Discussion

The World Health Organization classification scheme divides appendiceal neoplasms into epithelial tumors, mesenchymal tumors, lymphomas, and secondary tumors. The epithelial tumors include premalignant lesions (adenomas and serrated lesions), carcinomas (mucinous adenocarcinoma, low-grade appendiceal mucinous neoplasm (LAMN), signet ring cell carcinoma, undifferentiated carcinoma) and neuroendocrine neoplasms.2,3The diagnosis of appendiceal neoplasm may be challenging and requires thorough history and physical examination, laboratory studies, imaging (CT/ MRI), endoscopy and diagnostic tumor biopsy or surgery. Serum carcinoembryonic antigen (CEA) levels should be obtained as for colorectal cancers. Colonoscopy may show an appendiceal orifice mass. Tumor markers CA-125 and CA 19-9 may be elevated in patients with appendiceal primary tumors and peritoneal disease.4 Normal levels of CA-125 and CA 19-9 are associated with improved survival and decreased rates of recurrence.5 CT of the chest, abdomen, and pelvis allows evaluation of the primary tumor and assessment of metastatic disease.5 The diagnosis is often unknown prior to operative intervention for presumed appendicitis. Malignant neoplasia is identified in 2.3-12.0% of patients having appendectomy for appendicitis. Risk factors for appendiceal cancer in this appendicitis group are older age and periappendiceal abscess.2Risk factors that predispose locally invasive appendiceal adenocarcinoma to intraperitoneal dissemination and metastasis have been described.6 One study showed that T4 depth of invasion, N2 nodal status, and mucinous tumor were associated with peritoneal metastasis.6 Another study showed that the incidence of lymph node metastasis was associated with both larger tumor size and advanced T stage.7 The patient described in this case report had a T4b neoplasm but had no lymph node metastases and has no evidence of metastatic disease to date. Management of appendiceal neoplasms varies depending on the pathology. For appendiceal adenocarcinoma, treatment depends on whether the neoplasm has perforated and led to intraperitoneal dissemination. There is extensive literature describing ruptured appendiceal adenocarcinoma with widespread intra-peritoneal mucinous ascites leading to pseudomyxoma peritonei (PMP) and peritoneal carcinomatosis. However, there are currently no standard guidelines for management of locally invasive perforated appendiceal adenocarcinoma without PMP or intra-peritoneal dissemination.2,3For patients like the one presented in this case report with locally advanced perforated appendiceal adenocarcinoma without PMP or carcinomatous, en-bloc R0 resection, when possible, with postoperative systemic chemotherapy would likely be the best option. The lack of standardized nomenclature for appendiceal neoplasms contributes to treatment algorithm inconsistencies. The following is the most recent update in pathologic terminology and management recommendations for the most common appendiceal neoplasms. The proposed algorithm for management is shown in Figure 2.Appendiceal AdenomaAppendiceal adenomas are benign polyps of the mucosa like adenomas elsewhere in the colon and rectum. Most do not have presenting symptoms and are found incidentally but some patients may have symptoms of appendicitis.3 Histologic exam resembles colonic tubular, villous, or tubulovillous adenomas. There is cellular crowding and often low-grade dysplastic changes of nuclear elongation and stratification, pleomorphism, and increased mitotic figures. Adenomas are associated with KRAS mutations and loss of chromosome 5q. The majority of adenomas are microsatellite stable and lack BRAF mutations. Like colonic adenomas, appendiceal adenomas are premalignant and follow the adenoma-carcinoma sequence.8Treatment for appendiceal adenoma confined to the mucosa is appendectomy with negative margins.Low-Grade Appendiceal Mucinous NeoplasmPatients with low-grade appendiceal mucinous neoplasms (LAMN) range in age from 20-90 years with most in the 7th decade. They are more common in women.3 Patients present with symptoms of appendicitis or abdominal pain, distension or an abdominal mass. LAMNs have uncertain malignant potential.2 About 15-20% are found incidentally when undergoing surgery for an unrelated etiology.3 Grossly, the appendix appears normal but may be dilated due to