Wolfgang B. Gaertner
Elizabeth C. Wick
Genevieve Melton-Meaux
Presentation
A 44-year-old female presents with a 2-day history of right lower-quadrant pain associated with anorexia and nausea. WBC is 12,000. An abdominal ultrasound shows a thickened appendix with minimal free fluid in the right lower quadrant. The patient undergoes an uneventful laparoscopic appendectomy and is discharged to home on postoperative day 1. Pathology returns 2 days later and shows a 1.5-cm carcinoid tumor located at the midappendix with invasion of the mesoappendix.
Differential Diagnosis
Appendiceal tumors are exceedingly rare with an age-adjusted incidence of 0.12 cases per 1,000,000 people per year. It is estimated that appendiceal cancer is found in 1% of all appendectomy specimens. In addition to being a rare form of cancer, the vast majority of appendiceal carcinomas are not diagnosed preoperatively; rather, they present with acute appendicitis or are detected as an incidental finding during operative exploration for another surgical disorder. Although carcinoid tumors were once considered the most common type of appendiceal tumor, the reported incidence has decreased since the 1970s and the incidence of appendiceal adenocarcinoma has increased.
Workup
The patient is further evaluated with a computed tomography (CT) scan of the abdomen and pelvis that shows postoperative changes in the right lower quadrant but no evidence of metastatic disease or enlarged lymph nodes. A chest X-ray is also performed and is normal. Further histologic evaluation reveals positive Ki67 staining and mitotic activity >2 cells/mm2. The patient inquires if she needs further treatment.
Discussion
Neuroendocrine tumors (NETs) of the appendix occur in 1 of 100 to 300 patients undergoing appendectomy. Autopsy series report an overall incidence ranging from 0.009% to 0.17%, suggesting a natural degeneration of small benign lesions during later life. NETs (formerly known as carcinoids) originate from sub-epithelial neuroendocrine cells, usually present in the fourth decade, and favor the female gender. Some authors have ascribed a higher incidence in females to higher rates of laparoscopy and appendectomy among women. Crohn’s disease has also been identified as a risk factor for gastrointestinal (GI) NETs overall. NETs comprise 32% to 57% of all appendiceal tumors. They predominantly affect the small intestine (44.7%), followed by the rectum (19.6%), and the appendix (16.7%). Primary adenocarcinoma of the appendix, although also quite rare, has seen an increase in incidence over the past 20 years with reports of up to 26% of all appendiceal malignancies.
Diagnosis and Treatment
Most appendiceal NETs are asymptomatic and are found incidentally. Patients usually present with nonspecific abdominal pain at the lower right abdomen that leads to appendectomy. Although most patients undergo some form of abdominal imaging, a CT scan of the abdomen and pelvis should be performed whenever an appendiceal mass is suspected (Figure 1). While CT is being increasingly used for the workup of abdominal pain, it is unlikely that the routine application of this imaging technique would be warranted with respect to associated cost and diagnostic yield. Appendiceal NETs occur more frequently at the appendiceal tip (60% to 70%), followed by the body (5% to 21%), and base (7% to 10%). With regard to size, 60% to 76% are <1 cm, 4% to 27% are 1 to 2 cm, and 2% to 17% are >2 cm in diameter. Tumors are graded as benign, borderline malignant, low-grade malignant, or high-grade malignant. The majority of reported metastasized GI lesions have been graded as low-grade malignant. Assessing the mitotic activity (>2 cells/mm2) of so-called low-grade malignant lesions and the presence of proliferation marker Ki67 may be of prognostic value as well.
FIGURE 1 • CT of a patient with an appendiceal mucinous cystadenoma.
