Appendiceal Epithelial Neoplasms Research Articles

Pathological diagnosis and clinical significance of appendiceal epithelial neoplasms

Appendiceal epithelial neoplasms including benign and malignant, are clinically rare. There were quite a lot of changings in classification systems for them and different pathological diagnostic terminologies were used, resulted in confusions of understanding and communication for both pathologists and clinicians. Basically, appendiceal epithelial neoplasms include adenoma, serrated lesion and polyps, mucinous neoplasms, carcinoma and neuroendocrine neoplasms. Appendiceal mucinous neoplasms and goblet cell carcinoma are exclusively seen in the appendix. Though some appendiceal neoplasms are similar to those in large bowl, however, the molecular mechanism is different. The classification, pathological diagnosis and clinical significance of appendiceal epithelial neoplasms were summarized based on the fifth edition of WHO classification on digestive system tumors and other related literatures.

Standardization of the pathologic diagnosis of appendiceal mucinous neoplasms.

Although the understanding of appendiceal mucinous neoplasms (AMNs) and their relationship with disseminated peritoneal mucinous disease have advanced, the diagnosis, classification, and treatment of AMNs are still confusing for pathologists and clinicians. The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (GPSG-KSP) proposed a multicenter study and held a workshop for the “Standardization of the Pathologic Diagnosis of the Appendiceal Mucinous Neoplasm” to overcome the controversy and potential conflicts. The present article is focused on the diagnostic criteria, terminologies, tumor grading, pathologic staging, biologic behavior, treatment, and prognosis of AMNs and disseminated peritoneal mucinous disease. In addition, GPSG-KSP proposes a checklist of standard data elements of appendiceal epithelial neoplasms to standardize pathologic diagnosis. We hope the present article will provide pathologists with updated knowledge on how to handle and diagnose AMNs and disseminated peritoneal mucinous disease.

Correlation of molecular and morphological features of appendiceal epithelial neoplasms.

The aims of this study were to identify the genetic features of appendiceal epithelial neoplasms and correlate the genetic features with morphology. We analysed the genetic features of a series of 47 appendiceal epithelial neoplasms of various morphologies by using targeted next-generation sequencing of 11 genes commonly mutated in gastrointestinal neoplasms. Seven of nine serrated polyps harboured BRAF mutations, which are rare in other types of appendiceal tumours. Most cases of low-grade appendiceal mucinous neoplasms (LAMNs) exhibited GNAS and KRAS mutations. LAMNs with a coexisting serrated polyp were all KRAS mutated. Four LAMNs with mutations in the Wnt/β-catenin pathway, either through inactivating mutations in APC or RNF43 or activating mutations in CTNNB1, had focal proliferation of mucin-poor low-grade tumour cells, reminiscent of colorectal adenomas. Mutations in the Wnt/β-catenin pathway were also identified in high-grade appendiceal mucinous neoplasms, suggesting that Wnt/β-catenin pathway activation is the driving force for the progression of LAMN to a higher-grade lesion. Adenomatous polyps of the appendix frequently had APC, KRAS and TP53 mutations and were morphologically and molecularly similar to adenomatous polyps of the colorectum. Our results indicate a close association between morphology and genetic events in appendiceal neoplasms and suggest a phylogenetic relationship between different entities.

Outcomes from cytoreduction and hyperthermic intraperitoneal chemotherapy for appendiceal epithelial neoplasms.

Appendiceal epithelial neoplasms are rare cancers. Management of peritoneal disease from appendiceal neoplasms has historically been with debulking surgery. In recent decades, the advent of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has become the standard of care. Here, we report our single institution 10-year experience with CRS and HIPEC for appendiceal neoplasms. This is a retrospective review from 1 January 2008 to 1 June 2017 of all patients undergoing CRS and HIPEC for appendiceal neoplasms. Institutional ethics approval was granted for this project. One hundred and seventy-two patients underwent 208 CRSs during this time. Overall, 83.72% of patients had one CRS and HIPEC procedure. Pseudomyxoma peritonei from a perforated appendiceal mucinous neoplasm accounted for 67.9% of cases. The median peritoneal carcinomatosis index (PCI) was 14, with complete cytoreduction achieved in 74.2% of patients. Fifty-four percent of patients had at least one complication, with one (0.5%) peri-operative mortality in our cohort. For the entire cohort, the median overall survival was 104 months and a 5-year survival of 75%. In those having a complete cytoreduction, 5-year survival was 90%, with a median disease free interval of 63 months. PCI and completeness of cytoreduction were independent predictors of overall survival. Our results demonstrate that CRS and HIPEC for appendiceal neoplasms are safe and effective. Despite carrying some morbidity, it offers patients an excellent disease free and overall survival.

