Appendiceal Carcinomas Research Articles

Morphologic Heterogeneity of Carcinoma with Signet Ring Cell Features at Different Primary Sites

Introduction: Signet ring cells (SRCs) may be observed in carcinomas from multiple primary sites. Elucidating unknown primaries from metastases with SRCs represents a diagnostic challenge. This study examined morphologic characteristics of adenocarcinomas with SRCs from stablished primary sites and described objective features, which can aid in identifying the site of origin. Methods: The series encompasses 257 cases of adenocarcinomas with SRCs from gastroesophageal junction (GEJ, n = 38), stomach (n = 48), pancreatobiliary system (n = 16), colorectum (n = 40), appendix (n = 32), breast (n = 41), and lung (n = 42). H&E sections were examined and scored using architectural and cytologic criteria. Morphometric analysis was performed using QuPath software. Results: Extracellular mucin was more abundant in GEJ, colorectal, and appendiceal carcinomas. Poorly cohesive morphology was the most frequent pattern in gastric and breast carcinomas. The cytoplasmic mucin/vacuole was predominantly clear and targetoid in breast carcinomas. Breast and gastric carcinomas showed the highest nuclear to cytoplasmic (N/C) ratio, whereas appendiceal carcinoma the lowest. Conclusion: Morphological evaluation (extracellular mucin, architectural patterns, and the nature of cytoplasmic mucin/vacuole) represents an important step to determine the cancer site of origin in adenocarcinomas with SRCs and guides further ancillary studies. Cytological morphometry may help further refine morphological criteria and facilitate the construction of digital-pathology algorithms.

Prolonged Survival in Peritoneal Metastatic Appendiceal Carcinoma Patients Treated With Combined Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

IntroductionPrimary treatment for peritoneal dissemination of appendiceal cancer is the combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The endpoints were overall survival and evaluation of prognostic factors. MethodsClinicopathological and treatment-related factors were obtained from a prospective database. A total of 84 patients, 55 (65%) primary and 29 (35%) recurrent malignant appendiceal carcinomas with synchronous and metachronous peritoneal metastases, underwent multimodal treatment between 2011 and 2021. The endpoints of the study were overall survival and evaluation of prognostic factors. ResultsThe median follow-up was 4.8 y; the mean age was 54.5 y (range 25-77), with a sex distribution of 69% female and 31% male. The mean peritoneal cancer index was 11.3. The proportion of mucinous, intestinal-type, signet ring cell, and goblet cell carcinoma was 56%, 23%, 11%, and 10%, respectively. The 5-y survival rate of the whole cohort was 56.7%. In primary and recurrent diseases, the overall median survival was 8.4 and 4.9 y. Significantly improved survival was detected after complete cytoreduction resection (hazard ratio [HR] for CCR-2 versus CCR-0: 9.388, 95% confidence interval [CI] 3.026-29.124, P = 0.001) and initial local operation with undelayed admission to the center (HR 0.262, 95% CI 0.089-0.773; P = 0.015). The five independent factors in Kaplan–Meier analysis and univariable Cox regression analysis associated with significant adverse survival were cancer antigen (CA) 19-9 over 37 IU/mL, signet ring cell and intestinal-type histology, positive nodal status, grading, and peritoneal cancer index >20. Neoadjuvant chemotherapy administration did not impact survival (HR 1.220, 95% CI 0.612-2.432, P = 0.571). ConclusionsWith multimodal treatment, prolonged survival is attainable in stage IV primary and recurrent appendiceal carcinoma with peritoneal dissemination. Direct referral to specialized centers after confirmation of peritoneal metastasis is recommended because prompt definitive treatment may significantly improve survival.