Tumors <1 cm in size require no staging unless identified as high-grade malignant. Patients with tumors between 1 and 2 cm may benefit from additional screening. Plasma chromogranin A is the most important tumor marker available, with 80% to 100% of patients with NETs having increased levels. Chromogranin A levels also correspond to tumor load and levels >5,000 μg/L correlate with poor outcomes. Patients with elevated chromogranin A levels require further imaging. In these patients, 111In-labeled octreotide scintigraphy is the most sensitive imaging modality in the diagnosis and staging of metastatic disease. Patients with tumors >2 cm, incomplete resections, metastatic disease, or goblet cell tumors warrant further investigation including determination of plasma chromogranin A levels, 24-hour urinary levels of 5-hydroxyindoleacetic acid, CT scan of the abdomen and pelvis, and 111In-labeled octreotide scintigraphy. A significant number of coexistent malignant tumors can be found in patients with appendiceal NETs (7% to 48%), primarily throughout the GI tract. Therefore, high-risk or symptomatic patients should be evaluated either endoscopically or with further imaging to assess the remainder of the GI tract.
All noncarcinoid appendiceal malignancies should undergo right colectomy, whereas the type of surgical intervention for NETs depends upon the tumor’s size, histopathology, and location. As for all NETs, the risk of metastases increases with size. The risk of metastases in tumors <1 cm is virtually zero; tumors between 1 and 2 cm metastasize in 0% to 1%, and tumors >2 cm metastasize in 20% to 85%. These findings give the rationale for the hypothesis that patients with tumors >2 cm in diameter may benefit from an oncologic resection of the right colon.
Operative Treatment
NETs <1 cm in size, located at the body or tip of the appendix, and with no unfavorable histology or evidence of metastatic disease may undergo appendectomy. On the other end of the spectrum, patients with NETs >2 cm, goblet cell adenocarcinoid tumors of any size, positive mesoappendix or vascular invasion, localization at the base of appendix, positive margins, or evidence of nodal metastasis should undergo right colectomy (Table 1). With regard to NETs between 1 and 2 cm in size, one must take in account the operative risk. For patients with low risk and a NET between 1 and 2 cm with unfavorable histology (mitotic activity >2 cells/mm2 or presence of proliferation marker Ki67), a right colectomy is required. For patients with high operative risk and a NET between 1 and 2 cm in size with favorable histology and located at the body or tip of the appendix, appendectomy is recommended.
TABLE 1. Treatment Recommendations for Appendiceal NETs
With the widespread use of laparoscopic appendectomy, the question arises as if this technique is adequate for the treatment of appendiceal malignancies. Laparoscopic appendectomy for NETs seems to have a slightly higher rate of inadequate resection requiring further operative intervention. However, this has not been associated with a significantly worse prognosis compared to the open approach. The level of available evidence at present for recommendations with respect to use of laparoscopy is generally low for NETs in large part because of their low prevalence and often incidental detection.
Timing of a subsequent right colectomy should be within 3 months after appendectomy and can safely be performed laparoscopically. There are no data to support that a two-step approach may negatively affect prognosis. Adenocarcinoma of the appendix of any size should be treated with right colectomy due to the high rate of invasion and nodal metastases.
Special Considerations
Certain histologic characteristics should receive particular attention when treating appendiceal NETs. Goblet cell or crypt cell carcinoid (adenocarcinoid) tumors exhibit histologic features that differ from both ordinary carcinoid and adenocarcinoma and have shown to be more aggressive than NETs (Figure 2). Patients with these tumors tend to present at a later age (fifth decade), often present with a diffusely inflamed appendix on CT scan, and treatment should involve right colectomy regardless of the size of the tumor. While the role of proliferation markers such as Ki67 and mitotic activity (>2 cells/mm2) is not precisely defined for appendiceal NETs, these parameters seem to indicate metastatic potential for other NET locations and might justify more extensive resection when present. Serosal involvement is present in approximately 70% of all malignant NETs but has not been related to outcomes in the published literature.
FIGURE 2 • Microscopic view of a goblet cell carcinoid tumor. High-power view shows a typical goblet cell (arrow).
