Chapter 23: Small Bowel Cancer and Appendiceal Tumors

Small bowel cancer is a rare malignancy representing approximately 3% of gastrointestinal neoplasms (¹). In 2014, it was estimated that 9,160 new cases of small bowel cancer and 1,210 small bowel cancer–related deaths would occur (¹). The two most common histologies seen in cancers of the small intestine are carcinoids and adenocarcinomas (²). Because of the nonspecific clinical presentation of small bowel adenocarcinoma and the difficulty in imaging the small bowel, most patients with small bowel adenocarcinoma present with lymph node involvement or distant metastases. Even in patients with localized disease who undergo resection with curative intent, the prognosis is poor, and no studies have yet demonstrated a clear benefit from adjuvant therapy. However, there have been some recent advances in the use of chemotherapy as palliative treatment. In this chapter, the epidemiology, diagnosis, and treatment of small bowel cancers, in particular small bowel adenocarcinoma, are reviewed.

Epidemiology

Based on an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, the age-adjusted incidence rate for small bowel cancers has slowly increased from 0.9 per 100,000 persons in the years 1973 to 1982 to 1.8 per 100,000 persons in the years 2000 to 2004 (^3,4). The majority of this increase has been attributed to an increase in the incidence of carcinoid tumors. A recent analyses of 67,643 patients with small bowel malignancies between 1973 and 2004 using the National Cancer Data Base and SEER showed carcinoids to be dominant with 37.4% cases compared to 36.9% cases of adenocarcinomas (⁵). The incidence of histologic subtypes varies in the different sections of the small intestine, with adenocarcinomas representing 80% of duodenal cancers and carcinoids representing 60% of ileal cancers.

The incidence of small bowel adenocarcinoma peaks in the seventh and eighth decades of life, with a mean age at diagnosis of 65 years. A slightly increased incidence is seen in men and blacks (⁶).

One of the more interesting aspects of small bowel adenocarcinoma is its rarity in comparison to large intestine adenocarcinoma. Even though the small intestine represents approximately 70% to 80% of the length and over 90% of the surface area of the alimentary tract, the incidence of small bowel adenocarcinoma is 30-fold less than the incidence of colon adenocarcinoma. Numerous theories have been proposed to explain the small intestine’s relative protection from the development of carcinoma. Proposed protective factors have centered on two concepts. First, the rapid turnover time of small intestinal cells results in epithelial cell shedding prior to the necessary acquisition of multiple genetic defects. Second, the small bowel’s exposure to the carcinogenic components of our diet are limited due to rapid small bowel transit time, the lack of bacterial degradation activity that occurs in the small bowel, and the relatively dilute, alkaline environment of the small bowel. In a population-based comparison of adenocarcinomas of the large (n = 261,521) and small (n = 4,518) intestine identified from the SEER registry, small bowel adenocarcinomas demonstrated a distinctly worse stage-adjusted cancer-specific survival compared to colorectal adenocarcinomas (⁷).

Anatomy

The small intestine is divided into three sections. The duodenum represents the first 25 cm of the small intestine and is subdivided into four anatomic segments. The proximal portion of the first (ascending) segment of the duodenum is intraperitoneal, and then the distal portion, as well as the rest of the duodenum, becomes retroperitoneal. The second (descending) segment of the duodenum contains the ampulla of Vater, through which the pancreatic and biliary secretions exit. The third (horizontal) segment of the duodenum is the longest, and as it crosses the left border of the aorta, the fourth (ascending) segment of the duodenum begins. The duodenal-jejunal junction is characterized by the attachment of the suspensory ligament of Treitz. The next segment of the small bowel, the jejunum, is approximately 2.5 m long, and the final segment, the ileum, is approximately 3.5 m long.

Etiology

Little is known about the etiology of small bowel adenocarcinoma. As seen in colorectal adenocarcinomas, adenocarcinomas of the small intestine undergo a similar phenotypic adenoma-carcinoma transformation (^8,9,10). An increase in the size of small bowel adenomas and the presence of a villous histology are risk factors for the development of invasive adenocarcinoma.

Common underlying genetic or environmental factors of both large and small intestine adenocarcinomas have been suggested by studies that have demonstrated an increased risk of small bowel adenocarcinoma in patients with colon adenocarcinoma and vice versa (¹¹). In small bowel adenocarcinoma, microsatellite instability occurs at a similar rate to that seen in colorectal cancer (CRC). In a study of 89 patients with small bowel adenocarcinoma identified from a Swedish population-based cancer registry, the rate of microsatellite instability was 18% (¹²). This result along with the known clinical association between hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and small bowel adenocarcinoma indicate that in a subset of patients with small bowel adenocarcinoma, a germline mutation in one of the mismatch repair proteins contributes to carcinogenesis.

The possible role of pancreaticobiliary secretions in the development of adenocarcinoma of the duodenum has been suggested by the anatomic clustering of duodenal carcinomas in the periampullary area. For example, in patients with familial adenomatous polyposis (FAP), 80% of small intestinal adenocarcinomas will occur in the second portion of the duodenum. One study evaluating 213 cases of duodenal carcinomas identified from the Los Angeles County tumor registry determined that 57% of the cases originated in the second part of the duodenum (¹³).

Environment and Dietary Risk Factors

A number of case-control studies have analyzed associations between environmental and dietary factors and the development of small bowel adenocarcinoma. Two studies have demonstrated that there is an association between the ingestion of smoked or salt-cured foods and the development of small bowel adenocarcinoma (^14,15). An association between tobacco use and cancer risk has been inconsistently demonstrated. Case-control studies have demonstrated an association between an increased risk of small bowel adenocarcinoma and high alcohol intake, high sugar intake, high red meat intake, low fiber intake, celiac disease, peptic ulcer disease, and prior cholecystectomy (^{14,15,16,17,18}). Studies of the relationship with obesity have been conflicting, although a recent case-cohort study of 500,000 subjects with 134 incident cases of small bowel cancer showed a statistically nonsignificant trend toward increased risk in subjects with high body mass index (BMI) (hazard ratio [HR] 1.5 [95% CI, 0.76-2.96] for BMI >27.5 kg/m² compared with 22.6-25.0 kg/m²) (¹⁹).

