Continuing Education Activity

Appendiceal malignancies are a rare group of tumors often found incidentally during surgical removal of the appendix. Histologically, this malignancy accounts for 0.5% to 1% of all biopsy specimens following appendectomies. Clinically, this condition most commonly presents as acute appendicitis due to obstruction of the appendiceal lumen. As it is for all malignancies, early detection is critical as the late diagnosis could lead to much poorer outcomes. This activity seeks to quantify and define appendiceal malignancies. It describes current recommendations for the evaluation and management of these disease processes. It highlights the role of the interprofessional team in treating patients with these conditions.

Objectives:

• Summarize the epidemiology of appendiceal malignancies.
• Describe features of the history and physical that may suggest underlying malignancy.
• Identify the appropriate treatment regimen for each type of appendiceal malignancy.
• Review the benefits of an interprofessional team approach to the treatment of appendiceal malignancy.

Introduction

Appendiceal malignancies are a rare group of tumors often found incidentally during surgical removal of the appendix. Histologically, this malignancy accounts for 0.5-1 % of all biopsy specimens following appendectomies.[1][2] Clinically, this condition most commonly presents as acute appendicitis due to obstruction of the appendiceal lumen. As it is for all malignancies, early detection is critical as the late diagnosis could lead to much poorer outcomes.

Etiology

The mechanisms that result in appendiceal malignancies are not well understood. It has, however, been postulated that appendiceal mucinous neoplasms (AMN, a major subset of appendiceal tumors) follow the same adenoma-carcinoma sequence as seen in colorectal carcinoma. This sequence begins with a point mutation in the KRAS proto-oncogene and then mutations and/or deletions in the TP53 gene on Chr 17p. Next, truncating mutations on the APC gene on 5q and the beta-catenin gene all contribute to its onset. An alternative microsatellite instability (MSI) theory has been postulated to result from mutations in nucleotide mismatch repair genes e.g., hMSH2, hMLH1, PMS1, PMS2, and GTBP.[3][4][5]

Epidemiology

Cancer of the appendix is observed in less than 2% of appendiceal specimens. There has been a steady rise in the number of appendectomies performed in the United States, as well as the incidence of appendiceal cancer.[6][7]  Gastroenteropancreatic neuroendocrine tumors ( GEP-NETs) account for the most common malignancy of the appendix.[7][8][9] Although appendiceal adenocarcinoma is more frequently found amongst men in their 6 to 7 decade of life, in recent decades, there has been a decrease in the age at diagnosis.[10] An increased association with colonic neoplasia and chronic ulcerative colitis has been noted.[2] The appendix is the third most common site for neuroendocrine tumors after the rectum. At the time of diagnosis, over a third of cases are metastatic.[11]

Pathophysiology

Obstruction of the appendiceal lumen by the malignant cells leads to inflammation of the appendix, venous stasis, and, ultimately, infection of the appendix.[7] In mucinous tumors of the appendix, there may be a cystic dilation of the appendix due to obstruction of the appendiceal lumen by mucoceles.[12][13] These processes are the basis for the commonest clinical presentation of this disease, acute appendicitis.

Histopathology

Appendiceal tumors are broadly categorized into epithelial (mucinous, non-mucinous adenocarcinoma, and signet ring cell tumors) and non-epithelial (neuroendocrine tumors, lymphomas, and sarcomas). Goblet cell carcinomas are an aggressive type and share features from both broad groups. Sixty-five percent of all appendiceal tumors are of neuroendocrine origin, while adenocarcinomas make up about 20%.[8][9]

The mucinous group of neoplasms is a heterogeneous group ranging from simple adenomas to adenocarcinomas and complex pseudomyxoma peritonei.[12] They are graded based on the degree of mucosal involvement as mucinous adenoma, low-grade appendiceal mucinous neoplasms (LAMN), which are confined to the mucosa of the appendix, and high-grade mucinous adenocarcinoma that is invasive and spread beyond the muscularis mucosa.[14][7] The diagnosis of mucinous neoplasms is largely dependent on the presence of mucin, and they stain diffusely positive for CK20 (100%), MUC5AC (80%), and DPC4 (71%) and negative for CK 7 (71%). This CK positivity pattern is similar to that of CRC.[2]