A proposal of Brazilian Society of Surgical Oncology (BSSO/SBCO) for standardizing cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) procedures in Brazil: pseudomixoma peritonei, appendiceal tumors and malignant peritoneal mesothelioma

Cytoreductive surgery plus hypertermic intraperitoneal chemotherapy has emerged as a major comprehensive treatment of peritoneal malignancies and is currently the standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome as well as malignant peritoneal mesothelioma. Unfortunately, there are some worldwide variations of the cytoreductive surgery and hypertermic intraperitoneal chemotherapy techniques since no single technique has so far demonstrated its superiority over the others. Therefore, standardization of practices might enhance better comparisons between outcomes. In these settings, the Brazilian Society of Surgical Oncology considered it important to present a proposal for standardizing cytoreductive surgery plus hypertermic intraperitoneal chemotherapy procedures in Brazil, with a special focus on producing homogeneous data for the developing Brazilian register for peritoneal surface malignancies.

Utility of Appendiceal Calcifications Detected on Computed Tomography as a Predictor for an Underlying Appendiceal Epithelial Neoplasm.

Mucinous appendiceal neoplasms can contain radiopaque calcifications. Whether appendiceal radiographic calcifications indicate the presence of an appendiceal epithelial neoplasm is unknown. This study aimed to determine whether appendiceal calcifications detected by computed tomography (CT) correlate with the presence of appendiceal epithelial neoplasms. From prospective appendiceal and pathology databases, 332 cases of appendiceal neoplasm and 136 cases of control appendectomy were identified, respectively. Only cases with preoperative CT scans available for review were included in the study. Images were reviewed by two abdominal radiologists. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated, and the kappa statistic was used to determine agreement between the radiologists' interpretations. Interobserver agreement between the radiologists was substantial, with a kappa of 0.74. Appendiceal mural calcifications were identified on CT scans in 106 appendiceal neoplasm cases (32%) and in 1 control case (1%) (P=0.0001). In the appendiceal neoplasm subgroup, the presence of radiographic calcifications was associated with mucinous histology (35% vs 17%; P=0.006; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.78) and with well-differentiated histologic grade (40% vs 24%; P=0.002; OR, 0.47; 95% CI, 0.29-0.76). The findings showed a sensitivity of 31.9% (95% CI, 26.9-37.2%), a specificity of 99.3% (95% CI, 96-100%), a PPV of 99.1% (95% CI, 94.9-100%), and an NPV of 37.4% (95% CI, 32.4-42.6%). This case-control study showed that appendiceal mural calcifications detected on CT are associated with underlying appendiceal epithelial neoplasms and that the identification of incidental mural appendiceal calcifications may have an impact on decisions regarding surgical intervention.

Retrospective study of non-mucinous appendiceal adenocarcinomas: Role of systemic chemotherapy and cytoreductive surgery.