S1737 Goblet Cell Adenocarcinoma: A Rare and Aggressive Appendiceal Neoplasm

Introduction: Goblet cell adenocarcinoma (GCA) is a rare and unique appendiceal neoplasm, containing features of both adenocarcinoma and neuroendocrine tumors (NETs). Also termed "goblet cell carcinoids" and previously considered a low-grade malignancy, these tumors are now known to be much more aggressive than traditional carcinoid tumors due to coexistence of high grade adenocarcinoma. In fact, up to 40% of cases present after development of distant metastasis, most commonly to the peritoneum. This has led to pressure for updated nomenclature removing the term "carcinoid" to prevent confusion and potential for incorrect management. Case Description/Methods: A 69-year-old Filipino male with minimal past medical history presented with a four day history of sharp, bloating-type abdominal pain and difficulty passing gas. He denied any other symptoms, specifically nausea, vomiting, constipation or diarrhea. Screening colonoscopy performed 3 years prior with intubation of the terminal ileum was normal. CT of the abdomen/pelvis demonstrated a small bowel obstruction due to a mass, appearing to arise from the terminal ileum, encompassing the cecum and appendix. Colonoscopy was requested, however after discussion with colorectal surgery service, the decision was made to proceed directly to surgical resection, given likelihood of malignancy. Pathology revealed goblet cell adenocarcinoma with peritoneal metastasis, consistent with stage 4B (T4b N2 M1b). Discussion: Goblet cell adenocarcinomas are more aggressive and have a worse prognosis than NETs. Therefore, they must be staged and treated as appendiceal carcinomas. The mixed histology of these tumors, has led to misdiagnosis and poor outcomes. Given the rapid spread of these tumors, a recent normal screening colonoscopy should not preclude prompt investigation of abdominal symptoms in at-risk patients, to include cross-sectional imaging, because surgical resection remains the primary curative treatment strategy. Furthermore, if suspected, preoperative colonoscopy for biopsy should not delay surgical resection. Current debate exists regarding extent of surgical resection required for Stage 1-2 GCAs. Additional treatment strategies for Stage 3-4 GCAs include 5-fluorouracil based adjuvant chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC). The low five-year survival, 57% for Stage 3 and 19% for Stage 4, emphasize the importance of early diagnosis and treatment.Figure 1.: A. CT abdomen/pelvis without contrast demonstrating a diffusely dilated, air-filled gastrointestinal tract extending from the stomach through the rectosigmoid colon. No transition point or obstruction noted. B. CT abdomen/pelvis with rectal contrast demonstrating an interposition of the hepatic flexure of the colon posterior and medial to the right lobe of the liver. No evidence of obstruction or strangulation noted. C. Endoscopy demonstrating a twisted, almost volvulus-like appearance at the splenic flexure, though without clear transition points.

P-302 Prognostic factors in stage IV appendiceal adenocarcinoma

Appendiceal carcinomas (AC) account for 1-2% of colorectal cancers (CRC), but there is limited data to guide treatment. We sought to identify prognostic factors for overall survival (OS). We identified histologically confirmed cases of appendiceal adenocarcinomas with metastatic disease and information about OS diagnosed between 2004 and 2016 from the National Cancer Database (NCDB). Kaplan-Meier method and log-rank test were used to estimate and compare OS. Recursive partitioning analysis (RPA) analysis was performed on the entire cohort. 6,792 patients met our inclusion criteria: 5,742 patients underwent surgical resection of the primary tumor and 1,050 patients did not. Surgical status, age, comorbidity status, cancer center type, chemotherapy use, and income were significant prognostic factors for OS by RPA, in that order. Patients who underwent surgery, were younger than 75 years, were treated at an academic institution, and were from communities with median income >=$63,000 (N=1,309) had the best median OS of 60.8 months, followed by similar patients from communities with median income < 0.0001). For patients who did not undergo surgery, OS decreased by 6 months if they had comorbidities (11 vs. 17 months, p< 0.0001). Surgical status, age, comorbidity status, cancer center type, chemotherapy use, and income were significant prognostic factors for OS by RPA, in that order. The best OS was seen in patients who underwent surgery, were younger than 75 years, were treated at an academic institution, and from communities with median income >=$63,000.

Outcomes of appendiceal adenocarcinomas compared to right and left-sided colorectal adenocarcinomas: An analysis from the National Cancer Database (NCDB).

42 Background: Appendiceal carcinomas (AC) account for 1-2% of colorectal cancers (CRC) and are generally treated like other CRC. However, there is limited data to guide treatment. While AC originate on the right side of the colon, it is unclear if they behave like as right-sided CRC (R-CRC). We seek to learn how AC differ from right versus left-sided CRC (L-CRC). Methods: We identified histologically confirmed cases of appendiceal and colorectal adenocarcinomas with information about stage and overall survival (OS) diagnosed between 2004 and 2016 from the National Cancer Database. Kaplan-Meier method and log-rank test were used to estimate and compare OS. Results: 833,939 patients met our inclusion criteria: 15,138 (1.8%) AC, 447,551 (53.7%) L-CRC, 308,794 (37.0%) R-CRC, and 62,456 (7.5%) transverse CRC (T-CRC). Median age at diagnosis of all patients was 68 years (range:18-90); AC was lowest at 61 years for stage I-III disease and 58 years for stage IV disease. Stage IV AC was more common in females 3628/5739 (63.22%). AC had the best OS among site groups in stage I-III. Median OS for stage I-III AC was 128.8 months (95% CI: 117.9-139.0), with 5-year OS rate of 0.69 (95% CI: 0.67-0.70); L-CRC median OS was 111.6 months (95% CI: 110.9-112.4), with 5-year OS rate of 0.681 (95% CI: 0.680-0.683); R-CRC median OS was 88.5 months (95% CI: 87.8-89.1), with 5-year OS rate of 0.613 (95% CI: 0.611-0.615); and T-CRC median OS was 86.2 months (95% CI: 84.7-87.6), with 5-year OS rate of 0.608 (95% CI: 0.604-0.613) (p &lt;0.0001) (Table). Similar difference was observed in stage IV patients (Table). Conclusions: Patients with AC had significantly better OS for stages I-III and stage IV compared to patients with L-CRC, R-CRC, and T-CRC, though outcomes were more similar to L-CRC. The difference is more evidence for patients with stage IV disease. T-CRC had similar OS to R-CRC, as anticipated. [Table: see text]