Genetic Cancer Syndromes

The genetic cancer syndromes HNPCC, FAP, and Peutz-Jeghers syndrome (PJS) are all associated with small bowel adenocarcinoma. The estimated lifetime risk for small bowel adenocarcinoma is 1% to 4% in patients with HNPCC, 5% in those with FAP, and 13% in those with PJS (^20,21,22,23). Patients with HNPCC develop small bowel adenocarcinoma at a younger age, with a median age at diagnosis of 49 years. Patients with PJS, an autosomal dominant polyposis disorder characterized by multiple hamartomatous polyps throughout the intestinal tract, have a markedly increased risk for small bowel adenocarcinoma, with one meta-analysis demonstrating a 520-fold increased relative risk (²⁴). Duodenal adenomas are seen in approximately 80% of patients with FAP, and regular endoscopic screening for the development of adenocarcinoma is required for these patients. The optimal frequency of endoscopic screening depends on a number of factors, such as the number of polyps, polyp size, polyp histology, and amount of dysplasia present (²⁰). With the early use of colectomy in patients with FAP, duodenal adenocarcinomas and desmoid tumors are now a more common cause of death in this population than cancer arising from the colorectum.

Inflammatory Bowel Disease

Inflammatory bowel disease, particularly Crohn disease, is associated with the development of small bowel adenocarcinoma. The increase in risk varies depending on both the extent and duration of small bowel involvement. In one study, the cumulative risk of small bowel adenocarcinoma in patients with Crohn disease was 0.2% at 10 years and 2.2% at 25 years (²⁵). Because Crohn disease frequently involves the ileum, 70% of the small bowel cancers in patients with Crohn disease will occur in the ileum. Patients with Crohn disease who develop small bowel adenocarcinoma appear to have a worse prognosis, with one study of 37 patients with small bowel adenocarcinoma demonstrating significantly shorter overall survival (OS) in the patients with Crohn disease (²⁶).

Molecular Profile

Early limited data has begun to accumulate regarding molecular characterization of small bowel adenocarcinomas. Accumulation of genetic defects such as loss of e-cadherin and smad4 and mutations in KRAS, P53, and SMAD4 have been implicated in the adenoma-dysplasia-carcinoma sequence of small bowel adenocarcinomas (²). In a pivotal study comparing chromosomal copy number aberrations in 85 gastric, colorectal, and small bowel adenocarcinomas, hierarchical clustering revealed a substantial overlap of sba copy number profiles with matched colorectal adenocarcinomas but less overlap with profiles of gastric adenocarcinomas, indicating a genetic profile similar to CRC (²⁷). Large screening of somatic mutations in 83 patients revealed KRAS, TP53, APC, SMAD4, PIK3CA, erbb2, braf, and fbxw7 mutations in >5% of small bowel adenocarcinomas (²⁴). Understanding the biology of small bowel adenocarcinomas may lead to the possibility of developing targeted therapy in this rare cancer.

Presentation and Diagnosis

Clinical Presentation

The symptoms associated with small bowel adenocarcinoma are nonspecific and frequently do not occur until advanced disease is present. The most commonly reported symptoms are abdominal pain (45%-76% of patients), nausea and vomiting (31%-52%), weight loss (22%-29%), and gastrointestinal bleeding (8%-34%). Delays in diagnosis are common, with one retrospective study reporting a mean delay of 7.8 months from the time of initial physician evaluation until a final diagnosis was made (²⁸). According to the National Cancer Database, 39% of patients present with stage I/II disease, 26% present with stage III disease, and 32% present with stage IV disease (²⁹).

Diagnosis

Given the nonspecific presenting symptoms, a high index of suspicion is a crucial first step in diagnosis. Because imaging of the small intestine is difficult, multiple tests may be needed. However, with the availability of wireless capsule endoscopy, the need for older small bowel imaging techniques has declined.

A barium small bowel follow-through study has been the radiographic gold standard for small bowel evaluation. In patients with advanced-stage disease, this technique has a sensitivity of approximately 60% for diagnosing small bowel tumors. Enteroclysis, in which contrast material is infused directly into the small intestine through a nasogastric tube, provides a slightly higher sensitivity than small bowel follow-through. Endoscopic evaluation of the small intestine, or enteroscopy, requires expertise and is frequently unable to evaluate the entire small intestine.

The incorporation of wireless capsule endoscopy, which was approved by the US Food and Drug Administration in 2001, has allowed a much simpler and improved method for evaluating the lumen of the small intestine. This technique has primarily been applied to the evaluation of obscure gastrointestinal bleeding, for which it has shown superiority over other imaging and endoscopy techniques (³⁰). In one study evaluating capsule endoscopy in 60 patients with suspected small bowel pathology but without gastrointestinal bleeding, the overall diagnostic yield of capsule endoscopy was 62% (³¹). In that study, all patients had undergone upper and lower gastrointestinal endoscopy, and many had undergone enteroclysis, small bowel follow-through, push enteroscopy, and abdominal computed tomography (CT). In a large single-center retrospective review of 562 patients who underwent capsule endoscopy, small bowel tumors were found in 8.9% of cases (³²). The major limitations of capsule endoscopy are that no tissue sampling can be conducted and that the patients cannot have bowel obstruction, which could result in the capsule’s becoming trapped in the bowel.

Three-dimensional imaging with either CT or magnetic resonance imaging (MRI) is useful in identifying locoregional lymph node involvement and the presence of distant metastatic disease. For tumors of the duodenum, endoscopic ultrasonography can be useful in assessing both the tumor and nodal status. Although not directly studied for duodenal adenocarcinomas, endoscopic ultrasonography has been demonstrated to improve staging accuracy for both ampullary and pancreatic cancers.