263 Background: The majority of studies evaluating appendiceal epithelial neoplasms have focused on those with mucinous histology. Few studies have reported on non-mucinous appendiceal adenocarcinomas. We performed the largest single-center study to investigate this histologic subtype, in order to describe the natural history and impact of both cytoreductive surgery (CRS) and systemic chemotherapy. Methods: We retrospectively reviewed 172 pts with non-mucinous appendiceal adenocarcinoma evaluated at the UT-MD Anderson Cancer Center between 1990 and 2015. Patient demographics, tumor characteristics, therapy received, and outcomes were recorded. Response assessment was semi-quantitative (response vs. no response) according to the treating physician. Overall survival (OS) and time to progression (TTP) were calculated using Kaplan Meier product-limit method and survival rates compared using the log rank test. Results: Median age at diagnosis was 52.9 yrs (M:F 1:1). Most pts presented with advanced stage: stage I (1.7%), stage II (32.5%), stage III (14.5%), and stage IV (51.2%). No patient had well-differentiated histology. 56% had moderate and 44% poor histology. Median OS by stage was 90.9m [95% CI: 70.8 to 172.9] for stage II, 52.1m [95% CI: 28.9 to NA] for stage III and 28.3m [95% CI: 22.9 to 31.9] for stage IV, (p < 0.0001). In pts with metastatic disease (n = 128) CRS was attempted in 20 (15.6%) and was complete (CCS 0/1) in 12. The median OS for pts achieving complete CRS was 48.6m. Systemic chemotherapy was administered to 92% (118/128) of metastatic pts. The median TTP was 9.4m [95% CI: 8.0 to 11.5] and semi-quantitative response rate was 54%. The majority of pts received either oxaliplatin-based, 57%, or irinotecan-based, 23%, first-line chemotherapy regimens. No statistical difference in TTP (p = 0.9) or OS (p = 0.07) between different chemotherapies was seen. Conclusions: In contrast to mucinous appendiceal neoplasms, non-mucinous appendiceal adenocarcinomas rarely present with low-grade (well-differentiated) histology. Treatment approaches appear more akin to colorectal cancer with most metastatic pts undergoing systemic chemotherapy and a minority undergoing CRS.

Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms.

Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms. However, for nonsurgical candidates, systemic treatment may be considered. The purpose of this analysis was to determine the benefit of biologic therapy (anti-vascular endothelial growth factor and anti-epidermal growth factor receptor) in addition to systemic chemotherapy in this select patient population. The MD Anderson Cancer Center tumor registry was retrospectively reviewed for systemic treatment-naive appendiceal epithelial neoplasm patients registered between January 2000 to July 2007 for prior cytoreductive surgery and hyperthermic intraperitoneal chemotherapy status, histologic grade, signet ring pathology, systemic chemotherapy, biologic therapy, tumor markers (carcinoembryonic antigen, carbohydrate antigen [CA] 125, and/or CA19-9), progression-free survival (PFS), overall survival (OS), and disease control rate. Kaplan-Meier method, log-rank, and Cox proportional hazard regression models were used for statistical analysis. A total of 353 patients were identified; 130 patients met the inclusion criteria. Fifty-nine patients received biologic therapy. The use of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab improved both OS (42months vs. 76months, hazard ratio 0.49 [95 % confidence interval 0.25-0.94] P=0.03) and PFS (4months vs. 9months, hazard ratio 0.69 [95 % confidence interval 0.47-0.995], P=0.047) for all histologic subtypes. Moderately differentiated tumors had an improved PFS relative to well-differentiated tumors, 9months versus 3months (P=0.05). Bevacizumab in combination with chemotherapy appears to play a role in surgically unresectable appendiceal epithelial neoplasm patients, with an improvement in PFS and OS. Anti-VEGF agents should be strongly considered in the management of patients with higher-grade appendiceal epithelial neoplasms who are suboptimal candidates for surgical resection.

Assessment of the impact of systemic chemotherapy (SC) on the quality of life (QOL) in patients with metastatic unresectable appendiceal epithelial neoplasms (AEN).