Epidemiology of and prognostic factors for appendiceal carcinomas: a retrospective, population-based study.

The aim of this study is to evaluate the epidemiology of and prognostic factors for appendiceal carcinomas (ACs). All cases of ACs registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2014 were retrospectively identified in this study. Age-adjusted incidence and survival rates were calculated. We analyzed 7170 patients with ACs. We observed a significant increase in the reported annual age-adjusted incidence of ACs from 1973 (0.18/100,000) to 2014 (1.11/100,000). The elevation of the incidence was noted in all the histological types, stages, and grades. The most common histological type varied by race, with the appendiceal mucinous adenocarcinoma (AMA) being the most common in white, Asian/Pacific Islander, and American Indian/Alaskan Native patients, and the appendiceal adenocarcinoma (AA) being the most common in African American patients. In multivariate analysis of patients with all ACs, gender (P < 0.001), year of diagnosis (P < 0.001), age (P < 0.001), race (P < 0.001), tumor grade (P < 0.001), disease stage (P < 0.001), retrieved regional lymph nodes (P < 0.001), type of surgery performed (P = 0.002), and histologic subtype (P < 0.001) were predictors of outcome. Survival time for all ACs increased from the 1973-1993 period to the 1994-2014 period (HR 0.76; 95% CI, 0.69 to 0.85). Additionally, the 5-year survival rates were 88% for malignant carcinoid, 70% for goblet cell carcinoid, 51% for colonic type adenocarcinoma, 59% for mucinous adenocarcinoma, and 25% for signet ring cell type. We observed increased reported incidence of ACs and increased survival durations over time, suggesting that clinicians pay more attention to ACs and mastering the characteristic of these tumors.

Nintedanib in metastatic appendiceal carcinoma.

TPS723 Background: Appendiceal carcinomas are rare with an incidence of about 0.12 cases per 1,000,000 people per year. There is limited, mostly retrospective data in the treatment of metastatic appendiceal carcinomas. Generally, fluoropyrimidine-based therapy is used in the first line, adapting regimens for metastatic colorectal cancer. However, beyond progression, no treatments have shown clear activity. In appendiceal cancer, high vascular endothelial growth factor receptor (VEGFR)2 expression has been correlated with poor survival. Moreover, malignant ascites has been demonstrated to have elevated levels of VEGF. Nintedanib is an oral tyrosine kinase inhibitor of VEGFR which demonstrated activity in lung and ovarian cancer in clinical trials, and has undergone investigation in heavily pretreated metastatic colorectal cancer. Given the analogies between appendiceal and colorectal cancer and potentially ovarian cancer, and the limited information about the optimal treatment of metastatic appendiceal carcinomas, further investigation with nintedanib is warranted. Methods: This is a single arm, open label, investigator initiated, two-stage phase II trial (NCT 03287947) in metastatic appendiceal cancer patients after failure (defined as progression on or within 6 months or intolerance) of initial fluoropyrimidine-based therapy and at least one measurable site of disease. The trial started enrolling patients in June 2018, and up to 39 subjects will be enrolled. They will be treated with 200 mg of oral nintedanib twice daily and undergo disease evaluation every two months. The primary objective of this study is to evaluate the disease control rate (DCR), the composite of objective response and stable disease per RECIST 1.1. Secondary objectives include evaluation of safety and toxicity, objective response rate (ORR), 6-month progression free survival (PFS) and overall survival (OS). DCR, ORR &amp; 6-month PFS will be estimated with the corresponding 95% Clopper-Pearson confidence interval. PFS &amp; OS will be estimated using Kaplan-Meier techniques. Exploratory objectives include evaluation of serum VEGF, ascites VEGF, hypertension and paracentesis frequency in subjects with ascites at study entry. Clinical trial information: NCT 03287947.

Appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid are genetically distinct from primary colorectal-type adenocarcinoma of the appendix

AbstractThe appendix gives rise to goblet cell carcinoids, which represent special carcinomas with distinct biological and histological features. Their genetic background and molecular relationship to colorectal adenocarcinoma is largely unknown. We therefore performed a next-generation sequencing analysis of 25 appendiceal carcinomas including 11 goblet cell carcinoids, 7 adenocarcinomas ex-goblet cell carcinoid, and 7 primary colorectal-type adenocarcinomas, using a modified Colorectal Cancer specific Panel comprising 32 genes linked to colorectal and neuroendocrine tumorigenesis. The mutational profiles of these neoplasms were compared with those of conventional adenocarcinomas, mixed adenoneuroendocrine carcinomas, and neuroendocrine carcinomas of the colorectum. In addition, a large-scale pan-cancer sequencing panel covering 409 genes was applied to selected cases of goblet cell carcinoid/adenocarcinoma ex-goblet cell carcinoid (n=2, respectively). Mutations in colorectal cancer-related genes (eg, TP53, KRAS, APC) were rare to absent in both, goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid, but frequent in primary colorectal-type adenocarcinomas of the appendix. Additional large-scale sequencing of selected goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid revealed mutations in Wnt-signaling-associated genes (USP9X, NOTCH1, CTNNA1, CTNNB1, TRRAP). These data suggest that appendiceal goblet cell carcinoids and adenocarcinomas ex-goblet cell carcinoid constitute a morphomolecular entity, histologically and genetically distinct from appendiceal colorectal-type adenocarcinomas and its colorectal counterparts. Altered Wnt-signaling associated genes, apart from APC, may act as potential drivers of these neoplasms. The absence of KRAS/NRAS mutations might render some of these tumors eligible for anti-EGFR directed therapy regimens.

Appendiceal carcinoma associated with microsatellite instability.

Approximately 15% of colorectal cancer (CRC) cases exhibit microsatellite instability (MSI), which appears to be associated with unique biological behavior. The present study presents a case of appendiceal carcinoma associated with MSI that responded well to adjuvant chemotherapy. Clinical, pathological and immunohistochemical (IHC) characteristics have been described. The 60-year-old male patient had suffered from recurrent lower abdominal pain associated with abdominal distention for 6 months; then, following an acute attack, he was subjected to laparoscopic appendectomy. The histopathological examination revealed moderately differentiated appendiceal adenocarcinoma with mucinous areas, without lymphovascular or perineural invasion. The IHC examination was positive for keratin-20 and caudal type homeobox 2, and negative for MutL Homolog 1, MutS Homolog (MSH) 2 and MSH-6. A postoperative colonoscopy revealed diverticulosis, without the presence of polyps or tumors. However, an abdominal axial computerized tomography scan revealed thickening of the distal portion of the appendix, increased density of the greater omentum, and metastases to the liver capsule, spleen and peritoneum. The treatment of choice was right hemicolectomy with peritoneal debulking, followed by 10 cycles of chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX regimen). After 5 years of follow-up, the patient remains in good condition, without clinical or radiological signs of recurrence. The good response to chemotherapy corresponds with the observations made in other colon cancers with MSI. Therefore, testing for MSI in appendiceal carcinomas may provide useful information on prognosis and predict response to chemotherapy.

Association of HIPEC with survival in patients with ovarian metastases of gastrointestinal origin.

e15124 Background: Metastatic ovarian involvement in primary gastrointestinal (GI) carcinomas (CA) is associated with a poor prognosis. We performed a survival analysis in patients with ovarian metastases, based on site of primary GI CA (appendiceal, colorectal (CRC), gastric, and pancreatic). We also examined the association between hyperthermic intraperitoneal chemotherapy (HIPEC) and death in these patients. Methods: A search was conducted in a single institution pathology database for patients with primary GI CA and ovarian metastases diagnosed from 2010 to 2017. The search yielded 39 patients, and data pertaining to tumor characteristics and treatment were obtained by chart review. Chi-square (log rank) test was used to test for associations between both site of primary GI CA and HIPEC, and death, and Kaplan-Meier analysis was done. P-value &lt; 0.05 was deemed statistically significant. Results: CRC accounted for the majority of patients (51.29%) with appendiceal CA accounting for 23.08% and gastric and pancreatic cancer making up the remainder. Primary site of malignancy was associated with survival (p = 0.036), favoring those with appendiceal and colorectal primaries. A total of 30 patients (76.92%) received HIPEC. Having undergone HIPEC was significantly associated with survival (p = 0.017). Conclusions: Ovarian metastases secondary to gastric and pancreatic cancer were associated with inferior survival as compared to those with appendiceal or colorectal primaries. A significant association was demonstrated between HIPEC and survival. Further investigation to define the role of HIPEC in the treatment of carcinomas of gastrointestinal primaries is warranted.