Signet ring cell carcinomas are an aggressive group of epithelial tumors, with up to 60% of cases already showing distant metastasis at the time of diagnosis.[15][16]

Neuroendocrine tumors are often found at the tip of the appendix, are well-differentiated, and are relatively indolent in their course.[17] Typical microscopic findings include uniform submucosal cell conglomerates in a nested or insular pattern that have nuclei showing the distinctive endocrine “salt and pepper” chromatin pattern. Chromogranin A is a useful biomarker to predict relapse even before there is radiographic evidence.[17] As the appendix is primarily lymphoid tissue, appendiceal lymphomas may arise. The etiology is Burkitt lymphoma with a mean age of 18 years old and diffuse large B cell lymphomas in the elderly.[18]

History and Physical

In over 50% of cases, the are no symptoms, and this malignancy is detected incidentally. However, most symptomatic patients, almost 30% of those with appendiceal cancer, would present as acute appendicitis.[19] However, the histopathologic subtype of acute appendicitis identifies the possible rate of acute presentation of the tumor. As such, the most prevalent clinical presentation of the appendiceal adenocarcinoma is acute appendicitis. [1] Factors that should increase suspicion for appendiceal neoplasm include age greater than 50 years with a family history of colon cancer or inflammatory bowel disease (IBD), features suggestive of chronic appendicitis, or the presence of unexplained anemia.[7] The patient may have non-specific abdominal pain, right lower quadrant pain, weight loss, anorexia, fever, vomiting, features of intestinal obstruction from intussusception, and fatigue.[12] Physical examination may reveal right lower quadrant abdominal tenderness with guarding, abdominal mass, presence of ascites, and features of metastatic disease. The patients with GEP-NETs who are complicated with hepatic metastasis might present with signs and symptoms related to carcinoid syndrome. [20]

Evaluation

The mainstay of an initial evaluation is imaging studies. Sonographic findings include elongated or cystic lesions in the right lower quadrant (RLQ) with features of internal onion skin appearance representing lamellated mucin, which is a pathognomonic finding.[12] A defect in the appendiceal wall with leakage may be indicative of a ruptured mucinous neoplasm.[12] In patients presenting with features of acute appendicitis, a multidetector CT scan or MRI revealing an appendix greater than 15 mm with thickened or irregular walls is suspicious for neoplasia.[21] Other CT findings that suggest PMP would include but are not limited to scalloping from metastatic deposits on serosal surfaces and cavities, and sometimes, a rim-like calcification may be noted.[22] A percutaneous needle biopsy may be essential in confirming disseminated mucinous metastatic spread to the peritoneum.[23] Plain x-rays of the abdomen are of little clinical value and may rarely show curvilinear iliac fossa calcification. Carcinoembryonic antigen (CEA) levels have some diagnostic and prognostic value with normal values indicating a better prognosis.[24] Endoscopy is indicated in patients who have been diagnosed with mucinous adenocarcinoma as there is an increasing incidence of synchronous or metachronous colonic polyps and masses.[21][14] Histologic evaluation of the appendiceal specimen is required for a definitive diagnosis.

Evaluation of ileocolic nodal basin along with a comprehensive hepatic assessment to exclude liver metastasis has an important role in the management of appendiceal cancers, including the GEP-NETs, or formerly named carcinoid tumors. Moreover, peritoneal evaluation should be considered in the patients who are diagnosed with goblet cell carcinoma, and appendiceal mucinous neoplasms, and the findings of the peritoneal cancer index score should be precisely recorded.[25]

Despite the inconclusive role of abdominal radiological measures in the diagnosis of appendiceal cancer, malignant features of appendiceal cancers including wall irregularity and soft tissue thickening within a low attenuative, round, well-encapsulated cystic mass in the right or quadrant, is highly suggestive of neoplastic appendiceal mucocele. In these patients, further systematic evaluation to exclude the presence of ascites, peritoneal involvement, and scalloping of the liver surface, is mandatory. [26]

Treatment / Management

Surgical therapy is the mainstay of therapy for cancers of the appendix; however, advanced cases with distant metastasis may be surgically unresectable. [27] Appendectomy with a wide mesoappendix resection in order to rule out lymph node involvement can both be diagnostic and curative as most appendiceal tumors are diagnosed following histologic evaluation of appendiceal specimens.[28] Other surgical modalities such as a right hemicolectomy are indicated when there is nodal involvement, a large neuroendocrine tumor with unclear margins, and greater than 3 mm meso-appendiceal invasion.[29] Cytoreductive surgery and heated intraperitoneal chemotherapy are particularly useful in mucinous tumors of the appendix. Surgically unresectable epithelial tumors of the appendix with distant metastasis may benefit from 5 fluorouracil-based adjuvant chemotherapy and palliative care.

