 cm of the anal margin are also classified as anal canal carcinoma, external iliac lymph nodes become regional lymph nodes, and both N2 and N3 are abolished in the N category. With regard to appendix, Tis (low-grade appendiceal mucinous neoplasma) and tumor deposit(s) are newly introduced. Finally, the tumor-node-metastasis eighth edition offers a new structure, labeled a 'prognostic factors grid', which consists of prognostic factors for survival in both colorectal and anal cancer. CONCLUSIONS: Staging classification is updated regularly, which clinicians should always catch up with.

Goblet cell carcinoid of the appendix - An interobserver variability study using two proposed classification systems.

Goblet cell carcinoid (GCC) is an uncommon tumor of the vermiform appendix. Due to a broad spectrum of morphological differentiation, subclassification and grading of GCCs remains an area of controversy. Two separate systems have proposed classifying GCC tumors into three (classical GCC; adenocarcinoma ex-GCC, signet ring cell type; adenocarcinoma ex-GCC, poorly differentiated carcinoma type) OR two subgroups (low and high grade GCC) based on morphological criteria. We independently compared the inter-observer variability associated with each classification system. Overall, both systems had moderate interobserver agreement, with the two-tiered system (κ=0.54) performing slightly better than the three-tiered system (κ=0.42). GI-specialist pathologists had substantial agreement for both two and three-tiered systems (κ=0.65 vs. 0.65). Non-GI trained pathologists had lower overall agreement than GI trained pathologists, but their agreement was better using the two-tiered system (κ=0.44) than the three-tiered system (κ=0.22). A sub-analysis of 6 cases with a high rate of discordant classification revealed several challenges that exist in applying current criteria, including differentiating "goblet" vs. "signet ring" cell morphology, applying a 1 mm2 criteria to multifocal non-contiguous glandular and single infiltrating cell architecture, differentiating fibro-inflammatory stroma from desmoplastic stroma, and solid architecture in cases with abundant extracellular mucin, and distinguishing "reactive" nuclear atypia from true "cytologic atypia". Despite these challenges, the study identified better agreement among GI pathologists than non-GI trained pathologists. While GI pathologist review may be helpful, further research on objective classification criteria remains an area of interest.

Appendiceal Mucinous Neoplasms: Diagnosis and Management.

OBJECTIVE: Appendiceal mucinous neoplasms (AMNs) are a rare and heterogeneous disease for which clinical management is challenging. We aim to review the literature regarding modalities of treatment to guide the management of AMNs. METHODS AND REVIEW CRITERIA: We conducted a PubMed search in February 2016 for English-language publications, using the terms "appendiceal," "appendix," "carcinoma," "cancer," "mucinous," "treatment," "genes," "target," "genomic," and terms listed in the articles' subheadings. Published reports and abstracts from the American Society of Clinical Oncology meetings were also searched. RESULTS: In this review, we summarize current data and controversies in AMN classification, clinical presentation, molecular alterations, treatment outcomes with regard to cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and the role of systemic chemotherapy. CONCLUSION: Appendiceal mucinous neoplasms are a heterogeneous group of tumors with a rising incidence. Treatment is based on stage and histology. Low-grade tumors are treated surgically with resection of the primary site in early stage disease, or peritoneal debulking and HIPEC in patients with advanced stage disease. Treatment of high-grade tumors requires further prospective trials, and options include debulking surgery and HIPEC with or without preoperative chemotherapy. Trials evaluating novel therapies based on the molecular profiling of AMN tumors are needed to evaluate therapeutic options in patients who are not surgical candidates. IMPLICATIONS FOR PRACTICE: This review provides a reference to guide gastroenterologists, pathologists, surgeons, and oncologists in the management of appendiceal mucinous neoplasms (AMNs), a rare and heterogeneous disease with no consensus on histologic classification or guidelines for treatment algorithms. This review summarizes all AMN classifications and proposes a treatment algorithm based on stage and histology of disease.