Staging and Prognosis

The TNM (tumor, node, metastasis) staging system for small bowel adenocarcinoma is shown in Table 23-1 (³³). In a study of 4,995 patients who were diagnosed with small bowel adenocarcinoma between 1985 and 1995 (identified in the National Cancer Database), the 5-year disease-specific survival (DSS) rate was 65% for patients with stage I disease, 48% for patients with stage II disease, 35% for patients with stage III disease, and 4% for patients with stage IV disease (²⁹). A multivariate analysis from this study identified age >75 years, primary duodenal tumor site, non–cancer-directed surgery, and higher-stage disease as poor prognostic factors. Though significant on a univariate analysis, a poorly differentiated histology was not a significant prognostic factor on multivariate analysis (P = .089). In other studies, the histopathologic factors reported to be correlated with poor survival were poorly differentiated histology, positive margins, lymphovascular invasion, lymph node involvement, and T4 tumor stage (^26,34,35,36). The 5-year OS rates from various single-institution studies for resected small bowel adenocarcinoma are presented in Table 23-2.

Treatment

Surgical Management

For patients with localized disease, complete removal of the tumor with negative surgical margins and local lymph node removal are critical for a potentially curative resection. For jejunal and ileal lesions, an oncologically successful resection requires a wide local excision with lymphadenectomy. Lesions located in the duodenum generally require a pancreaticoduodenectomy; however, for small distal lesions in the third and fourth portions of the duodenum, a wide local excision may be an option. In a surgical series of 68 patients with duodenal adenocarcinoma, no differences in the 5-year OS rates, local recurrence rates, or margin-negative resection rates were seen between the 50 patients who underwent pancreatic resections and the 18 patients who underwent distal duodenal segmental resections (³⁷). The presence of locoregional lymph node involvement should not deter surgical intervention because well over one-third of patients will survive long term (^29,38). This is in contrast to patients with lymph node–positive pancreatic cancer, of whom only 7% survive 5 years (³⁹). As is seen with colon cancer, the total lymph nodes (TLNs) assessed during surgery and the number of positive lymph nodes (PLNs) have prognostic implications in small bowel adenocarcinomas. In a SEER registry retrospective review of 1,991 patients, the 5-year DSS for patients with stage II disease appeared to be associated with the TLNs assessed (44%, 69%, and 83% for 0 TLNs, 1 to 7 TLNs, and >7 TLNs, respectively) (⁴⁰). Furthermore, the 5-year DSS with stage III disease was associated with the number of PLNs (58% and 37% for <3 PLNs and ≥3 PLNs, respectively) (⁴⁰).

Patterns of Recurrence

Recurrence after potentially curative resection of small bowel adenocarcinoma occurs most commonly at distant sites. In a series of 146 patients who underwent resection for small bowel adenocarcinoma, 56 patients relapsed at a median of 25 months, with the sites of relapse reported as distant in 59%, peritoneum in 20%, abdominal wall in 7%, and local in 18% (⁴¹). In a second study of 30 patients who underwent potentially curative resection for small bowel adenocarcinoma, 21 patients experienced a relapse, with the sites of relapse being the liver in 67% of the patients, lung in 38%, retroperitoneum in 29%, and peritoneum in 25% (³⁴).

Patients with duodenal adenocarcinoma have a higher rate of locoregional failure than for jejunal and ileal adenocarcinoma, with one study reporting a 39% rate of locoregional failure among 31 patients after curative resection of duodenal adenocarcinoma (⁴²). In that study, positive margin status was the strongest predictor of local recurrence, with 4 of the 5 patients who had a margin positive resection developing a local recurrence. However, distant recurrences are still predominant, with a retrospective review of recurrence patterns in 67 patients with resected duodenal adenocarcinoma revealing local recurrences in 33% of the patients and distant recurrences in 67% (⁴³).

Adjuvant Therapy

Currently, there is no evidence demonstrating a benefit from adjuvant therapy in patients with small bowel adenocarcinoma who undergo potentially curative resection. However, owing to the rarity of small bowel adenocarcinoma, only a limited number of primarily small retrospective studies have been conducted (Table 23-3). Selection bias is the major limitation of these retrospective studies because the patients selected to receive adjuvant therapy were the patients believed to be at highest risk for disease recurrence. One prospective phase III study conducted by the European Organization for Research and Treatment of Cancer randomized 93 eligible patients with periampullary carcinoma (defined as adenocarcinoma of the distal common bile duct, ampulla of Vater, or duodenum) to receive either no adjuvant therapy or concurrent 5-fluorouracil (5-FU) and radiation therapy (⁴⁴). The 5-year OS rates were similar in the two groups, but 30% of the patients assigned to receive adjuvant therapy did not actually receive it, and no description of the results in the duodenal adenocarcinoma subgroup were reported.

In a series by Kelsey et al, no differences in the 5-year OS rates were seen between the patients who did or did not receive adjuvant therapy after resection of duodenal adenocarcinoma. However, in the subgroup of patients who had undergone a margin-negative resection, the 5-year OS rate was 53% in the patients who underwent resection only and 83% in the patients who had resection and adjuvant chemoradiation therapy (P = .07) (⁴²). A trend toward improvement of disease-free survival and OS was seen in patients receiving adjuvant therapy in a retrospective series at MD Anderson Cancer Center (n = 54) (⁴⁵). However, in the subgroup analyses in patients with high-risk disease, defined by a lymph node ratio ≥10%, adjuvant therapy was associated with significant improvement in OS (⁴⁵). In contrast, in a single-institution retrospective review at Mayo Clinic, no benefit of adjuvant chemotherapy or chemoradiotherapy was seen in patients with resected small bowel adenocarcinoma (⁴⁶).

Limited data are available regarding a neoadjuvant (preoperative) treatment approach for duodenal adenocarcinoma. In one report in which 11 patients underwent neoadjuvant chemoradiation therapy followed by resection for duodenal adenocarcinoma, a complete pathologic response was seen in 2 patients, and none of the 11 patients had histopathologic nodal involvement at the time of surgery (⁴²).