Necessity of appendectomy for mucinous borderline ovarian tumors. Systematic review.

The benefit of performing an appendectomy during the surgical treatment of a mucinous borderline ovarian tumor (mBOT) is still controversial, even though clinical guidelines recommend this procedure. Our aim was to systematically assess the available evidence on appendectomy in the case of diagnosis of mBOT. A comprehensive search of the literature was conducted using electronic databases using the search terms: (borderline OR low malignant potential) AND (appendectomy OR appendix). A total of 12 articles were retained after systematic review, including a total of 667 patients with borderline ovarian tumor. Appendectomy was performed in 232 of the patients presenting with a mBOT. Two (0.86%) appendiceal carcinomas were confirmed on pathological examination. Both appendices were grossly abnormal at the time of surgery. Our systematic review demonstrates that available evidence regarding the role of appendectomy in mBOT is fragmented and weak. Nevertheless, this review provides adequate evidence to highlight that appendiceal involvement in mBOTs appears to be extremely rare and microscopic appendiceal involvement is highly unlikely in apparently normal appendices. In spite of the diversity of the included studies, the lack of appendiceal involvement in all cases with apparently normal appendix is strikingly common. We can conclude that in the case of normal appearance of the appendix at the time of primary surgery, appendectomy is not mandatory. Furthermore, a patient with a normal appendiceal appearance during primary surgery with post-operative diagnosis of mBOT addition of a second look intervention seems unnecessary and even hazardous.

Appendiceal Adenocarcinoma Masquerading as an Ovarian Mass: A Case Report

Introduction: Primary appendiceal carcinomas are rare neoplasms of the gastrointestinal tract that have seen an increase in diagnosis over the past 10 years. The most common presentation is acute appendicitis or abdominal distension, although occasionally they may present as an adnexal mass due to their anatomical location. We present a case report of the diagnosis of an appendiceal adenocarcinoma found on colonoscopy that presented as a gynecological neoplasm. Case: A 77 year old female was referred to the office from gynecological oncology for evaluation an 8cm x 7cm right pelvic mass seen on CT scan. The CT was ordered due to complaints of several months of weakness, 30lb weight loss, and intermittent localized right lower quadrant abdominal pain. The mass was extensive and was causing deviation of her bladder and severe right-sided hydroureter. A colonoscopy done about 10 years ago was normal. History was significant for right-sided breast cancer status post right radical mastectomy, total abdominal hysterectomy, and 25 pack year history of smoking. Her family history was positive for esophageal cancer in her mother, but denied breast, ovarian, gastric, and colon cancers. Her vitals were within normal limits. Her abdominal exam was significant for tenderness to palpation in the right lower quadrant with fullness. On pelvic exam, there was a large, non-tender, fixed right-sided adnexal mass. Lab studies revealed CEA = 416.2; CA-125 = 11; and CA 19-9 = 1. A colonoscopy was performed prior to her planned surgical resection. Initial observation was unremarkable, including examination of the distal terminal ileum. The markedly elevated CEA level and location of the lesion warranted more aggressive investigation, and the appendiceal orifice was gently probed with a closed cold forceps. This revealed a large friable, appendiceal mass which was biopsied. The biospies revealed adenocarcinoma, with markers suggesting colon over ovarian etiology. An attempt was made to resect the tumor, but due to the extent of the disease and co-morbidities, this was not done and a palliative bypass was performed. Discussion: In this case, based on the right lower quadrant/pelvic mass, ovarian and colonic tumors were considered. On colonoscopy, care was given to search for tumors, particularly inside the appendiceal orifice. With a known elevated CEA in a patient with a right lower quadrant mass, a diagnosis of appendiceal adenocarcinoma was able to be made preoperatively on colonoscopy. Diagnosis of appendiceal adenocarcinoma is rarely made on colonoscopy and is often found incidentally on appendectomy.

Comprehensive genomic profiling of cancer of the appendix to reveal new routes to targeted therapies.

