Appendiceal Neoplasms

Abstract

Appendiceal neoplasms are a relatively rare gastrointestinal tumor, representing <1.5% of all appendectomy specimens with an annual incidence of <1:100,000 people. They are typically diagnosed during the 4th–6th decade, and most commonly present as an incidental finding or mistaken initially as acute appendicitis. They represent a wide-spectrum of aggressiveness and may be stratified into epithelial tumors and non-epithelial tumors. Mucinous lesions that perforate may lead to dissemination throughout the peritoneal cavity, resulting in pseudomyxoma peritonei. It is important to have proper staging, as appendectomy may be appropriate for localized disease, although some lesions may require a right colectomy. For more advanced lesions, cytoreductive/debulking surgery and heated intraperitoneal chemotherapy (HIPEC) may be appropriate for certain forms of disseminated disease.

Refer to Algorithm in Fig. 67.1

• A. Many tumors of the appendix present acutely, often initially mistaken for acute appendicitis and are only found intra-operatively or following pathology examination. Others present as asymptomatic incidental lesions during a work-up for other symptoms (i.e., CT scan) and allow the opportunity for a more definitive evaluation. Appendiceal tumors can be divided into epithelial (i.e., adenoma, adenocarcinoma), non-epithelial (e.g., carcinoid), and mixed lesions. Other rare lesions include sarcomas, lymphomas, and mixed lesions such as goblet cell carcinoids.

• B. Appendiceal neoplasms are rare, with a reported incidence of 1.2 cases per 100,000 people per year in the United States. In general, the history and physical examination are non-specific. Patients are often over 50 years of age, with a mean age of 62–65 years, and there is a slight male predominance. In many cases, patients are asymptomatic, especially in early stage disease. Those patients with symptoms may present with right lower quadrant abdominal pain (mimicking appendicitis), which is classically from obstruction of the lumen by the tumor. As disease progresses, mucin throughout the abdomen (i.e., pseudomyxoma peritonei) may lead to abdominal distension, obstructive symptoms and even a mass. Unfortunately this indicates advanced disease.

• C. Radiological evaluation is one of the most important aspects for evaluation. Plain radiographs may be indicated in those patients with a concern for obstruction or perforation, although non-specific. Cross-sectional imaging with CT is useful both in the initial evaluation as well as for surveillance. CT will help in the staging of mucinous adenocarcinoma to evaluate for lymph node and distant metastases. CT will also help with calculation of the peritoneal cancer index (PCI) (Fig. 67.2). Abdominal MRI has been incorporated in several surveillance strategies to follow solid and mucinous peritoneal disease. Both allow for evaluation of the appendix as well as the entire abdomen (Table 67.1). Fluoroscopic studies such as small bowel follow-through and gastrografin enema are seldom indicated as primary studies. PET scans may be helpful for solid tumors to detect recurrence but typically are unreliable for small lesions <1 cm and not helpful for detecting pseudomyxoma peritonei. Somatostatin receptor scan may be used in those patients with carcinoid tumors >1 cm to help detect distant disease.

• D. There is no diagnostic laboratory test for the majority of the appendiceal tumors. Laboratory testing may include baseline CBC, chemistry and coagulation panels as indicated by appropriate risk stratification. For patients with suspected epithelial lesions, the tumor marker carcinoembryonic antigen (CEA) should be evaluated. Carcinoid lesions may be evaluated with urinary 5-HIAA metabolites and serum chromogranin A.

• E. Endoscopy is not classically useful to detect the primary lesion. In some cases, mucin may be visualized extruding from the appendiceal orifice that may suggest the presence of a mucinous neoplasm. More importantly, those patients with an appendiceal neoplasms including carcinomas, carcinoid and neuroendocrine tumors have an ~10–20% risk of concomitant lesions elsewhere in the colon. Prior to any surgical intervention, endoscopic clearance of the colon should be performed.

• F. Nomenclature for mucinous neoplasms of the appendix is evolving and contributes somewhat to the confusion regarding the optimal treatment. In general, low-grade mucinous neoplasms encompass serrated or villous adenomas, cystadenoma, or mucinous neoplasms of uncertain behavior. Of note, mucocele is a morphologic term to describe a dilated fluid filled appendix, and does not relate to the biological aggressiveness. They are slow-growing and typically indolent. They may rupture (or iatrogenically ruptured during surgery), leading to mucin throughout the abdomen. Localized tumors may typically be treated with appendectomy and have good long-term prognosis. If epithelial cells are present outside the appendix in the peritoneum, this may lead to more aggressive behavior and result in pseudomyxoma peritonei (refer to section I in algorithm in Fig. 67.1).