intraluminal mucin accumulation. They may also present with appendiceal perforation, mucin within the appendiceal wall, or acellular mucin outside of the appendix.2 On histologic exam, LAMNs consist of well differentiated, glandular, mucinous neoplastic epithelial cells.1,3 LAMNs frequently have KRAS mutations and loss of chromosome 5q.3 Almost 100% of mucinous appendiceal neoplasms express Keratin 20, CDX2 and MUC2.3 They are also associated with GNAS mutations with elevated cAMP levels leading to increased expression of MUC2 and MUC5AC and increased mucin production.3Prognosis depends on LAMN perforation and the presence of mucinous neoplastic epithelium outside the appendix. LAMNs confined to the appendix with no extra-appendiceal perforation are treated by appendectomy with negative margins. This may require a partial cecectomy if the tumor involves the base of the appendix.2,5 The specimen should be placed in a retrieval bag when done by the laparoscopic approach to decrease the risk for mucin spillage. When the risk for mucin spillage is considered high, an open approach should be considered. LAMNs with extra-appendiceal acellular mucin have a low 3-7% risk for peritoneal recurrence and generally have a good prognosis. LAMNs with intraperitoneal spread of cellular mucin containing neoplastic epithelium have a higher 33-78% risk of peritoneal recurrence and overall poorer prognosis.3 Patients with perforated LAMNs with intraperitoneal spread of acellularmucin should have routine surveillance imaging to rule out peritoneal recurrence or disease progression.2,3 Patients with perforated LAMNs with intraperitoneal cellular mucin containing neoplastic epithelium should undergo a right hemicolectomy or right hemicolectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).2,3High-grade appendiceal neoplasms are histologically similar to LAMNs but have more aggressive cytologic atypia.2AdenocarcinomaAppendiceal adenocarcinomas occur in the 5th-7th decade with mean age 60 and are more common in men.1 Patients may present with signs and symptoms of acute appendicitis. Adenocarcinomas may be mucinous or nonmucinous and are subclassified into adenocarcinoma not otherwise specified, mucinous adenocarcinoma, signet ring cell adenocarcinoma and undifferentiated carcinoma.3Mucinous adenocarcinoma is the most common adenocarcinoma of the appendix - about 40% of all adenocarcinomas. They consist of malignant glandular mucinous epithelium within the wall of the appendix with infiltrative destructive invasion, high- grade cytologic atypia and extracellular mucin in >50% of the neoplasm.2,3Adenocarcinomas are associated with mutations of chromosome 18q, frequently have KRAS mutations, and histologically express p53, CD44, and CDX2.3 Intraperitoneal dissemination of mucinous adenocarcinoma is similar to LAMN except that the malignant epithelium contains high-grade cytologic atypia and the mucin is more cellular.3 Signet ring cell adenocarcinomas are rare and have a poor prognosis.5 Non-mucinous adenocarcinomas, like that presented in this case report, behave like colonic adenocarcinomas. Patients with invasive mucinous or nonmucinous adenocarcinomas and signet ring cell adenocarcinomas should undergo a right hemicolectomy with lymphadenectomy due to 20-67% risk of lymph node metastases.1 These patients require oncologic resection that includes high ligation of mesenteric vessels, removal of the associated lymph node basin, and grossly negative 5-cm margins. Patients with mucinous adenocarcinoma with widespread intraperitoneal deposits should undergo CRS and HIPEC. There is no advantage to right hemicolectomy over appendectomy when peritoneal metastases are present unless it is necessary to achieve complete cytoreduction.2,3 Systemic chemotherapy should be administered to patients with lymph node or distant organ metastases. Goblet cell carcinoid tumors are mixed adeno-neuroendocrine carcinomas with neuroendocrine tumor features such as positive chromogranin A staining. They are clinically more aggressive than neuroendocrine tumors and treatment is the same as for appendiceal adenocarcinomas.2Pseudomyxoma PeritoneiPMP is characterized by appendiceal neoplasm perforation with intraperitoneal accumulation of mucin resulting in gelatinous mucinous ascites.5,9 PMP occurs in 20% of patients with mucinous appendiceal neoplasms and more commonly