522 Background: AEN is a rare malignancy ranging from indolent well-differentiated carcinoma to highly aggressive signet ring carcinoma. Optimal therapy is cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC). Yet some patients (pts) are suboptimal for CRS/HIPEC, and are considered for SC. We have previously reported our retrospective analysis suggesting overall survival (OS) benefits from SC. We then opted to assess the impact of SC on QOL in unresectable AEN pts for which no standard of care exists. Methods: 50 pts who initiated SC were prospectively enrolled at our institution between Oct. 2008 and Nov. 2011. EORTC (3.0) QLQ-C30 and QLQ-OV28 surveys were provided at baseline and quarterly for one year. Data were analyzed with Linear Fixed Effects models using SAS Proc Mixed. Baseline and 6 month follow-up scores were tested separately for all QOL outcomes. Subscale means were converted to scaled values from 0 to 100. Positive change over the interval indicated improvement, except in symptom scales where positive change indicated worsening symptomatology. Results: 26 pts (52%) were male, median age was 64 (37-80). All pts received 5-FU-based treatment, and 37 (74%) received a biologic agent. 18 pts (36%) had poorly differentiated histology. Statistically significant change was noted in 2 subscales (Table). Overall, the Global subscale demonstrated no significant change from baseline (MME=2.9095, p=0.4422). Conclusions: In light of the possible OS benefit of systemic treatment in unresectable AEN as previously presented, our data suggest that palliative SC does not decrease QoL and in fact correlates with improved emotional well-being, and diminished symptoms including myalgias, arthragias and weakness. Awareness of these clinical and psychiatric results will better enable clinicians to ensure optimal outcomes for their AEN patients while on treatment.[Table: see text]

Role of biologic therapy in the treatment of unresectable appendiceal epithelial neoplasms (AEN).

628 Background: AEN ranges from benign appearing cells to poorly differentiated signet cell adenocarcinoma. Currently, cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is believed to be optimal treatment. Systemic chemotherapy (SC) +/- biologic therapy (BT) is considered when CRS is not feasible. VEGF expression reportedly is a poor prognostic indicator in AEN pts. The purpose of this analysis is to determine the benefit of BT in chemotherapy naïve suboptimal candidates for CRS. Methods: A retrospective chart review of AEN pts registered in our tumor registry between Jan. 2005 to Dec. 2009 was undertaken. Electronic medical records (EMR) were reviewed for CRS, HIPEC, histology, stage, SC + BT, CEA, CA-125, and/or CA 19-9, response (R), and progression-free survival (PFS). All patients were required to be radiographically restaged at MDACC. R was defined as clinical or radiographic benefit. K-M method, Log-Rank, and Cox proportional hazard regression models were used for statistical analysis. Results: Of 625 pts with a diagnosis of AEN, 132 (21%) fulfilled the inclusion criteria and were evaluable for PFS and R. Sixty-five (49%) pts received SC + BT; 67 (51%) pts received SC alone. SC included: 5-FU = 28 (21%), FOLFIRI = 20 (15%), FOLFOX = 71 (54%), and other = 13 (10%). BT included: bevacizumab = 58 (89%), EGFR inhibitor = 6 (9%); 1 pt (2%) received both. Median lines of BT = 1 (range: 1-3). Histologically, 51 (38%) were poorly differentiated and 33 (25%) were signet ring; 26 (20%) had both features. After a median follow-up of 33M, 40 (62%) had stable disease, 12 (19%) partial response, and 12 (19%) progressive disease. Biologic therapy improved median PFS and OS (17M vs. 7M, p-value = 0.007; 68M vs. 50M, p-value = 0.08, respectively). Multivariate analysis indicated improved PFS (HR: 0.49; 95% CI: 0.3-0.8; p-value: <0.001) and OS (HR: 0.52; 95% CI: 0.3-0.8; p value = 0.007) in favor of biologic therapy. Conclusions: Biologic therapy in combination with chemotherapy appears to have a role in surgically unresectable AEN pts with improvement in PFS and OS. Tissue/blood correlatives and quality of life analysis are underway. Prospective analysis including cost-benefit should be considered.

Systemic chemotherapy in the setting of unresectable appendiceal epithelial neoplasms (AEN).