• G. Carcinoid (Neuroendocrine) tumors of the appendix are derived from hormone-active neuroendocrine cells. While various hormones (growth hormone, calcitonin) may be produced, most commonly they secrete serotonin, which is subsequently metabolized to 5-hydroxyindoleacetic acid (5-HIAA). This metabolite is excreted in the urine and classically used to monitor disease. The majority are located at the tip of the appendix, are less than 1 cm, and when large can be associated with a desmoplastic inflammatory response in the mesentery. Outcomes correlate with stage, of which size is the primary factor (Table 67.2). While lymph node involvement is rare in lesions <1 cm, up to 30% of carcinoids over 2 cm will have nodal metastases. In general, outcomes are good, with 5-year survival for tumors limited to local and regional disease >80%; though 25–30% for stage IV disease. Goblet cell carcinoid represents a mixed epithelial and neuroendocrine tumor variant that presents with a wide spectrum of biological aggressiveness. Whereas the majority are incidental findings on appendectomy, ~10–15% will present with metastatic disease. Outcomes are typically worse than routine carcinoids with 5-year survival for patients with local/regional disease 45–82%, and those with stage IV disease <20%.

• H. Lymphoma and sarcoma represent less common tumors than may be found in the appendix. Lymphoma is more common among these more rare conditions, yet the appendix may be the primary disease site. Patients are commonly 30–40 years old, and commonly present in with symptoms of appendicitis or obstructive symptoms from intussusception or local inflammation. Sarcomas are much rarer, with Kaposi’s sarcoma and leiomyosarcoma among the subtypes.

• I. Pseudomyxoma peritonei may occur in the setting of appendiceal tumors or those from peritoneal or ovarian sources. This process is describes mucin to varying degrees in the peritoneum as well as strong and mucinous epithelial cells. In the setting of appendiceal neoplasms, it results from a rupture of low-grade mucinous neoplasms. The outcome is directly proportional to the amount of mucin, which is a result of the degree of epithelial cell presence or absence in the mucin. Often this will be confined to the right lower quadrant, but may also present as disseminated peritoneal adenomucinosis or peritoneal carcinomatosis. The former may spread throughout the abdominal cavity, whereas the latter may also infiltrate the abdominal organs.

• J. Adenocarcinoma of the appendix may include mucinous and non-mucinous subtypes. These tumors may rupture and lead to seeding of the peritoneal cavity and pseudomyxoma peritonei. These tumors invade the appendiceal wall and may spread by both nodal (less commonly) and peritoneal surfaces. Non-mucinous adenocarcinoma of the appendix closely resemble colonic adenocarcinoma with metastases more commonly to the lymph nodes and hematogenously to the liver. Outcomes correlate to colon cancer and are determined by the stage (Table 67.3). Mucinous subtypes have a comparatively worse prognosis than non-mucinous lesions. A variant of mucinous adenocarcinoma is the signet ring cell subtype that is much more aggressive and tends to lead to diffuse metastases throughout the peritoneal cavity. It characteristically has a very poor prognosis.

• K. As many lesions are incidental findings or originally felt to represent appendicitis, appendectomy is one of the more common “diagnostic” modalities for appendiceal neoplasms. However, appendectomy en bloc with resection of the mucinous lesion may also be curative for localized, non-ruptured benign lesions, carcinoids <1 cm with negative margins, and benign mucoceles. When dealing with the latter, it is important to avoid perforation and spillage to minimize the changes of peritoneal mucinosis. Carcinoids 1–2 cm with otherwise negative features and clear margins may be candidates for therapy with an appendectomy; however, this is controversial due to the risk of lymph node metastases.