in females (ratio 4:1) between the ages of 60-70.9 In 2010, the American Joint Committee on Cancer (AJCC) and World Health Organization (WHO) classified PMP into 2 groups: low-grade PMP and high-grade PMP.5,8,9 Low-grade PMP, also known as diffuse peritoneal adenomucinosis (DPAM), is associated with LAMN and is characterized by intraperitoneal spread of acellular or cellular mucin with low-grade cytology and no significant mitotic activity.8,9 The mucin in the peritoneum adheres to but does not invade or penetrate surrounding visceral structures within the peritoneum.5Normal baseline CA-125 and CEA returning to normal after surgery are associated with the ability to achieve complete cytoreduction in this patient population. Elevated baseline CA19-9 is associated with worse progression-free survival.2 High-grade PMP, also known as peritoneal mucinous carcinomatosis (PMCA), is associated with mucinous adenocarcinoma and is characterized by intraperitoneal spread of mucin containing high-grade malignant neoplastic epithelium with moderate to severe cytologic atypia.8,9 High-grade PMP has a strong predilection for peritoneal lesions that invade visceral structures.5There is considerable debate over the management of PMP and the treatment algorithm has not been standardized. Prior to CRS, treatment was surgical debulking. Sugarbaker introduced and popularized the use of CRS and HIPEC for patients with PMP.5,9 CRS removes all visible macroscopic disease and HIPEC is used to provide directed highly concentrated intraperitoneal chemotherapy to penetrate any remaining microscopic disease.5Right hemicolectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is currently recommended for appendiceal adenocarcinoma with peritoneal carcinomatosis or PMP. HIPEC most commonly includes Mitomycin C or platinum chemotherapy agents.2 Several studies have shown improved prognosis and disease-free survival in patients having CRS and HIPEC for appendiceal cancer associated with peritoneal carcinomatosis.10, 11 Furthermore, patients who underwent both CRS and HIPEC versus CRS alone had improved survivability.10 Five- and ten-year survival rates for low-grade PMP are 75% and 68% respectively. Five- and ten-year survival rates for high-grade PMP are 14% and 3% respectively. Several studies have shown no clear disease-free survival or overall survival advantage for patients who underwent preoperative chemotherapy prior to CRS and HIPEC.12 The use of early postoperative intraperitoneal chemotherapy (EPIC) has been shown to improve survival in patients with appendiceal adenocarcinoma with peritoneal carcinomatosis compared with HIPEC alone without increasing postoperative morbidity and mortality.4,13Patients who undergo CRS and HIPEC require routine surveillance for recurrence that includes physical examination, CT imaging of the chest, abdomen and pelvis and tumor markers (CEA, CA-125, CA 19-9) every 6 months for the first 2 years, and then yearly for at least 3 years. MRI may be superior to CT for postoperative surveillance after (CRS) and (HIPEC).5Serrated Tumors of the AppendixSerrated tumors of the appendix occur in older patients and affect both males and females equally.3 They are found incidentally or in patients who present with signs and symptoms of appendicitis. They are classified into hyperplastic polyps, sessile serrated adenoma/polyps (+/- cytologic dysplasia), and traditional serrated adenoma/polyps (+/- cytologic dysplasia).11 Hyperplastic polyps are benign and have low risk for malignant transformation. Sessile serrated polyps consist of serrated, dysplastic epithelium in the basal crypts with increased mitotic figures and mild nuclear atypia.3Traditional serrated adenomas have villous growth pattern with complex serration. Due to the risk of malignant transformation, serrated neoplasms confined to the appendix without involvement of the adjacent cecum are treated by appendectomy with negative margins. Right hemicolectomy with regional lymphadenectomy is the preferred option for patients with large serrated lesions suspicious for malignant degeneration or those that involve the cecum or other organs. This case report adds to current literature by providing an unusual presentation of appendiceal adenocarcinoma, by providing a review of classification schemes and pathologic variations, and by providing a proposed treatment algorithm.