608 Background: Cancers of the appendix are rare forms of malignancy that include two major mucin producing tumors, mucinous adenocarcinoma (MA) and goblet cell carcinoid (GCC). There is no clear standard of care for management of these malignancies. We queried whether comprehensive genomic profiling (CGP) of MA and GCC would reveal differences in the pattern of genomic alterations (GA) of these two subtypes of appendiceal cancer and serve as a guide for targeted therapies for this disease. Methods: DNA was extracted from 40 microns of FFPE sections from 20 clinically advanced appendiceal carcinomas (9 GCC and 11 MA). Comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation based libraries to a high mean coverage depth of &gt;600X for 3,230 exons of 182 cancer-related genes, plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of GA including base substitutions, short insertions and deletions, copy number alterations and fusions/rearrangements. Clinically relevant GAs were defined as GAs linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Base substitutions in KRAS were seen in 73% of MA and 11% of GCCs. TP53 mutations were seen in 64% of MA and 22% of GCCs. MYC (36%), SMAD4 (27%), and APC (27%) mutations were found in MA but were absent in GCC. Other GA of low frequency, but clinically relevant in both subsets included ERBB2, GNAS, ARID1A, PIK3CA, NRAS, CTNNB1, BRCA1, BRAF, KDR, PTEN, MCL1, IDH1, FBXW7, and RICTOR. Conclusions: KRAS and TP53 mutations are common in appendiceal MA, but rare in appendiceal GCCs. This confirms the differences in biology and has implications regarding the use of targeted therapies such as anti-EGFR antibody treatments. The high frequency of clinically relevant genomic alterations uncovered in this study that can potentially serve as targets for therapies, either approved or in clinical trials, raises hope that CGP can lead to improvement in outcomes for patients with this aggressive form of malignancy.

Combination of CT imaging and endoscopy in diagnosis of appendicovesical fistula caused by appendiceal adenocarcinoma

The appendiceal diseases, particularly appendicitis, are the most common disorders in the digestive system localized at the right lower quadrant area. However, appendiceal carcinoma with vesico-appendiceal fistula is a rare clinical phenomenon. Lacking specific symptoms, appendiceal carcinomas with fistula formations are often misdiagnosed as acute appendicitis cases. The purpose of this study is to increase awareness of appendiceal neoplasms and appendicovesical fistulas. We reported our experiences in three complex cases related to digestive and urological systems, and reviewed the literature on diagnosis with various X-ray imaging techniques for this lesion. In this report, the first case failed to be diagnosed. The other two patients with appendicovesical fistulas secondary to appendiceal adenocarcinomas were successfully detected with computed tomography (CT) and cystoscopy. The patients recovered after right hemicolectomies and en bloc partial cystectomies and survived without tumor metastasis up to 7-year follow-up. In conclusion, a combined use of CT imaging and endoscopy techniques provides an accurate diagnostic alternative for appendicovesical fistula secondary to appendiceal adenocarcinoma.

Prior appendectomy does not protect against subsequent development of malignant or borderline mucinous ovarian neoplasms

BackgroundDue to concern that mucinous malignant or borderline ovarian neoplasms (MON) may represent metastatic deposits from appendiceal primaries, gynecologic oncologists routinely perform appendectomy in these cases. However, a multidisciplinary critique of this practice is lacking. MethodsThe New England Case–Control study database was utilized to compare the effect of prior appendectomy against known risk factors for MON. Pathology and operative reports of local cases of MON were reviewed to estimate the frequency of microscopic mucinous lesions in the appendix. Protein expression patterns among mucinous ovarian, colorectal, and appendiceal cancers were compared by immunohistochemistry. ResultsFrom the New England Case–Control study, 287 cases of MON were compared against 2339 age-matched controls. Prior appendectomy did not reduce the risk of MON (OR 1.28, 95% CI 0.83–1.92, p=0.23), while prior tubal ligation, parity, and breastfeeding were each protective against MON. Active smoking (OR 2.04, 95% CI 1.48–2.80, p<0.001) was associated with an increased risk of MON. Among 196 mucinous adnexal tumors, appendectomy did not reclassify any MON as appendiceal in origin. By immunohistochemistry, mucinous ovarian carcinomas tended to be CK7+/CK20−/MUC2−/CDX2−, whereas mucinous colorectal and appendiceal adenocarcinomas were typically CK7−/CK20+/MUC2+/CDX2+, although with some overlap in immunophenotype. Additionally, PAX8 was positive in a subset of MOC and negative in all appendiceal carcinomas. ConclusionPrior appendectomy is not protective against development of malignant or borderline MON. Routine appendectomy during surgery for MON seldom reveals an unsuspected GI primary in early stage tumors but may aid in final diagnosis in advanced stage cases. FundingNational Cancer Institute grants P50-CA105009 and R21 CA-156021; The Honorable Tina Brozman ‘Tina's Wish’ Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF); Dana-Farber Cancer Institute — Susan Smith Center for Women's Cancers; Robert and Deborah First Fund; The Gamel Family Fund; Mary Kay Foundation; Sandy Rollman Ovarian Cancer Foundation; Arthur Sachs/Fulbright/Harvard; La Fondation Philippe; La Fondation de France.