The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.

The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

The 7th Edition of the AJCC Staging Classification Correlates with Biologic Behavior of Mucinous Appendiceal Tumor with Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC).

PURPOSE: We evaluated the 7th edition of the American Joint Committee on Cancer (AJCC) staging classification in terms of overall survival (OS) in patients with PMP treated with cytoreductive surgery (CRS)/hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A total of 208 PMP patients treated with CRS/HIPEC were identified from a prospective database. Patients with peritoneal mucinous carcinomatosis (PMCA) were retrospectively staged at time of diagnosis according to AJCC staging classification. Patients with disseminated peritoneal adenomucinosis (DPAM) were evaluated in a separate group. RESULTS: Median follow-up was 5.2 years. Of 208 patients, 124 had PMCA and 84 patients had DPAM. According to the AJCC staging classification 47 lymph node (LN) negative patients with well-differentiated PMCA, were classified as a stage IVA. 77 patients with either moderately or poorly differentiated PMCA irrespective of LN status, or well-differentiated PMCA with positive LN were classified as stage IVB. 84 patients with DPAM, constituted a separate group. OS of stage IVA and IVB patients was 100, 90, 67, and 91, 50, and 27 for 1, 3, and 5 years, respectively (p < 0.001). OS of DPAM patients was 96, 90, and 88 % for 1, 3, and 5 years, respectively (p = 0.025 comparing to IVA). PFS was estimated for IVA and IVB PMCA patients who were considered disease free after CRS/HIPEC and was 78, 52, and 43 % in the IVA patients and 65 %, 15 %, and 0 in the IVB group at 1, 3, and 5 years, respectively (p = 0.004). The adjusted HR for AJCC stages (IVA/IVB) was 3.7 (95 % confidence interval 2.0-6.7) (p < 0.001). CONCLUSIONS: The 7th edition of the AJCC staging classification is a simple, reproducible, and valid classification for staging patients with PMCA undergoing CRS/HIPEC.

Curative Surgical Resection as a Component of Multimodality Therapy for Peritoneal Metastases from Goblet Cell Carcinoids.

BACKGROUND: The impact of histopathologic features on oncologic outcomes for patients with peritoneal metastases from goblet cell carcinoid (GCC) undergoing multimodality therapy, including cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC), is unknown. METHODS: This study prospectively analyzed 43 patients with GCC undergoing CRS-HIPEC between 2005 and 2013. Pathology slides were re-reviewed to classify GCC into histologic subtypes according to the Tang classification. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. RESULTS: The 43 patients in this study underwent 50 CRS-HIPEC procedures for peritoneal metastases from GCC, and the majority received neoadjuvant and/or adjuvant systemic chemotherapy. The GCC demonstrated an aggressive phenotype with frequent lymph node and peritoneal metastases without systemic dissemination. The majority of the patients had Tang B GCC. The estimated median overall survival times after surgery for the patients with Tang A, B, and C GCC were respectively 59, 22, and 13 months. In a multivariate Cox-regression analysis, poor survival was associated with patients who had Tang B or C GCC, those undergoing incomplete macroscopic resection, and those with symptoms at the time of CRS-HIPEC. The patients with Tang A GCC demonstrated oncologic outcomes similar to those with intermediate-grade (American Joint Committee on Cancer [AJCC] grade 2) disseminated mucinous appendiceal neoplasms, whereas the patients with Tang B and C GCC demonstrated survival rates similar to or worse than those with high-grade (AJCC grade 3) disseminated mucinous appendiceal neoplasms. CONCLUSIONS: Tang classification is an independent prognostic factor for poor survival after multimodality therapy for GCC. Patients with Tang C GCC demonstrate limited survival and are not ideal candidates for a surgical approach.

Digestive neuroendocrine tumors: reclassifying of 26 cases according to 2010 who classification.