Differential Diagnosis

An appendiceal mass may be mistaken for any one of the following conditions. They include acute appendicitis, cystic lymphangioma, mesenteric cyst, retroperitoneal cyst, ovarian cyst, ovarian cancer, and Meckel diverticulum.[30]

Surgical Oncology

Despite the non-significant annual incidence of appendiceal cancers, with 1.2 cases per 100000 in the United States still, almost 30% of this spectrum might present acutely. The most common appendiceal malignancies are Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), goblet cell carcinoma (GCC), colonic-type adenocarcinoma, and mucinous neoplasm.[31] 

Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

(GEP-NETs) are the most common histopathological subtypes. They might rarely metastasize to the liver and or lymph nodes. Therefore, in patients with suspicious GEP-NETs (carcinoid tumor), further evaluation of the liver and the ileocolic lymph node basin are essential. Basically, the primary tumor size dictates the demanding surgical steps. Accordingly, in the carcinoid tumors of less than 1-centimeter size, an appendectomy with negative margins is the only requested surgical management. Although in the carcinoid tumor of greater than 2 cm, a right hemicolectomy is indicated, the surgical plan in appendiceal carcinoid lesions of 1 to 2 cm is still equivocal. However,  in the presence of mesenteric invasion, and enlarged lymph nodes, and or equivocal surgical margins, right hemicolectomy is recommended.

Goblet Cell Carcinoma

Goblet cell carcinomas are a ubiquitous entity of appendiceal malignancies in that they share the diagnostic features of both appendiceal adenocarcinoma and neuroendocrine tumors. A comprehensive peritoneal evaluation with further peritoneal cancer index score (PCIS) documentation should be undertaken. Those patients with a non-metastatic and an equal or higher than 2 cm size will benefit from a right hemicolectomy. However, a consensus on the approach for other goblet cell carcinomas is still lacking. [32]

Lymphoma

Non-Hodgkin lymphomas (NHL), and its subtypes, including mucosa-associated lymphoid tissue (MALT) lymphomas, might initially present with acute appendicitis. The surgical management in this extremely uncommon appendiceal malignancy is limited to a simple appendectomy. However, a comprehensive systemic evaluation to exclude any potential metastatic site should be included.[33]

Adenocarcinoma

Adenocarcinoma of the appendix, a rare appendiceal neoplasm with three various histopathological subtypes, is most commonly present with acute appendicitis. The standard treatment is performing a right hemicolectomy, irrespective of the tumor size and or the involvement of the lymph node basin.[34]

Mucocele and Mucinous Neoplasm

Appendiceal mucocele, which might be the result of a benign or malignant spectrum of mucosal hyperplasia, and various cystic formations, might present with acute appendicitis. Several pre-operative radiological features, including a well-encapsulated cystic structure in the right lower quadrant, would raise the impression of an appendiceal mucocele; however, definitive diagnosis requires intraoperative evaluation and histopathological reports. The preferred surgical management is an appendectomy with great cautionary measures to prevent capsular rupture. In terms of peritoneal spread, providing documentation of the peritoneal involvement, along with tissue diagnosis with biopsies, is recommended. Moreover, suspicious mucinous neoplasm of the appendix should be managed with the peritoneal examination and record the PCIS in the presence of mucin. Patient selection for the laparoscopic approach in the management of appendiceal mucocele is extremely important and is limited to those with radiologic features suggestive of a homogenous cyst.[35]