The MD Anderson Approach to Nonmetastatic Disease

At the University of Texas MD Anderson Cancer Center, patients with high-risk, resected small bowel adenocarcinoma are typically offered postoperative adjuvant chemotherapy. In general, patients who are considered to be at high risk are those with lymph node involvement and positive resection margins. The lack of proven benefit from adjuvant chemotherapy for this tumor type must be discussed with the patient. However, the rationale for considering adjuvant chemotherapy is based on

1. The known poor prognosis of patients with high-risk disease

2. The predominantly systemic relapse pattern for small intestinal adenocarcinoma

3. The proven activity of chemotherapy in the treatment of metastatic small intestinal adenocarcinoma

4. The known benefit of adjuvant chemotherapy in large intestinal adenocarcinoma, which appears to have a number of similarities to small intestinal adenocarcinoma

5. The extremely limited amount of high-quality data to support or refute the role of adjuvant therapy for small bowel adenocarcinoma

Based on the substantial activity of a 5-FU and platinum combination in the metastatic disease setting, we generally utilize the combination of capecitabine and oxaliplatin (CAPOX) as adjuvant therapy for nonmetastatic small bowel adenocarcinoma. In addition to systemic chemotherapy, radiation therapy is considered for patients with duodenal adenocarcinoma who are at high risk for a local recurrence based on the presence of positive margins or T4 disease.

Metastatic Disease

In general, chemotherapy for metastatic small bowel adenocarcinoma has been based on the principles used for treating colon cancer. Several single-institution retrospective series have demonstrated a survival benefit in patients with metastatic or unresectable small bowel adenocarcinoma who received chemotherapy when compared to patients who did not receive chemotherapy (^41,47).

Most of the studies evaluating chemotherapy for small bowel adenocarcinoma have been retrospective, with only four prospective phase II studies reported (Table 23-4). One multicenter study conducted by the Eastern Cooperative Oncology Group reported on the combination of 5-FU, doxorubicin, and mitomycin C (FAM) in 39 patients with adenocarcinomas of the duodenum, jejunum, ileum, or ampulla of Vater. The overall response rate was 18%, with a median OS time of 8 months (⁴⁸). A single-institution study conducted at MD Anderson evaluated CAPOX in 30 patients with metastatic or locally advanced small bowel or ampullary adenocarcinomas. The overall response rate was 50%, with a median time to progression of 9.8 months and an OS time of 20.3 months (⁴⁹). An example of a response to CAPOX chemotherapy in a patient treated in that study is shown in Fig. 23-1. In 33 patients treated with continuous infusional 5-FU and leucovorin in combination oxaliplatin (modified 5-FU and oxaliplatin [FOLFOX] regimen), the objective response rate was 48.5%, and the median OS was 15.2 months (⁵⁰). Another prospective, multicenter, first-line study (n = 23) using CAPOXIRI (capecitabine, oxaliplatin, and irinotecan) showed a response rate of 39% and a median survival of 12.7 months (⁵¹).

Several retrospective studies have confirmed the substantial activity of 5-FU combined with a platinum agent for metastatic small bowel adenocarcinoma, with response rates of 18%-46% (^52,53,54,55). In one of the largest retrospective studies to date, a total of 80 patients with metastatic small bowel adenocarcinoma were treated with various regimens: 29 received 5-FU with a platinum (19 received cisplatin, 4 received carboplatin, and 6 received oxaliplatin); 41 received 5-FU–based therapy without a platinum (32 received 5-FU alone, 3 received FAM, 3 received 5-FU and mitomycin, and 3 received other 5-FU combinations); and 10 received non-platinum–based and non-5-FU–based therapy (⁵⁵). Patients who received 5-FU combined with a platinum agent had a higher overall response rate (46% vs 16%; P < .01) and longer median progression-free survival (PFS) time (8.7 vs 3.9 months; P < .01) than patients who received other chemotherapy regimens. Although not statistically significant, there was also a trend toward improved median OS times in patients who received 5-FU plus a platinum agent (14.8 vs 12.0 months; P = .1). A French multicenter study in SBA receiving frontline chemotherapy with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19), and LV5FU2-cisplatin (n = 16) demonstrated a median PFS of 7.7, 6.9, 6.0, and 4.8 months, respectively (⁴⁷). The corresponding median OS was 13.5, 17.8, 10.6, and 9.3 months, respectively (⁴⁷). In the subgroup analysis, patients treated with LV5FU2-cisplatin had poorer PFS (P < .01) and OS (P = .02) compared with oxaliplatin-based chemotherapy (⁴⁷).

Irinotecan-based chemotherapy is also active against metastatic small bowel adenocarcinoma. One retrospective study reported that 5 of 12 patients responded to irinotecan-based therapy (3 patients responded to 5-FU plus irinotecan, 1 responded to capecitabine plus irinotecan, and 1 responded to single-agent irinotecan) (⁵³). A second study of salvage therapy with irinotecan in the second-line setting noted stable disease in 4 of 8 treated patients (⁵⁴). Among the 19 patients in the AGEO study treated with 5-FU plus irinotecan, 1 had a partial response, and stable disease was seen in 7 patients (⁴⁷). Responses to gemcitabine-based therapy have also been noted, although the number of patients treated has been small. The role of targeted therapies against the vascular endothelial growth factor (VEGF) or epidermal growth factor receptors (EGFRs) has not been studied in small bowel adenocarcinoma.

The MD Anderson Approach to Metastatic Disease

The substantial response rates and prolonged OS times recently reported with modern-day chemotherapy combinations in small bowel adenocarcinomas strongly argue for an aggressive approach in treating patients with metastatic small bowel adenocarcinoma. Given the extremely encouraging results with CAPOX and FOLFOX for metastatic small bowel adenocarcinoma, we generally recommend these regimens at MD Anderson. Following frontline CAPOX or FOLFOX chemotherapy, patients are then treated with an irinotecan-based regimen. In addition, patients with limited metastatic disease who respond to initial chemotherapy are considered for surgical resection if all disease sites can be successfully excised. Investigations are ongoing at MD Anderson to evaluate the role of EGFR inhibition in addition to CAPOX chemotherapy for small bowel adenocarcinoma. More effective treatments for small bowel adenocarcinoma remain needed, and participation in clinical trials for this rare tumor type is strongly encouraged. A proposed treatment algorithm for small bowel adenocarcinoma is presented in Fig. 23-2.