BACKGROUND: The classification of digestive neuroendocrine tumors is difficult due to their heterogeneity and rareness. AIMS: Reclassify the digestive neuroendocrine tumors according  to  the  WHO-2010 classification .  Methods: A retrospective study included   26 patients having digestive neuroendocrine     tumors ,  is achieved  in our  Pathology  Laboratory  of the Military Hospital of  Tunis between 2000 and 2013. RESULTS: The mean age of patients was 49.64 years. The Sex ratio was  1.36. It was 6 gastric tumors, 5 small intestine tumors , 5 pancreatic tumors, 5  appendix tumors , one hypatic tumor, one  gall bladder  tumor , one rectal tumor and one colon tumor. According to the WHO -2000 classification, tumors are categorised into 11 well differentiated  endocrine tumors, 13 well differentiated  endocrine carcinoma  and 2 poorly differentiated carcinoma . According to the WHO -2010 classification, tumors were re-evaluated as  16 neuroendocrine tumors grade 1, 6 neuroendocrine tumors grade 2 and 4 neuroendocrine carcinoma . CONCLUSION: There was a concordance between the two classifications in 93% of cases. The WHO -2010 classification may allow a  better classification for the digestive neuroendocrine tumors, however there are some histological categories that remained difficult to classify.

Digestive neuroendocrine tumors: reclassifying of 26 cases according to 2010 who classification.

BACKGROUND: The classification of digestive neuroendocrine tumors is difficult due to their heterogeneity and rareness. AIMS: Reclassify the digestive neuroendocrine tumors according  to  the  WHO-2010 classification .  Methods: A retrospective study included   26 patients having digestive neuroendocrine     tumors ,  is achieved  in our  Pathology  Laboratory  of the Military Hospital of  Tunis between 2000 and 2013. RESULTS: The mean age of patients was 49.64 years. The Sex ratio was  1.36. It was 6 gastric tumors, 5 small intestine tumors , 5 pancreatic tumors, 5  appendix tumors , one hypatic tumor, one  gall bladder  tumor , one rectal tumor and one colon tumor. According to the WHO -2000 classification, tumors are categorised into 11 well differentiated  endocrine tumors, 13 well differentiated  endocrine carcinoma  and 2 poorly differentiated carcinoma . According to the WHO -2010 classification, tumors were re-evaluated as  16 neuroendocrine tumors grade 1, 6 neuroendocrine tumors grade 2 and 4 neuroendocrine carcinoma . CONCLUSION: There was a concordance between the two classifications in 93% of cases. The WHO -2010 classification may allow a  better classification for the digestive neuroendocrine tumors, however there are some histological categories that remained difficult to classify.

Clinicopathologic and molecular analysis of disseminated appendiceal mucinous neoplasms: identification of factors predicting survival and proposed criteria for a three-tiered assessment of tumor grade.

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2-6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7-14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

Classification of and cytoreductive surgery for low-grade appendiceal mucinous neoplasms.

BACKGROUND: Low-grade appendiceal mucinous neoplasm (LAMN) is a precursor lesion for pseudomyxoma peritonei (PMP), which, if treated suboptimally, may later disseminate throughout the abdominal cavity. The role of cytoreductive surgery for these relatively early lesions is unclear. METHODS: Clinicopathological details and treatment outcomes of patients with a LAMN and disease limited to the appendix or immediate periappendiceal tissues, referred to a national treatment centre between 2002 and 2009, were evaluated prospectively. RESULTS: Of 379 patients with a diagnosis of PMP, 43 (median age 49 years) had LAMNs localized to the appendix and periappendiceal tissue. Thirty-two patients initially presented with symptoms of acute appendicitis or right iliac fossa pain. Two distinct lesions were identified: type I (disease confined to the appendiceal lumen) and type II (mucin and/or neoplastic epithelium in the appendiceal submucosa, wall and/or periappendiceal tissue, with or without perforation). Type I lesions were managed by a watch-and-wait surveillance policy with serial measurement of tumour markers and computed tomography in 14 of 16 patients. Seventeen of 27 patients with type II lesions underwent risk-reducing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with low morbidity. After a median follow-up of 40 months, there was no disease progression in either treatment pathway. CONCLUSION: This study identified two LAMN subtypes. Type II lesions have pathological features of increased risk for dissemination and should be considered for risk-reducing cytoreductive surgery.