568 Background: AEN is a malignancy including both indolent well-differentiated and highly aggressive signet ring carcinoma. Optimal therapy is believed to be cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC). Yet, some patients (pts) will recur, are suboptimal for surgery, and are considered for systemic chemotherapy (SC). The purpose of this study is to compare SC regimens in treatment-naïve surgically unresectable AEN pts. Currently, no standard exists. Methods: A retrospective review of AEN pts who were registered in our tumor registries between Jan. 2005 to Dec. 2009 was completed. Electronic medical records were reviewed for CRS, HIPEC, histology, stage, SC received, CEA, CA-125, and/or CA 19-9, response (R), and progression-free survival (PFS). All patients were required to be restaged at their respective institution with R defined as clinical or radiographic benefit. K-M method, Log-Rank, and Cox proportional hazard regression models were used for statistical analysis. Results: Of 659 pts with AEN diagnosis, 134 pts were evaluable for PFS and R. Forty-eight (36%) pts were poorly-differentiated; 29 (22%) signet ring; and 22 (16%) had both features. Thirty-four (25%) were well-differentiated. After a median follow-up of 35M, adjusting PFS for prior CRS, HIPEC, histology, ascites, and biologic therapy, pts who received 5-FU alone fared worse vs. FOLFOX [HR: 2.39; 95% CI: 1.2-4.6; p-value = 0.01]. FOLFIRI trended in favor of improved PFS, but was underpowered. No statistical difference in R was noted (Table). Conclusions: In the treatment of surgically unresectable AEN, combination chemotherapy resulted in improved PFS vs. single agent 5-FU. Quality of life analysis will be reported at a later date. Randomized prospective analysis should be considered. [Table: see text]

Combined goblet cell carcinoid and mucinous cystadenoma of the vermiform appendix

Goblet cell carcinoid is an uncommon primary tumor of the vermiform appendix, characterized by dual endocrine and glandular differentiation. Whether goblet cell carcinoid represents a morphological variant of appendiceal classical carcinoid or a mucin-producing adenocarcinoma is a matter of conjecture. Rare cases of goblet cell carcinoid with other concomitant appendiceal epithelial neoplasms have been documented. In this report, we describe a rare case of combined appendiceal goblet cell carcinoid and mucinous cystadenoma, and discuss the possible histopathogenesis of this combination.

Is there a role for neoadjuvant chemotherapy in the management of non-carcinoid epithelial neoplasms of the appendix?

15115 Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC) are considered the standard of care for patients with pseudomyxoma peritonei (PMP) and carcinomatosis of appendiceal origin. The role of neoadjuvant chemotherapy (CTX) in the management of these patients is unknown. Methods: Retrospective analysis of all patients evaluated for the treatment of appendiceal epithelial neoplasms at a tertiary center between 1992 and August 2006. All diagnoses were confirmed pathologically and classified by a single group of pathologists. Patients with carcinoid tumors or metastases to the appendix were excluded. Tumor histology, stage, peritoneal-based disease, and the potential for complete cytoreduction dictated treatment. Results: 250 consecutive patients were evaluated, 140 of whom had low grade disease. 114 underwent CRS and HIPEC. Median follow-up was 24 mos from referral. Average time to referral was 13 mos after diagnosis (range 0–243); 85% had undergone prior surgical therapy (median 1.3 operations, range 1–4); 22% had previous CTX consisting of many different regimens. 5- and 10-year survival for patients with low grade tumors treated with CRS and HIPEC alone (n=80) were 84% and 68%, respectively. 21 patients with low grade tumors had CTX prior to CRS and HIPEC. There was no effect on overall survival (p = 0.61). 5-and 10-year survival of 39 patients with low grade histology who did not receive CRS and HIPEC was 55% and 30%, respectively (p = 0.009). 83 patients with intermediate and high-grade disease who received CTX but not CRS and HIPEC had a 5- year survival of 27%. 5-year survival for patients with intermediate or high grade disease who underwent CRS and HIPEC (n=13) was 67%. Conclusions: Patients with peritoneal-based disease from non-carcinoid epithelial neoplasms of the appendix who undergo CRS and HIPEC have a more favorable survival. Currently there is no survival advantage to the use of CTX before CRS and HIPEC for low grade appendiceal neoplasms. The role of neoadjuvant CTX and biologic agents for patients with high grade neoplasms needs to be determined. Early referral to a peritoneal malignancy center will help standardized treatment for these patients. No significant financial relationships to disclose.

Appendiceal Epithelial Neoplasms and Pseudomyxoma Peritonei, A Distinct Clinical Entity With Distinct Treatments

Appendiceal Epithelial Neoplasms and Pseudomyxoma Peritonei, A Distinct Clinical Entity With Distinct Treatments

The natural history, gross pathology, and histopathology of appendiceal epithelial neoplasms

Aim To report the pathology of appendiceal epithelial neoplasms a review of the Washington Cancer Institute experience and a PubMed literature search was performed. Findings Epithelial appendiceal neoplasms present a significant oncologic challenge. The clinical and pathologic features are unusually varied as compared to other gastrointestinal cancers and require expert clinical judgment for proper management. Conclusions Appendiceal epithelial neoplasms should be regarded as a distinct clinical entity with special clinical treatments used for optimal management.