Pseudomyxoma Peritonei Syndrome

Patients with appendiceal mucinous neoplasms, similar to the patients with neoplastic mucinous tumors of gastric, ovarian, pancreatic, and colorectal origin might develop peritoneal involvement that is called pseudomyxoma peritonei (PMP) syndrome. Appropriate treatment varies from curative to palliative approaches. Cytoreductive surgery accompanied by hyperthermic intraperitoneal chemotherapy (HIPEC) mainly with mitomycin, is considered the mainstay of treatment for patients with PMP syndrome with appendiceal origin. The surgical approach includes radical peritonectomy, to ablate both visceral and parietal peritoneum and intraperitoneal hyperthermic chemotherapy agents instillation. [36]

Staging

The appendiceal malignancy TNM staging has been comprehensively revised over the last 8 years and several modifications were added to the former seventh edition. While appendiceal cancers have been classified as a distinct spectrum and separated from colorectal cancers in the seventh edition, the following distinguished modifications are allocated to the eighth edition; 1) low-grade appendiceal mucinous neoplasms were introduced as T in situ, 2) T4 tumors definitions have been expanded from the tumors with visceral peritoneal perforation indexes and include those with the presence of mucin on the serosal layer of the appendix and or mesoappendix, 3) Similar to the colorectal TNM classification, any evidence of tumor deposits, including the presence of satellite lesions in the subserosal layer, without any metastatic lymphadenopathy should be categorized as N1c, 4) Sub-category of M1c (non-peritoneal metastasis) has been added, and the specific category of pseudomyxoma peritonei was removed from M1a.

Stage classification

Appendiceal carcinomas are categorized into two main subtypes of mucinous and nonmucinous. Histological grading to include G1 to G3 grades as the poorly differentiated appendiceal carcinomas are specifically important in the grading of metastatic mucinous appendiceal carcinomas. Moreover, two subcategories of intraperitoneal acellular mucin and intraperitoneal grade 1 tumor were added to stage IVA. [37]

Prognosis

Prognosis is dependent on the histologic type, advanced stage, and grade, spread of mucin beyond the RLQ as well as the presence of cellular mucin.[12] Five-year survival rates range from 27% to 93%. Signet ring cell tumors have the worst prognosis (27%) while neuroendocrine the most favorable (93%).[8] The 10-year survival rate for mucinous adenocarcinoma is less than 10%.[38]

The specific histopathologic subtype of appendiceal cancer dictates the predicted survival and overall prognosis. Accordingly, goblet cell carcinomas, which share the biologic features of both adenocarcinomas and appendiceal neuroendocrine tumors, harbor a more favorable prognosis in comparison with adenocarcinoma. However, the overall prognosis of these tumors is less favorable in comparison with the appendiceal neuroendocrine tumors.[25][39]

The risk of early-onset perforation within a specific histopathologic subtype of appendiceal cancer, including appendiceal adenocarcinoma, does not necessarily correlate with the overall prognosis. 

Complications

Pseudomyxoma peritonei (PMP) represents the growth of neoplastic mucinous producing cells in the peritoneal cavity with a resulting mucinous ascites. PMP may be the presenting stage for a majority of patients and is classified based on the grade as disseminated peritoneal adenomucinosis (DPAM) associated with LAMN and has fewer mitotic figures and simple epithelial cells and high-grade peritoneal mucinous adenocarcinomatosis (PMAC) usually associated with mucinous adenocarcinoma.[10][40][7].

Adhesions and intestinal obstruction may usually occur in the setting of metastatic disease.[22] Metastasis to ovaries and retroperitoneal as well as hydroureteronephrosis, a rare complication may occur.[41][42]

Deterrence and Patient Education

Appendiceal tumors usually present clinically with features of acute appendicitis and are often diagnosed following histologic examination of appendectomy specimen. It is important to follow up on the histological examination of appendectomy specimens to ensure tumors of the appendix are not missed.

Enhancing Healthcare Team Outcomes

Although appendiceal neoplasms are rare, over 50% of cases are asymptomatic, and a third of cases are metastatic at the time of diagnosis leading to poorer outcomes. It is therefore essential that an interprofessional team comprising the surgeons, physician assistants, nurse practitioners, and radiologists have a very high index of suspicion and communicate effectively especially in the presence of risk factors like chronic appendicitis in older patients, colonic neoplasia and chronic ulcerative colitis to ensure reduced morbidity and mortality. In addition to these, the services of the palliative care team, social workers, and case managers would be important to contribute to the care of these patients.