[Mucinous neoplasms of the vermiform appendix, Pseudomyxoma peritonei, and the new WHO classification]. / Muzinöse Neoplasien der Appendix vermiformis, Pseudomyxoma peritonei und die neue WHO-Klassifikation.

Mucinous neoplasms of the appendix are rare tumors, some of them characterized by an enigmatic discrepancy between a benign morphologic appearance and an aggressive biologic potential, associated with a poor prognosis and high mortality. The clinical picture of pseudomyxoma peritonei is, with few exceptions, caused by mucinous appendiceal neoplasms and differs in many aspects from usual peritoneal carcinomatosis. The controversy regarding terminology, diagnostic criteria, classification and therapy of these tumors has lasted for decades. The revised edition of the World Health Organization Classification of Tumors of the Digestive System proposes a uniform reporting system for mucinous appendiceal neoplasms and the peritoneal disease associated with it, thereby creating a comparable basis for pathological diagnosis, clinical therapy and further scientific studies.

[Neuroendocrine neoplasms of the appendix and colorectum]. / Neuroendokrine Neoplasien der Appendix und des Kolorektums.

Appropriate diagnosis and treatment of neuroendocrine neoplasms (NENs) of the appendix and colorectum requires a detailed knowledge of their proper classification according to the updated WHO and TNM systems. The WHO classification distinguishes well differentiated NEN, the neuroendocrine tumors (G1 and G2 NETs), from the poorly differentiated carcinomas (G3 NECs). While NETs are common in the appendix and rectum, NECs occur predominantly in the colon. G1 appendiceal and rectal NETs of 1 cm in size or below that do not invade either the muscular wall or vessels bear almost no metastatic risk and can be treated by appendectomy or endoscopic resection. G2 appendiceal and rectal NETs larger than 1 cm in size in combination with other risk factors have an increased risk of metastasis and need to be treated more aggressively. NECs of the colon usually require chemotherapy in addition to resection. Today, most patients with NETs of the appendix and rectum have an excellent prognosis when these diagnostic and therapeutic guidelines are borne in mind.

The 2019 World Health Organization Classification of appendiceal, colorectal and anal canal tumours: an update and critical assessment.

The recently published 5th edition 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System brings significant changes from the 2010 4th edition. An emphasis on uniformity in nomenclature and grading for tumours across all organ systems is a particular feature of the 5th edition blue book series that is reflected in the gastrointestinal tract (GIT) classification. For example, simplified two tiered grading is reinforced for preinvasive lesions throughout the GIT, with dysplasia at all sites now being considered either low or high grade. Similarly, a uniform approach to classification and grading of GIT neuroendocrine neoplasms has been consolidated, with an emphasis on distinguishing grade 3 neuroendocrine tumours from neuroendocrine carcinomas. In this review, we discuss and critically assess the important and sometimes controversial changes made to the classification of tumours of the lower GIT, comprising the colorectum, vermiform appendix and anal canal. The particularly controversial decision to endorse the term 'sessile serrated lesion' for lesions previously termed 'sessile serrated polyp/adenoma' is explored. The morphological, molecular, and clinical insights behind the substitution of the term 'goblet cell adenocarcinoma' for 'goblet cell carcinoid' are assessed. The evolution of the classification of appendiceal mucinous neoplasms is considered. Inflammatory bowel disease related dysplasia and its evolving subtypes, with major implications for pathologists in routine practice, is explained.

Comparison of model fit and discriminatory ability of M category as defined by the 7th and 8th editions of the tumor-node-metastasis classification of colorectal cancer and the 9th edition of the Japanese classification.

