Cancer of the Appendix and Pseudomyxoma Peritonei Syndrome

Introduction

Malignant tumors of the appendix are rare, making up approximately 0.4% of all intestinal neoplasms. About 1% of all large bowel cancers arise from the appendix. The histopathology of appendiceal malignancy has been confusing, and the approach to therapy is complex. Many of the tumors have perforated at the time of definitive surgical treatment, and thus the physician is required to manage both the primary tumor and its peritoneal surface dissemination. Despite the often widespread peritoneal metastases present at the time of initial diagnosis, liver and lymph node metastases are seldom present. Such patients often can be saved, and what once was regarded as a uniformly lethal condition (the spread of tumor on peritoneal surfaces) can be successfully treated. In this chapter I will describe the surgical treatment of patients with cancer of the appendix and the condition that arises from its perforation and spread—pseudomyxoma peritonei.

Pathology of Appendiceal Malignant Tumors

The two most commonly occurring malignant tumors of the appendix are carcinoid and adenocarcinoma. Approximately two thirds of appendiceal malignancies are carcinoid tumors, and the other third are variations of adenocarcinoma ( Table 60-1 ).

TABLE 60-1

Survey of Appendiceal Tumors ^∗

Feature	Carcinoid	Adenocarcinoid	Pseudomyxoma Peritonei	Mucinous Adenocarcinoma	Adenocarcinoma
Approximate incidence	66%	Rare	20%	Rare	10%
Location	Tip of appendix	Diffuse along appendix	Middle to tip of appendix	Diffuse along appendix	Base of appendix
Major symptom	Incidental finding	Expanding abdomen, ovarian mass	Expanding abdomen, ovarian mass, hernia, appendicitis	Appendicitis	Appendicitis
Prognosis	<1 cm 100% cure >2 cm 50% cure	Poor	Localized 100% cure Adenomucinosis 90% cure at 5 yr	84% cure at 5 yr if unperforated; 30% cure at 5 yr if perforated	Follows Duke stages A-80% cure B-50% cure C-20% cure
Histopathology of peritoneal surface implants	Carcinoid	Carcinoid plus mucinous adenocarcinoma	Adenomucinosis	Mucinous carcinomatosis	Intestinal type (nonmucinous) adenocarcinoma
Clinical syndromes	Carcinoid	Mucinous peritoneal carcinomatosis	Pseudomyxoma peritonei	Mucinous peritoneal carcinomatosis	Peritoneal carcinomatosis
Treatment	<1 cm appendectomy only >2 cm right colectomy + cytoreductive surgery	Appendectomy only or cytoreductive surgery + intraperitoneal chemotherapy	Appendectomy + cytoreductive surgery + intraperitoneal chemotherapy	Cytoreductive surgery + intraperitoneal chemotherapy	Right colectomy + cytoreductive surgery + intraperitoneal chemotherapy if peritoneal implants

∗ In separating pseudomyxoma peritonei, mucinous adenocarcinoma, and adenocarcinoma, it must be remembered that these represent a spectrum of disease and are probably not distinct clinical entities. Benign mucocele is not included as an appendiceal tumor but rather is a cystic process. A perforated mucocele resulting from an appendiceal adenoma may progress into pseudomyxoma peritonei. Tumors that histologically are between adenomucinosis and mucinous adenocarcinoma are designated as hybrid type.

Carcinoid Tumors

By far the most common tumor within the appendix is the carcinoid tumor. This lesion is usually found incidentally at appendectomy. It is a small, hard, yellow tumor mass in the distal portion of the appendix. The appendix is the site of 45% of all gastrointestinal carcinoid tumors. The incidence in females is higher than in males, probably because of the greater number of incidental appendectomies performed in women undergoing hysterectomy and cholecystectomy.

Although 90% of appendiceal carcinoids are incidental, approximately 10% are associated with acute appendicitis. The carcinoid syndrome is rarely the presenting feature of appendiceal carcinoids, but if it does occur, it usually heralds metastases to the liver.

The selection of treatment options for a carcinoid tumor depends on its size and, in large tumors, on the extent of local spread. It is extremely important to determine these clinical features at the time of exploration because the histopathologic features of aggressive tumors are the same as those with no malignant potential.