A variety of terms have been used to describe appendiceal mucinous lesions that are not frankly malignant, including cystadenomas, mucinous tumor of uncertain potential, disseminated peritoneal adenomucinosis, and malignant mucocele. Most reports describe these lesions as low-grade mucinous neoplasms. They have the potential to spread to the peritoneal cavity producing mucinous intraperitoneal ascites, resulting in pseudomyxoma peritonei and their malignant potential largely depends on the degree of cellular atypia. Perforated neoplasms or lesions ruptured intraoperatively result in pseudomyxoma peritonei. Lesions confined to the appendix with benign histology should be treated by appendectomy. Involvement of the base of the appendix requires cecectomy. Mucinous adenocarcinomas are more common in the appendix than the colon and account for 40% to 67% of all appendiceal adenocarcinomas. These tumors can also rupture and spread throughout the peritoneum causing pseudomyxoma peritonei and peritoneal carcinomatosis. Localized lesions should be treated with right colectomy, while selective ruptured lesions can benefit from cytore-ductive surgery and hyperthermic intraperitoneal chemotherapy.
The current treatment algorithm for appendiceal cancer best relies on a tissue diagnosis of carcinoid versus noncarcinoid histology. However, this requires a frozen section in the operating room, which could substantially delay an operation, and the results may differ from the final report anyway. Instead of relying on tissue diagnosis, some authors have proposed that all appendiceal malignancies should be treated with right colectomy. To further support this approach, reports have shown a decrease in NETs that would be appropriate for appendectomy alone and an overall underutilization of right colectomy in the treatment of appendiceal tumors. Other more recent reports have shown no difference in survival rates between right colectomy versus appendectomy alone, suggesting that appendectomy may be a viable treatment option even for larger tumors, therefore questioning the benefit of right colectomy with the currently available data. Although any cancer operation should be planned with curative intent, once advanced disease is present, right colectomy may be warranted to prevent complications such as bowel obstruction or endocrine-related syndromes. Although the role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has become well established in properly selected patients for treatment of appendiceal adenocarcinoma, specifically the mucinous subtype, this form of therapy is not applicable to appendiceal NETs.
Postoperative Management
Patients with appendiceal NETs >2 cm, incomplete resections, and metastatic disease or goblet cell tumors require postoperative screening that includes serial plasma chromogranin A levels and abdominal CT. 111In-labeled octreotide scintigraphy should be performed to stage patients with metastatic disease.
The calculated risk of metastases from tumors <1 cm is zero, while a definite increase occurs with a tumor size >2 cm, with a rate of metastases of 20%. Appendiceal NETs usually metastasize to the regional lymph nodes rather than to the liver. Five-year survival ranges from 80% to 89% for all stages. Patients with local disease have a 5-year survival rate ranging from 92% to 94%, those with regional metastases 81% to 84%, and those with distant metastases 31% to 33%. Surveillance for synchronous or metachronous tumors is warranted because the risk of a second primary malignancy in the GI tract is significantly increased in patients with NETs.
TAKE HOME POINTS
· NETs are common neoplasms of the appendix, occurring in 1 of 100 to 300 patients undergoing appendectomy.
· Patients with tumors >2 cm, unfavorable histology, incomplete resection, and metastatic disease or goblet cell tumors warrant further oncologic staging and postoperative screening.
· Small appendiceal NETs (<1 cm) have an excellent prognosis after appendectomy.
· NETs >2 cm, goblet cell adenocarcinoid tumors of any size, positive mesoappendix or vascular invasion, localization at the base of appendix, positive margins or evidence of nodal metastasis require right colectomy. Right colectomy should also be considered in NETs 1 to 2 cm in diameter with unfavorable histology.
SUGGESTED READINGS
Goede AC, Caplin ME, Winslet MC. Carcinoid tumour of the appendix. Br J Surg. 2003;90:1317–1322.
McGory ML, Maggard MA, Kang H, et al. Malignancies of the appendix: beyond case series reports. Dis Colon Rectum. 2005;48:2264–2271.
Murphy EM, Farquharson SM, Moran BJ. Management of an unexpected appendiceal neoplasm. Br J Surg. 2006;93:783–792.