High-level Microsatellite Instability in Appendiceal Carcinomas

High-level microsatellite instability (MSI-high) is found in approximately 15% of all colorectal adenocarcinomas (CRCs) and in at least 20% of right-sided cancers. It is most commonly due to somatic hypermethylation of the MLH1 gene promoter region, with familial cases (Lynch syndrome) representing only 2% to 3% of CRCs overall. In contrast to CRC, MSI-high in appendiceal adenocarcinomas is rare. Only 4 MSI-high appendiceal carcinomas and 1 MSI-high appendiceal serrated adenoma have been previously reported, and the prevalence of MSI in the appendix is unknown. We identified 108 appendiceal carcinomas from MD Anderson Cancer Center in which MSI status had been assessed by immunohistochemistry for the DNA mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 (n=83), polymerase chain reaction (n=7), or both (n=18). Three cases (2.8%) were MSI-high, and 1 was MSI-low. The 3 MSI-high cases included: (1) a poorly differentiated nonmucinous adenocarcinoma with loss of MLH1/PMS2 expression, lack of MLH1 promoter methylation, and lack of BRAF gene mutation, but no detected germline mutation in MLH1 from a 39-year-old man; (2) an undifferentiated carcinoma with loss of MSH2/MSH6, but no detected germline mutation in MSH2 or TACSTD1, from a 59-year-old woman; and (3) a moderately differentiated mucinous adenocarcinoma arising in a villous adenoma with loss of MSH2/MSH6 expression, in a 38-year-old man with a strong family history of CRC who declined germline testing. When the overall group of appendiceal carcinomas was classified according to histologic features and precursor lesions, the frequencies of MSI-high were: 3 of 108 (2.8%) invasive carcinomas, 3 of 96 (3.1%) invasive carcinomas that did not arise from a background of goblet cell carcinoid tumors, and 0 of 12 (0%) signet ring and mucinous carcinomas arising in goblet cell carcinoid tumors. These findings, in conjunction with the previously reported MSI-high appendiceal carcinomas, highlight the low prevalence of MSI in the appendix as compared with the right colon and suggest that MLH1 promoter methylation is not a mechanism for MSI in this location.

Surgical management of primary appendiceal malignancy

Primary appendiceal neoplasms are rare, with carcinoid being more common than carcinoma. Preoperative diagnosis is infrequent. We report a series of 24 primary appendiceal neoplasms treated over a 5-year period. All primary appendiceal neoplasms diagnosed in a university teaching hospital between April 2003 and June 2008 were identified from the prospective histopathology database. Patient records were reviewed for clinical, operative and pathological data. Fourteen carcinomas and 10 carcinoids were identified in the 5-year period. The former presented at median age 55.8 years with median symptom duration of 35 days, compared with 48 years and 3 days, respectively, for carcinoids. An abdominal mass was commoner in carcinomas (8/14 vs 1/10). Six patients with carcinoma underwent appendicectomy followed by completion right-hemicolectomy, two of whom had residual disease; seven underwent primary right-hemicolectomy and one had abscess drainage. Five patients with appendiceal carcinoma died of the disease during a median follow-up of 633 (256-1158) days. Six patients underwent appendicectomy for acute appendicitis, one had a primary right-hemicolectomy for a caecal mass. Three had a subsequent right-hemicolectomy for a high-risk carcinoid. An appendiceal carcinoid was an incidental finding in three right-hemicolectomy specimens removed for other indications. No metastases or deaths were recorded at median follow-up 451 (51-975) days. Appendiceal carcinomas follow a more protracted clinical course than carcinoids, which usually present as acute appendicitis. Caution is needed when diagnosing simple appendicitis in older patients with longer symptom duration, particularly if a mass is present. Patients with appendiceal carcinoma should be offered completion right-hemicolectomy. Carcinoma has a poor prognosis.