BACKGROUND: In transitioning from the 7th edition of the tumor-node-metastasis classification (TNM-7) to the 8th edition (TNM-8), colorectal cancer with peritoneal metastasis was newly categorized as M1c. In the 9th edition of the Japanese Classification of colorectal, appendiceal, and anal carcinoma (JPC-9), M1c is further subdivided into M1c1 (without other organ involvement) and M1c2 (with other organ involvement). This study aimed to compare the model fit and discriminatory ability of the M category of these three classification systems, as no study to date has made this comparison. METHODS: The study population consisted of stage IV colorectal cancer patients who were referred to the National Cancer Center Hospital from 2000 to 2017. The Akaike information criterion (AIC), Harrell's concordance index (C-index), and time-dependent receiver operating characteristic (ROC) curves were used to compare the three classification systems. Subgroup analyses, stratified by initial treatment year, were also performed. RESULTS: According to TNM-8, 670 (55%) patients had M1a, 273 (22%) had M1b, and 279 (23%) had M1c (87 M1c1 and 192 M1c2 using JPC-9) tumors. Among the three classification systems, JPC-9 had the lowest AIC value (JPC-9: 10546.3; TNM-7: 10555.9; TNM-8: 10585.5), highest C-index (JPC-9: 0.608; TNM-7: 0.598; TNM-8: 0.599), and superior time-dependent ROC curves throughout the observation period. Subgroup analyses were consistent with these results. CONCLUSIONS: While the revised M category definition did not improve model fit and discriminatory ability from TNM-7 to TNM-8, further subdivision of M1c in JPC-9 improved these parameters. These results support further revisions to M1 subcategories in future editions of the TNM classification system.

[The current TNM system for gastrointestinal tumors part II]. / Aktuelles TNM-System der gastrointestinalen Tumoren Teil II.

Entirely new classifications are those for gastrointestinal stromal tumours, gastrointestinal neuroendocrine tumours, intrahepatic cholangiocarcinoma and perihilar extrahepatic bile duct carcinomas. Major and praxis-relevant alterations concern colorectal tumours and include new classifications of carcinomas and carcinoids of the appendix. Minor alterations are seen in the classification of hepatocellular carcinomas. No changes were made for tumours of the anal canal, the gallbladder (excluding the inclusion of tumours of the cystic duct) and tumours of the pancreas and the ampulla of Vater.

Nomenclature of appendiceal mucinous lesions according to the 2019 WHO Classification of Tumors of the Digestive System.

BACKGROUND/AIMS: To analysis the appendiceal mucinous lesions according to the World Health Organization (WHO) 2019 classification of tumors of the digestive system (non-neuroendocrine tumors of the appendix vermiformis) MATERIALS AND METHODS: Clinical and histopathological data of 37 patients with histopathologically proven appendiceal mucinous lesion from January 2010 to May 2019 were evaluated retrospectively. Pathology slides were re-evaluated by two pathologists according to the WHO 2019 classification of tumors of the digestive system. RESULTS: Totally 37 patients (male:19 female: 18) aged 23 to 93 years were analyzed. Majority of the patients (75.7 %) had underwent appendectomy due to preliminary diagnosis of acute appendicitis (n=22) or periappendiceal tumoral lesions (n=9), the others (n=9) underwent incidental appendectomy. Whereas acute appendicitis was histopathologically diagnosed in 16 (43.2%) patients, perforation was diagnosed in 12 (32.4%) patients (perforation without appendicitis=3, perforation with appendicitis=6). According to the initial, pathology reports were prepared as follows: mucocele (n=10), mucinous cystadenoma (n=9), low-grade mucinous neoplasm (n=6), mucinous adenocarcinoma (n=5), mucosal hyperplasia (n=5), hyperplastic polyp (n=1), adenomatous polyp (n=1). On the basis of the WHO 2019 classification, pathology reports were prepared as follows: low-grade mucinous neoplasm (n=17), simple retention cysts (n=6), hyperplastic polyp (n=6), mucinous adenocarcinoma (n=5), ruptured appendiceal diverticula (n=2), sessile serrated lesion (n=1). CONCLUSION: The term of appendiceal mucinous lesion, which is recently introduced into medical literature is suitable to distinguish between lesions with and without malignancy potential. The WHO 2019 classification system has been an important step in simplifying the classification of non- neuroendocrine tumors of the appendix vermiformis.