Adenocarcinoid Tumors of the Appendix (Goblet Cell Carcinoid)

In a small percentage of carcinoid tumors, malignant epithelial cells producing abundant mucus are scattered among the carcinoid tumor cells. Usually these tumors have dissecting mucus diffusely infiltrating the wall of the appendix. In contrast, nonmucinous carcinoid tumors present as an innocuous occurrence at the tip of the organ. Adenocarcinoid tumors present as acute appendicitis more frequently than do carcinoid tumors. The 5-year survival rate of such patients is greatly reduced compared with patients with carcinoid tumors because patients with adenocarcinoid tumors usually have peritoneal metastases at initial diagnosis. These patients have dissecting mucus produced in large quantity by the cancer. The wide distribution on peritoneal surfaces results in a grim prognosis unless they receive special treatments for peritoneal surface malignancy.

Epithelial (Noncarcinoid) Tumors of the Appendix

Mucinous Adenoma and Adenocarcinoma

The most common varieties of epithelial malignancy within the appendix are mucinous adenomas or mucinous adenocarcinomas. In the appendix, these mucinous appendiceal neoplasms are many times more common than the intestinal type of adenocarcinoma. In the colon, only approximately 15% of colonic adenocarcinomas are mucinous. This preponderance of mucinous tumors in the appendix is probably related to the high proportion of goblet cells within its epithelium ( Table 60-2 ).

TABLE 60-2

Comparison of Colorectal and Appendiceal Malignant Tumors

Feature	Colon	Appendix
Adenocarcinoma incidence	85%	10%
Carcinoid incidence	<1%	70%
Mucinous adenocarcinoma	10%-15%	20%
Signet ring adenocarcinoma	1/1000	1/10
Adenocarcinoid	Not reported	Rare
Differentiation of adenocarcinoma
Well-differentiated	20%	60%
Moderately differentiated	60%	20%
Poorly differentiated	20%	20%
Associated malignancy	Unusual	Common

On gross examination, it may be difficult or impossible to distinguish a mucinous tumor of the appendix from a benign mucocele. Both benign and malignant tumors of the appendix are likely to cause appendicitis, and mucin collections may be present within the right lower quadrant or throughout the abdominopelvic space. Two histologic features should be sought that will separate tumors that are inconsequential with complete removal from those capable of causing death from progressive pseudomyxoma peritonei syndrome:

1.
Invasion through the appendiceal wall by neoplastic glands
2.
Epithelial cells found within the extra-appendiceal mucin

If either of these clinical features occurs, special follow-up and aggressive treatments are required.

The most common clinical entity arising from an appendiceal mucinous neoplasm is pseudomyxoma peritonei. This clinical entity has a perforated appendiceal adenoma or villous adenoma as its primary site. Hyperplastic polyps, adenomatous polyps, and villous polyps within the appendix that have resulted in an appendiceal perforation are implicated in the pseudomyxoma peritonei syndrome. The mucus accumulations that are distributed in a characteristic fashion around the peritoneal cavity are referred to as adenomucinosis. Histologically, epithelial cells in single layers are surrounded by lakes of mucin. These epithelial cells show little atypia and absent mitosis and result in mucinous tumor accumulations that follow the flow of peritoneal fluid within the abdomen and pelvis.

Ronnett and colleagues, in their histologic description of the mucinous appendiceal tumors, found a small proportion of patients with pseudomyxoma peritonei syndrome who had small foci of mucinous adenocarcinoma within the large volume of adenomucinosis. These tumors presented with the typical pseudomyxoma peritonei syndrome but had a poorer prognosis, similar to that of patients with mucinous carcinomatosis. Tumors with a predominant histologic type of adenomucinosis but foci (less than 5% of fields) of mucinous adenocarcinoma are referred to as a hybrid histologic type.

Nonmucinous Adenocarcinoma

A less common histologic type of appendiceal adenocarcinoma is the intestinal type of tumor, often referred to as the nonmucinous type. This cancer is usually located at the base of the appendix and resembles colonic adenocarcinoma in its histopathologic appearance. It is locally invasive and results in peritoneal metastases proximal to the appendix, usually in the right paracolic sulcus and pelvis, especially in the cul-de-sac.

A third histologic type of appendiceal adenocarcinoma is the classical mucinous adenocarcinoma. This more invasive tumor type tends to involve the appendix diffusely. Yan and colleagues described three different variants as well, moderately, and poorly differentiated. The poorly differentiated histologic type contains signet ring cells.

Diagnosis of Appendiceal Malignant Tumors

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