Appendiceal tumors encompass a rare and diverse group of neoplasms. With an age-adjusted incidence of about 0.12 cases per 1 million individuals per year, appendiceal tumors represent only 1% of all CRCs diagnosed each year in the United States (^56,57). Historically, appendiceal tumors have been grouped together with CRCs. However, appendiceal tumors, in which outcomes are strongly determined by histologic subtype, tend to have a biology very different from that of CRC. Appendiceal tumors comprise two types: appendiceal carcinoid tumors and appendiceal epithelial tumors. Appendiceal carcinoid tumors account for approximately 50% of all appendiceal neoplasms, and appendiceal epithelial tumors represent the remaining 50% (⁵⁸). This chapter on appendiceal tumors discusses the management of these two tumor types (carcinoid and epithelial) and, in particular, the unusual clinical syndrome of pseudomyxoma peritonei (PMP).

Incidence

Data derived from the SEER database of the National Cancer Institute between 1973 and 1998 revealed that the most common histologic subtypes of malignant tumors of the appendix were adenocarcinomas (67%) and carcinoids (33%) (⁵⁶). However, this analysis captured neither adenomatous tumors nor benign carcinoids. The subtypes of adenocarcinoma were mucinous type (56%), nonmucinous intestinal type (38%), and signet ring cell type (6%). Alternatively, in a separate study of 7,970 appendectomy specimens, tumors were identified in 1% of specimens, with carcinoids representing 57% of all tumors identified (⁵⁸). Adenomas and adenocarcinomas represented 18% and 11% of the identified tumors, respectively.

Presentation and Prognosis

The majority of appendiceal tumors are identified incidentally at the time of pathological review of appendectomy specimens. Symptoms of appendicitis are most often the presenting symptom, especially with tumors located at the base of the appendix, where obstruction is more likely to occur. Other symptoms seen with more advanced appendiceal disease can reflect the nonspecific abdominal symptoms associated with peritoneal involvement: abdominal pain and distention, altered bowel motility, and early satiety. Metastatic carcinoid tumors may also present with symptoms related to the carcinoid syndrome, with episodic flushing, wheezing, and diarrhea. Patient age at presentation differs depending on histologic subtype of the tumor, with the mean age of 38 years for patients with carcinoid tumors and the mean age of 60 years for those with adenocarcinomas (⁵⁶).

Prognosis for appendiceal cancer is strongly dependent on the histopathologic subtype of the tumor, with patients who have carcinoids having a significantly better survival than do patients with adenocarcinomas (Fig. 23-3) (⁵⁶). In addition, patients with early-stage tumors identified incidentally at the time of appendectomy have a better prognosis than patients who are diagnosed once symptoms develop.

Prognosis for patients with epithelial tumors is also strongly dependent on histopathology of the tumor. Staging for appendiceal carcinomas is based on the TNM) seventh edition staging system and incorporates histological grade in the differentiation between stage IVA and IVB (Table 23-5) (³³).

For metastatic epithelial tumors of the appendix, prognosis is excellent for those with low-grade mucinous tumors, termed disseminated peritoneal adenomucinosis (DPAM), whereas appendiceal adenocarcinomas with high-grade histological features such as poor differentiation or signet ring cell morphology have a much poorer survival. Presence of lymph node metastases is a predictor of recurrence in early-stage tumors (⁵⁹). Stage IV mucinous appendiceal adenocarcinomas are categorized as either mucinous low grade (well differentiated) or mucinous high grade (moderate and poor differentiation) by the American Joint Committee on Cancer (AJCC) seventh edition. However, recent population-based efforts utilizing the SEER database have demonstrated that mucinous moderate-differentiated adenocarcinomas appear to have a prognosis more akin to mucinous well-differentiated carcinomas as opposed to mucinous poorly differentiated carcinomas (⁵⁹).

Appendiceal Carcinoid Tumors

Similar to other intestinal carcinoid tumors, appendiceal carcinoid tumors arise from neuroendocrine cells within the lamina propria and submucosa. Appendiceal carcinoid tumors can secrete serotonin and vasoactive substances responsible for the carcinoid syndrome, although this is rarely seen in patients in the absence of extensive liver metastases. Appendiceal carcinoid tumors are usually seen in young patients and are seen slightly more often in women (^60,61).

A rare histological variant of carcinoid tumors, termed goblet cell carcinoids or adenocarcinoids, is characterized by malignant cells that demonstrate both exocrine and neuroendocrine characteristics. This histological subtype has outcomes in between that of a carcinoid and that of an adenocarcinoma (see Fig. 23-3).

Management of Appendiceal Carcinoids

As most appendiceal carcinoid tumors are discovered incidentally from an appendectomy specimen, a critical and somewhat-controversial oncologic question relates to the need for performing a more complete surgical staging procedure. For appendiceal cancers, a complete surgical staging procedure would entail a right hemicolectomy with complete removal of the base of the appendix, mesoappendix, and draining lymph nodes.

The most useful criteria for determining the need for a complete right hemicolectomy are tumor size (≥2 cm in diameter) or mesoappendix involvement (⁶²). In a retrospective study of appendiceal carcinoids, Moertel et al reported no metastases in 127 patients with tumors <2 cm, whereas metastatic disease was seen in 3 of the 14 patients with tumors 2 to 3 cm and 4 of the 9 patients with tumors ≥3 cm (⁶³). Patients with an adenocarcinoid histological variant are generally treated as having an appendiceal adenocarcinoma.