661 - Tumors of the Appendix: the Experience of Ipo-Porto

ABSTRACT Introduction Malignant neoplasms of ileocecal appendix are rare, an clinical features are unspecific, often mimicking acute appendicitis. They are diagnosed in about 1% of appendicectomy specimens. The most common histologic types are mucinous adenocarcinoma, intestinal-type adenocarcinoma and carcinoid tumor. Methods The authors reviewed the primary appendix carcinomas treated in Instituto Portugues de Oncologia Francisco Gentil-Porto (IPOFG-Porto) between January 2000 and June 2011. Results Fourty two patients were treated during this period: 30 women (71%) and 12 men, aged between 20 and 90 years old (median age 58). Mucinous adenocarcinoma was the most common histologic subtype, with 27 cases (64%), followed by adenocarcinoma NOS (10 cases - 24%); carcinoids were 5 cases (12%). Fifteen percent presented as stage IV, 7% stage III, 24% stage II and 19% stage I. The primary treatment was surgery: 16 patients were submitted to appendicectomy, 6 patients to appendicectomy, ooforectomy and hysterectomy, 12 to hemicolectomy. Of patients submitted to appendicectomy, 11 (50%) had a second laparotomy in order to perform hemicolectomy. Five percent of the patients received adjuvant chemotherapy (mFOLFOX6). Hyperthermic Intraoperative Peritoneal Chemotherapy (HIPEC) was performed in 18 patients with stage IV disease (peritoneal carcinomatosis). The median follow-up was 35 months. Thirty three percent of the patients (n = 14) died because of disease progression and 62% (n = 26) were alive with no evidence of disease. Conclusion Appendiceal carcinomas are rare tumours and there is limited evidence on the indications for right hemicolectomy. The role of adjuvant chemotherapy for adenocarcinoma of the appendix is unknown. Optimal treatment of patients with intraperitoneal dissemination of appendiceal adenocarcinoma (mucinous peritoneal carcinomatosis) is unclear. Selected patients treated with aggressive surgical cytoreduction and HIPEC may have a favorable outcome in long term, but patient selection and the experience of the treating team are critical. The benefit of systemic chemotherapy for advanced disease is unknown. Disclosure All authors have declared no conflicts of interest.

Use of gene expression profiling to determine prognosis and therapeutic targets for patients with appendiceal carcinoma.

418 Background: Appendiceal carcinomas are rare neoplasms that often present as peritoneal surface malignancies. The tumors are treated similarly to primary colorectal metastases, despite having different biological environments. The aim of this study is to utilize genomic analyses to understand the underlying biology of appendiceal carcinoma in order to better guide prognosis and therapy. Methods: Forty-one metastatic human tumors to the peritoneum (26 appendiceal carcinoma, 15 colorectal carcinoma) were subjected to global gene expression analysis. Unsupervised hierarchical clustering was used to differentiate phenotypes based on differential gene expression. Phenotypes were further analyzed to find differences in oncogenic pathway deregulation and findings were validated using gene specific inhibitors in vitro. Results: Unsupervised hierarchical clustering revealed three distinct phenotypes, two consisting of predominantly low grade appendiceal samples (Cluster 1 and Cluster 2) and one consisting of predominantly colorectal samples (Cluster 3). Cluster 1 consisted of patients with good prognosis and Cluster 2 consisted of patients with poor prognosis (p = 0.046). Further characterization of Cluster 1 and Cluster 2 with oncogenic pathway signatures identified increased deregulation of the EGFR pathway in the poor prognosis cluster. Similarly, colon cancer cell lines with the poor prognosis phenotype were found to be more sensitive to gefitinib (EGFR inhibitor) (p = 0.038). Conclusions: The use of geneexpression profiling can be used to identify prognosis and novel therapeutic targets for patients with appendiceal carcinoma. These methods can serve as models to understand the biology of appendiceal carcinoma and to assist in the design of future trials for patients with appendiceal cancer. No significant financial relationships to disclose.

Descripción clínico-morfológica y factores pronósticos en carcinomas de apéndice cecal: Estudio de cohorte

Appendiceal malignant tumors. Review of 84 cases Background: Malignant appendiceal tumors account for only 0.5% of all gastrointestinal tumors and there are usually diagnosed during the pathological study of excised appendices. Aim: To assess the factors infl uencing the survival of patients with appendiceal carcinomas. Material and Methods: Retrospective re- view of records of all primary appendiceal carcinomas diagnosed in the pathology unit of a regional hospital between 1993 and 2008. The surgical procedure, clinical history, morphological features of tumor and survival were recorded. Results: Eighty four patients aged 32 ± 15 years (44 women) with appendiceal carcinoma were identifi ed. In 93% of patients, the clinical diagnosis was acute appendicitis. Sixty one patients (73%) had a carcinoid tumor, 20 (24%) an adenocarcinoma and three (3%), an adenocarcinoid tumor. Preoperative suspicion of a malignant tumor, level of tumor infi ltration, pathological type, involvement of surgical borders, tumor size over 2 cm in the case of carcinoid tumors and the degree of differentiation of adenocarcinomas, had prognostic value. For adenocarcinomas, performing a right hemicolectomy signifi cantly improved survival. Conclusions: Carcinoid tumors are the most common malignant tumor of the appendix. A right hemicolec- tomy may improve the survival of patients with appendiceal adenocarcinomas.