Immunohistochemical expressions of cytokeratins, mucin core proteins, p53, and neuroendocrine cell markers in epithelial neoplasm of appendix

Epithelial neoplasms of appendix are infrequent, and their pathological features are not fully characterized. We collected 33 cases of appendiceal tumors and examined immunohistochemically the expression of cytokeratins (CK, CK7, and CK20), mucin core protein (MUC1, MUC2, MUC5AC, and MUC6), E-cadherin, chromogranin A, and p53 protein. Gene analysis of TP53 was also conducted on exons 5 to 8. Clinically, mucinous tumors were predominant in females. Immunohistochemically, all the tumors expressed CK20, whereas CK7 was positive in one third of the cases. Similarly, MUC2 was expressed in all the tumors, whereas MUC1 and MUC5AC were detected in about a half of the cases. Although chromogranin A-positive cells are generally sparse in normal appendix, they were more common in mucinous tumors than in nonmucinous tumors. Contrary to the previous data reported (Mod Pathol 2002;15:599-605), mucinous carcinoma exhibited a higher frequency of p53-positive cells (mean 29%) compared with mucinous adenoma (2.8%) (P < .001), whereas nonmucinous tumors showed high levels of p53-positive cells to similar extent (51%-67%) in both adenoma and carcinoma. The high expression of p53 protein coincided with the presence of mutations in multiple sites of TP53 gene in mucinous tumors. This is the first report that characterized the immunophenotypic profile of appendiceal epithelial neoplasms with an emphasis of a higher frequency of p53 positivity in mucinous carcinoma cases compared with mucinous adenoma in the appendix.

Defective mismatch repair in the pathogenesis of low-grade appendiceal mucinous neoplasms and adenocarcinomas

Defective DNA mismatch repair has been proposed as a second pathway for colonic carcinogenesis, particularly in tumors arising in the right colon. We investigated whether tumors arising in the appendix are associated with defective DNA mismatch repair using immunohistochemistry for mismatch repair enzymes hMLH-1, hMSH-2, hMSH-6, and hPMS-2. These immunoassays have been shown to be highly sensitive and specific for defective DNA mismatch repair in sporadic and familial adenocarcinomas. Sporadic adenocarcinomas with defective DNA mismatch repair essentially always show loss of hMLH-1, while loss of hMSH-2, hMSH-6, or hPMS-2 is almost always due to germline mutation. In all, 35 cases of appendiceal epithelial neoplasms were evaluated, comprising 18 low-grade appendiceal mucinous neoplasms confined to the appendix; eight low-grade appendiceal mucinous neoplasms with extra-appendiceal spread (five peritoneum and ovaries, two peritoneum, one ovaries only); and nine invasive adenocarcinomas (three with metastatic disease). All immunohistochemical slides were reviewed by two pathologists. One (11%) invasive adenocarcinoma showed absent expression of hMSH-2 and hMSH-6, but preserved hMLH-1 and hPMS-2 expression. This case was a 26-year-old female with a history of synovial sarcoma who presented with acute appendicitis and appendiceal perforation (median age for other invasive carcinomas, 62 years; range 38–76 years). The appendiceal tumor was a moderately differentiated, colonic-type adenocarcinoma without significant extracellular mucin or tumor-infiltrating lymphocytes. The remaining invasive carcinomas and low-grade appendiceal mucinous neoplasms demonstrated preserved expression of all mismatch repair enzymes, including the seven cases in which extra-appendiceal tumor was also evaluated. We conclude that defective DNA mismatch repair does not play a role in the pathogenesis of low-grade appendiceal mucinous neoplasms. Defective DNA mismatch was found in 11% of invasive carcinomas, likely due to a germline mutation. These findings suggest that sporadic appendiceal neoplasia rarely arises through the defective DNA mismatch repair (mutator) pathway.