For patients with metastatic disease, the use of somatostatin analogues can alleviate the symptoms of the carcinoid syndrome but rarely causes objective tumor regression. Given the slow-growing nature of appendiceal carcinoid tumors, local modality therapies such as hepatic embolization or surgical resection may also be beneficial in selected patients with metastatic disease. For additional information on management of this type of tumor, please refer to Chapter 23.

Appendiceal Epithelial Tumors

Little is known about the risk factors or etiology of epithelial tumors of the appendix. Although generally viewed as a subset of CRC, most epithelial tumors of the appendix have a markedly different biology and natural history than do adenocarcinomas of the colorectum. In particular, a subset of appendiceal epithelial tumors that have disseminated peritoneal mucinous deposits derived from a ruptured appendiceal mucinous adenoma can demonstrate excellent long-term survival with aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) (^64,65).

Most appendiceal epithelial tumors begin as a mucinous adenoma with appendiceal distention caused by excessive mucin production. On gross inspection or radiographic evaluation, this dilated mucin-filled appendix is frequently referred to as a mucocele. With progressive growth, the appendiceal lumen can become obstructed and result in increased intraluminal pressure within the appendix, which can cause the appendix to rupture. Appendiceal rupture represents the critical step in the dissemination of the mucinous appendiceal tumor to the peritoneal cavity. For this reason, it is critical that care is taken when surgically removing an appendiceal mucocele to prevent rupture and peritoneal seeding during a routine appendectomy (⁶⁶). When resecting an appendiceal mucocele, the peritoneum should be inspected closely to evaluate any evidence of dissemination to the peritoneal cavity. During pathological examination of the appendix, any fluid or mucus in the peritoneal spaces surrounding the appendix should undergo cytologic examination (⁶²). In patients with localized disease, the presence of carcinoma requires a completion right hemicolectomy for oncologic staging.

Molecular Profile

The molecular characterization of appendiceal adenocarcinomas is limited. Mutations are frequently seen in these tumors and include KRAS, GNAS, AKT, MET, PIK3CA, and TP53 genes (^67,68,69,70). In a cohort of 149 patients with appendiceal adenocarcinomas at MD Anderson Cancer Center, KRAS, PIK3CA, and BRAF mutations were seen in 55%, 17%, and 4% of patients, respectively (⁷¹). The study also demonstrated that well- and moderately differentiated appendiceal adenocarcinomas were molecularly distinct from poorly differentiated appendiceal adenocarcinomas (⁷¹).

Pseudomyxoma Peritonei

Pseudomyxoma peritonei, or false mucinous tumor, is a term originally described by Werth in 1884, who described the pathological findings in a patient with a ruptured ovarian cystadenoma who had copious gelatinous intraperitoneal ascites (Fig. 23-4) (⁷²). This term has been applied broadly to include any mucinous tumor type involving the peritoneal cavity with any histologic grade of differentiation. However, this imprecise definition has resulted in the grouping of patients with dramatically different outcomes and has generated considerable confusion for patients and even among clinicians. A better understanding of disease biology has shown that this clinical term is most appropriately applied to the pathological subtype of appendiceal tumors called disseminated peritoneal adenomucinosis (⁷³).

However, the term PMP is frequently utilized to refer to the clinical syndrome of mucinous peritoneal deposits resulting from any mucinous appendiceal tumor. When used in this fashion, this term encompasses both DPAM and the appendiceal epithelial tumor subtype termed peritoneal mucinous carcinomatosis (PMCA). However, the inclusion of these two histological subtypes combines two appendiceal epithelial tumor types with markedly different OSs (Table 23-6) (^73,74).

Histopathologic Subtypes of Epithelial Appendiceal Tumors

Disseminated Peritoneal Adenomucinosis

Disseminated peritoneal adenomucinosis is characterized by peritoneal lesions composed of abundant extracellular, mucin-containing, scant, simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity, with or without an associated appendiceal mucinous adenoma (⁷³). In essence, the underlying epithelium in DPAM may have low-grade adenomatous changes but may not have any evidence of invasion or carcinoma. This subgroup of tumors (DPAMs) demonstrates the classic PMP clinical syndrome of massive amounts of benign-appearing mucinous ascites that over time slowly fill the entire peritoneal cavity (Fig. 23-5). Although spread to the peritoneal cavity is present, these tumors do not metastasize to regional lymph nodes or via hematogenous spread to the liver or other distant sites.

Patients with DPAM typically present with gradually increasing abdominal girth. For women, DPAM may present as a new ovarian mass, and for men it may present as a new-onset hernia. In women, secondary involvement of the ovaries is common, and because histopathological features of DPAM from a primary ovarian tumor are extremely rare, a thorough pathological examination of the appendix should be conducted (⁷⁵). When molecular and immunohistochemical evaluations have been performed on cases with both appendix and ovarian involvement, these evaluations have uniformly demonstrated the primary site of disease as the appendix (^76,77,78).

Peritoneal Mucinous Carcinomatosis

If evidence of invasion and carcinoma is present, then the pathological diagnosis of PMCA should be used (⁷³). Peritoneal mucinous carcinomatosis is characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma, with or without an associated primary mucinous adenocarcinoma. A subset of PMCA tumors that demonstrate features of both DPAM and PMCA have been termed PMCA with intermediate or discordant features (PMCA-I/D) (⁷³). In an analysis of 109 patients with clinical features of PMP, 60% were classified as DPAM, 27% were classified as PMCA, and 13% were classified as PMCA-I/D (^73,79). In this study, the 5- and 10-year survival rates for patients with DPAM were 75% and 68%, respectively. This was significantly higher than patients with PMCA, who demonstrated 5- and 10-year survival rates of 14% and 3%. Those patients with PMCA-I/D had survival more closely associated with that of PMCA patients (Fig. 23-6).

Although appendiceal PMCAs are invasive tumors with distant metastatic potential, the majority of these tumors will remain localized to the peritoneal cavity. Even in the subset of patients with very aggressive-appearing histologies, the rate of distant hematogenous metastases remains low. In one retrospective study of 90 appendiceal adenocarcinomas with either poor differentiation or signet ring cell morphology, the rate of extraperitoneal metastases was only 17% (⁸⁰).