• L. Right colectomy is reserved for patients with adenocarcinoma of the appendix and larger carcinoids (>2 cm; >1 cm with high-risk features; positive margins). Goblet cell appendiceal carcinoids have a 20–40% risk of lymph node metastases therefore a right hemicolectomy is recommended regardless of primary tumor size. For patients with low-grade mucinous neoplasms of the appendix in the setting of pseudomyxoma peritonei, there remains controversy. Whereas the traditional teaching has been right colectomy, more recently the shift has been towards appendectomy only and cytoreductive surgery ± HIPEC (see below). This is due, in part, to the fact that lymph node disease is a rare entity and the peritoneal disease is the primary driver of patient outcomes.

• M. Chemotherapy alone is typically for patients with metastatic disease who cannot undergo a complete cytoreduction. Certain patients will have an excellent response and may have the opportunity to subsequently undergo cytoreduction and HIPEC after down-staging. Some argue that even after complete cytoreduction and HIPEC, recurrence of these mucinous lesions is common, and adjuvant systemic chemotherapy is warranted. However, low-grade lesions are not classically responsive to systemic chemotherapy, and it is typically not recommended routinely. Conversely, chemotherapy may be considered for high-grade lesions and has some data to suggest improved progression-free survival.

• N. Complete cytoreduction with HIPEC has become the preferred treatment for appendiceal lesions with concomitant peritoneal involvement (carcinomatosis, pseudomyxoma peritonei). Complete cytoreduction involves removal of all gross disease or reduction of tumor deposits to ≤2.5 mm in thickness. This is performed in conjunction with heated intraperitoneal chemotherapy (HIPEC). In addition, some surgeons perform an omentectomy, peritoneal and diaphragm stripping, and even removal of Glisson’s capsule when involved. Bilateral oophorectomy may also be performed, especially in post-menopausal women. Tumor deposits on the small bowel may be resected or fulgurated. Intraperitoneal chemotherapy may be performed via an open or closed technique (Fig. 67.3). Mitomycin C (MMC) at a dose of 40 mg in 3 L of perfusate at 41–43 °C for 90 min (30 mg for 60 min with an additional 10 mg during 30 min). Floxuridine and 5-fluorouracil have also been used, but have demonstrated no benefit to date. Non-heated intraperitoneal chemotherapy (EPIC) for up to 7 days postoperatively via an implanted subcutaneous port may also be included. Recurrent disease is most often treated with repeat debulking or complete cytoreduction with additional HIPEC and has been reported result in long-term survival.

• O. Surgery is the primary treatment for most appendiceal neoplasms. Normally, only poor operative candidates, those with advanced or metastatic disease, or patients with a high PCI (i.e., >20) who are not likely to undergo successful cytoreduction and HIPEC therapy are treated non-operatively. Somatostatin may be useful for metastatic carcinoid tumors, often with extensive liver involvement for symptomatic relief. Adjuvant chemotherapy may include 5-FU-based therapy alone or in combination with oxaliplatin or the monoclonal antibodies such as bevacizumab or cetuximab. While they play a role for epithelial neoplasms, they generally result in limited improvement in progression-free survival (refer to section N in algorithm). Radiation therapy is rarely used in the treatment of appendiceal neoplasms.

Fig. 67.1

Algorithm for appendiceal neoplasms. ∗Appendectomy for <1 cm lesions and negative margins; Right colectomy for >2 cm lesions, positive (or questionable) margins, nodal involvement, invasion of mesoappendix >3 mm, or metastases to the liver only; Chemotherapy for diffuse metastases >1 site; $ May require HIPEC and cytoreduction in the setting of diffuse mucinosis; ∗∗ Diffuse mucinosis with PCI <16–20, or perforated primary without pseudomyxoma peritonei; # Diffuse mucin or carcinomatosis with PCI >16–20, diffuse systemic metastases, or carcinomatosis with concomitant metastases

Fig. 67.2

Peritoneal Cancer Index (PCI). This is a collective score with a maximum of 39 points from nine abdominal squares and 4 small bowel segments. Each area is scored between 0 (no disease) to 3 (deposits are >5 cm)

Table 67.1 Characteristics of Appendiceal Neoplasms on Cross-Sectional Imaging

Table 67.2 AJCC (seventh Edition) Staging Systems for Primary Appendiceal Neuroendocrine Carcinoma

Table 67.3 ACJJ staging (8th edition) of mucinous adenocarcinoma of the appendix

Fig. 67.3

Intraoperative photograph of heated intraperitoneal chemotherapy