Low-Grade Appendiceal Mucinous Neoplasms: A Single Institution Experience of 64 Cases With Clinical Follow-up and Correlation With the Current (Eighth Edition) AJCC Staging.

Background. In this single-institution study, we applied the current (eighth edition) American Joint Committee on Cancer pathologic staging criteria to 64 low-grade mucinous neoplasms of the appendix (LAMNs), examined their histopathologic features, and studied the patients' clinical outcomes. Design. Sixty-four LAMNs, with a median follow-up of 52 months, were reviewed. Results. The distribution of pathologic stages was pTis (n = 39), pT3 (n = 1), pT4a (n = 5), pT4aM1a (n = 8), and pT4aM1b (n = 11). Recurrence was observed in only 2 patients (both with pT4aM1b disease), one of whom died of disease. All remaining patients were disease-free after a median clinical follow-up of 60 months. Conclusions. Our study confirms that pTis LAMNs have an excellent prognosis and suggests that pT4a and pT4aM1a LAMNs may also have a low risk of developing progressive disease.

Differential protein immunoexpression profiles in appendiceal mucinous neoplasms: a special reference to classification and predictive factors.

Appendiceal mucinous neoplasms have been the focus of considerable debate in recent years. We histologically classified 70 appendiceal mucinous neoplasms into three categories: 32 mucinous adenoma, 23 mucinous neoplasm of uncertain malignant potential, and 15 mucinous adenocarcinomas. Immunohistochemistry was performed for 24 proteins in different functional categories, specifically, oncogenic proteins (bcl-2, beta-catenin, CEA, C-erbB2, c-kit, Cox-2, Cyclin D1, EGFR, Ki-67, NF-kappaB, VEGF), tumor suppressors (E-cadherin, FHIT, hMLH1, p53, p63, smad4), cell-cycle regulators (p21, p27, p16), and mucin proteins (MUC1, MUC2, MUC5AC, MUC6). Our data showed that 9 out of the 24 proteins were more frequently altered in the mucinous adenocarcinoma group than in the mucinous adenoma group (P<0.05), including beta-catenin (13% in mucinous adenoma vs 60% in mucinous adenocarcinoma), CyclinD1 (44 vs 87%), Ki-67 (high labeling index: 31 vs 67%), NF-kappaB (19 vs 60%), VEGF (16 vs 87%), E-cadherin (0 vs 47%), p53 (6 vs 40%), MUC2 (9 vs 67%), and MUC5AC (3 vs 40%). The distinct immunoexpression profile of mucinous neoplasm of uncertain malignant potential was placed between those of mucinous adenoma and mucinous adenocarcinoma (P<0.05). Moreover, the mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma categories displayed differences in terms of the number of altered markers among the nine proteins (P<0.05; mean 1.4 vs 2.6 vs 5.5, respectively). In mucinous adenocarcinoma, the p53 status was related to disease-free survival and overall survival of patients (P<0.05, both). NF-kappaB status and the number of altered protein markers made statistically marginal impacts on disease-free survival; also beta-catenin loss, on overall survival of patients. In conclusion, protein immunoexpression profiles may facilitate the classification of appendiceal mucinous neoplasms. In our study, the three tumor categories of mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma exhibited distinct immunoexpression profiles. Five and more altered protein markers, p53 overexpression, NF-kappaB positivity, and beta-catenin loss were predictive factors of adverse clinical outcomes in appendiceal mucinous adenocarcinomas.