Nonmucinous/Colonic-Type Adenocarcinoma

Occurring less frequently, nonmucinous or colonic-type adenocarcinomas of the appendix demonstrate a different tumor biology than mucinous appendiceal tumors. These cancers are more aggressive and appear to behave more like colonic adenocarcinomas. In a study by Kabbani et al, 43% of patients with nonmucinous apendiceal adenocarcinoma had evidence of extraperitoneal metastases (⁸¹). The patients with nonmucinous carcinomas in this study had a significantly worse OS and disease-free survival than those with mucinous carcinomas.

Treatment

Cytoreductive Surgery

Because of the relative rarity of this disease, prospective randomized clinical trials studying the treatment of appendiceal epithelial tumors are lacking. The majority of data evaluating the various treatment modalities in this disease have been derived from retrospective, single-institution studies. Surgical cytoreduction has been the primary mode of therapy for these tumors based on the following factors:

1. Lack of extraperitoneal disease spread

2. Primarily mucinous nature of peritoneal deposits

3. Indolent growth rate

4. Limited activity of systemic chemotherapy

5. Lack of an effective systemic mucolytic agent

The goal of surgical cytoreduction is complete tumor removal from the peritoneal cavity. Because of the large surface area of the peritoneum, surgical cytoreduction to remove all visible sites of disease can be challenging. Optimal CRS may involve removal of the appendix, right colon, intraperitoneal tumor debulking, resection of multiple abdominal and pelvic organs with peritoneal tumor studding, and stripping of all involved parietal peritoneum (⁸²). Following successful surgical cytoreduction, patients with the DPAM or PMCA tumors can experience reaccumulation of mucinous peritoneal implants, which may be complicated by fibrosis from prior surgery, requiring repeated surgical cytoreductive procedures.

In a 97-patient series from Memorial Sloan Kettering Cancer Center, in which surgical resection alone represented the primary treatment modality in over two-thirds of the patients, the 5-year OS rate was 90% for patients with DPAM and 50% for patients with PMCA (⁶⁴). In the 55% of patients who underwent a complete cytoreduction of all visible tumors, 91% had recurrent disease. The average number of surgical cytoreductions that patients underwent in this study was 2.2, with a range of 1 to 6 (⁶⁴). In patients who develop recurrence after CRS, repeat CRS should be attempted because survival in these patients is prolonged with repeat CRS (⁸³).

Hyperthermic Intraperitoneal Chemotherapy

In an attempt to diminish the rate of disease recurrence following CRS, the administration of intraperitoneal chemotherapy following a surgical cytoreduction has been used to try to treat any residual microscopic disease in the peritoneal cavity. Historically, a number of methods of delivering intraperitoneal chemotherapy have been utilized, although the most commonly utilized method is HIPEC administered at the time of cytoreduction.

At MD Anderson, following complete CRS, administration of heated mitomycin C at a dose of 25 mg/m² for patients who are chemonaïve or 20 mg/m² for patients who have received previous chemotherapy in a volume of 5 to 6.5 L of electrolyte solution at a flow rate of 3 to 3.5 L/min. Intraoperative hemodynamic monitoring and thermal monitoring are essential for optimal outcomes in these patients. The HIPEC is continued for 90 minutes with vigorous shaking of the closed abdomen. On completion of HIPEC, necessary bowel anastomoses are performed, and gastrostomy and jejunostomy tubes are placed for postoperative management of nutritional deficiencies and prolonged gastric ileus.

Intraperitoneal administration of chemotherapy offers an advantage of providing high concentrations of drug directly to the target, while hyperthermia provides a synergistic antitumor effect when combined with chemotherapy (⁸⁴). However, as a locally applied modality, the maximum penetration into tumor tissue is usually limited to 2 to 5 mm from the surface (⁸⁵). At present, no randomized study has compared the benefit of adding HIPEC to surgical cytoreduction, although single-institution series have indirectly suggested a benefit when disease-free survival rates of patients treated with surgical cytoreduction and HIPEC (37%-57%) (^74,76) are compared with the historical rates of surgical cytoreduction alone (9%-12%) (^64,77).

Cytoreductive surgery with HIPEC represents an aggressive treatment requiring significant surgical expertise and should only be conducted at centers experienced in performing peritoneal cytoreduction. Operation time is approximately 8 to 12 h, with an average hospital stay of 20 to 25 days. The 30-day postoperative mortality and morbidity range from 0% to 12% and 12% to 56%, respectively (^76,78).

In one of the largest retrospective multi-institutional registry-based study of 2,298 patients with PMP originating from an appendiceal mucinous neoplasm undergoing CRS, the reported median OS was 16.3 years, with a 10-year survival rate of 63% (⁸⁶). The treatment-related mortality was 2%, and major operative complications occurred in 24% of cases (⁸⁶). A high PCI, lack of complete cytoreduction, and lack of HIPEC were associated with poorer PFS and OS (⁸⁶).

Prognosis for patients undergoing CRS with HIPEC is primarily dependent on two critical factors: histologic classification and completeness of surgical resection. A quantitative score, the completeness of cytoreduction score proposed by Sugarbaker and colleagues, categorizes the completeness of cytoreduction (CC) based on the size of nodules remaining at the end of surgery: CC-0 (no visible disease), CC-1 (nodules <0.25 cm), CC-2 (nodules 0.25 to <2.5 cm), and CC-3 (nodules ≥2.5 cm) (⁶⁵). In an analysis of 224 patients with DPAM histology, Sugarbaker et al found that patients with complete cytoreduction (CC-0 or CC-1) had a 5-year OS rate of 86%, whereas patients with incomplete cytoreduction (CC-2 or CC-3) had a 5-year OS rate of 20% (P < .0001) (Fig. 23-7) (⁶⁵). The importance of completeness of cytoreduction has been confirmed by other authors, although various methods of categorizing a complete cytoreduction have been used (^74,76).

Additional prognostic measures include the peritoneal cancer index (PCI), a quantitative measure of the size and distribution of nodules on the peritoneal surface; the previous surgical score (PSS), a measure of the extent of prior cytoreduction; and the extent of disease on the small bowel and small bowel mesentery (^64,65,87,88). The prognostic value of these different factors relates primarily to their ability to predict the likelihood of obtaining a complete cytoreduction.

For patients who cannot undergo complete CRS, the benefit obtained from an incomplete cytoreduction remains unknown. If complete CRS cannot be performed, a surgical cytoreduction is generally considered only if there are particular symptoms that can be palliated by tumor debulking. Given that HIPEC has limited tumor penetration, use of HIPEC should be limited to patients with a complete or near-complete CRS.

Systemic Chemotherapy

The role of systemic chemotherapy has not been well delineated in appendiceal epithelial tumors and has generally been utilized in patients who are not candidates for surgical cytoreduction (⁸²). The challenges of using systemic chemotherapy to treat appendiceal tumors relate to the slow-growing nature of the disease, the primarily mucinous component of the tumors, and the challenges in radiographically measuring disease response.

Traditionally, PMP has been considered resistant to systemic chemotherapy, although a recently completed phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced, unresectable DPAM or PMCA has suggested a role for systemic chemotherapy (⁸⁹). In this study of 39 patients, a clinical benefit rate of 38% was determined based on the definition of either semiquantitative reductions in mucinous deposition or stabilization of previously progressive disease (⁸⁹). In this study, the 2-year cancer-related mortality rate was 39%. Elevations in tumor markers (CEA, CA 19-9, or CA-125) occurred in all patients, and a 50% reduction in one of these markers occurred in 51% of patients (⁸⁹). Although limited by the small sample size, tumor marker response did not appear to correlate with radiographically assessed clinical benefit rate (⁸⁹).

In an additional study supporting the role of systemic chemotherapy in patients with PMCA, Shapiro et al retrospectively reviewed data collected from 54 patients who were suboptimal surgical cytoreductive candidates (⁸²). Systemic chemotherapy in this report consisted of a fluoropyrimidine with or without a platinum agent in 69% of patients. Radiographic stabilization or response to therapy was noted in 55% of patients, median PFS was 7.6 months, and median OS was 56 months (⁸²). In this study, poorly differentiated histology and signet ring histology were both negative prognostic indicators for OS. Systemic chemotherapy may play a role in the management of poorly differentiated and signet ring cell adenocarcinomas of the appendix. In a retrospective review of 142 patients with these tumors, systemic chemotherapy resulted in a response rate of 44%, a median PFS of 6.9 months, and a median OS of 1.7 years (⁹⁰). Patients with response to chemotherapy and complete CRS were associated with improved PFS and OS (⁹⁰). Although data regarding role of targeted therapy is limited in appendix cancers, retrospective data suggest that combining bevacizumab with chemotherapy may improve survival outcomes in surgically unresectable appendiceal epithelial neoplasms (^71,91).

The studies discussed in this section suggest a role for chemotherapy in patients who are suboptimal candidates for CRS, but further prospective randomized clinical trials will be needed before any definitive statement regarding the exact benefit and timing of chemotherapy use can be made.

The MD Anderson Approach to Epithelial Appendiceal Tumors

Unlike CRC, appendiceal epithelial malignancies have a more indolent natural history that is determined by their underlying histopathology. At MD Anderson, patients with DPAM and well-to-moderately differentiated PMCA tumors are evaluated initially for CRS. Patients with a complete cytoreduction (CC-0 or CC-1) are treated with HIPEC utilizing intraperitoneal mitomycin at 42°C. If a complete CRS is not obtained, if radiographic imaging indicates that obtaining a complete cytoreduction is highly unlikely, or if medical comorbidities preclude a surgical procedure, then patients are considered for systemic chemotherapy. Also, HIPEC is utilized at MD Anderson for the control of refractory ascites. We have found that the use of HIPEC in patients who have undergone an incomplete CRS can provide long-term control of ascites and should be considered in patients with refractory ascites.

Given the indolent nature of well-to-moderately differentiated PMCA tumors, systemic chemotherapy is generally reserved for patients who either have clear evidence of disease progression on radiographic imaging or have significant tumor-related symptoms. Frontline chemotherapy is fluoropyrimidine based, and additional agents may be added based on the perceived tolerance of more aggressive combinations. Given the general good prognosis of these patients, it is critical that treatment is closely aligned with quality of life and that cumulative toxicities are kept to a minimum.

The use of multiagent systemic chemotherapy, as administered in CRC, is the treatment of choice for patients who have signet ring cells, poorly differentiated tumors, or nonmucinous tumors. Because patients with poorly differentiated or signet ring cell appendiceal adenocarcinomas have consistently shown worse outcomes following aggressive CRS, our approach has been only to consider surgical cytoreduction in these patients following initial treatment with systemic chemotherapy. In a recent retrospective study from MD Anderson, Lieu et al showed that patients with stage IV poorly differentiated or signet ring cell morphology appendiceal adenocarcinomas had a median OS of 24 months, which appears similar to the known OS for metastatic CRC (⁸⁰).

Although trials evaluating the benefit of VEGF inhibitors or EGFR inhibitors in appendiceal epithelial tumors are lacking, their effectiveness in CRC suggests a possible role for these agents in appendiceal epithelial tumors. Expression of VEGF has been demonstrated in appendiceal adenocarcinomas, and high levels of expression have been correlated with poor outcome (⁹²). Although not well studied, it appears that mutations in the K-ras oncogene are common, with 22 of 31 tested samples demonstrating an activating mutation in K-ras (⁹³).

Due to the rarity of appendiceal tumors, our understanding of these tumors is limited, and further research into the molecular characteristics of these tumors is needed. The role of CRS is well established for appendiceal epithelial tumors. The use of systemic chemotherapy in appendiceal epithelial tumors needs further study; in particular, the role of newer targeted therapies needs to be determined.