Appendiceal epithelial neoplasms account for approximately 1% of all colorectal cancers.¹ Table 1 itemizes the many different terms used for these malignancies. There is no consensus regarding proper nomenclature for these tumors. Pseudomyxoma peritonei syndrome is a poorly understood clinical entity. Pseudomyxoma peritonei as originally described by Werth is a group of malignancies characterized by abdominal distention, omental infiltration by mucinous tumor, and a large volume of mucinous ascites plus mucinous tumor.² Pseudomyxoma peritonei is a registered rare disease no. 843 by the National Organization of Rare Disorders.³⁴#

The primary tumor is an appendiceal adenoma or mucinous adenocarcinoma. The disease progresses as the appendix wall is perforated by the primary tumor and mucus along with mucinous tumor cells are released into the peritoneal cavity. The epithelial cells distribute themselves in a characteristic fashion around the peritoneal cavity. Because of marked variations in the natural history and in prognosis, mucinous peritoneal neoplasms with dissemination from a non-appendiceal primary site always need to be distinguished from the pseudomyxoma peritonei syndrome.#

In the 9th International Classification of Disease (ICD-9) revised in 2004, primary epithelial neoplasms of the appendix are grouped with colorectal malignancy. Table 2 contrasts the clinical and pathologic features of colorectal cancer and appendiceal neoplasms.#

Confusion still exists regarding the clinical entity, “pseudomyxoma peritonei”. Ronnett in 1995 described it as a poorly understood condition characterized by mucinous ascites and mucinous implants diffusely involving peritoneal surfaces. It is a slowly progressive disease characterized by recurrences after attempts at surgical removal. Most pathologists continue to use pseudomyxoma peritonei to refer to a spectrum of neoplastic conditions that lead to an extensive mucus accumulation within the abdomen and pelvis.⁵#

The pseudomyxoma peritonei syndrome includes mucinous appendiceal epithelial neoplasms that have disseminated beyond the primary site. A mucinous epithelial malignancy of the appendix is the primary site for this syndrome. The mucinous tumor may distend the wall of the appendix and cause poorly defined symptoms over several years prior to diagnosis.#

Other more invasive primary appendiceal neoplasms cause near complete destruction of the primary anatomic site of the disease, and invade the caecum.#

A controversy still exists over which appendiceal neoplasm should be included within the pseudomyxoma peritonei syndrome. I believe that all appendiceal epithelial neoplasms that produce copious mucus including the peritoneal mucinous adenocarcinomas should be included. Intestinal type adenocarcinoma (non-mucinous) of the appendix with peritoneal dissemination is not included as pseudomyxoma peritonei syndrome. Mucinous carcinomatosis from malignancy other than the appendix includes stomach tumors, mucinous colorectal cancers and small bowel cancers, urachal tumors, cystic mucinous tumors of the pancreas or those of the gallbladder and ovary.⁶⁷ These are not included as pseudomyxoma peritonei syndrome.#

The position of the appendiceal neoplasm within the appendix may be important. The appendiceal malignancies at the orifice are usually high-grade intestinal type cancers that behave very similarly to colon cancer in their patterns of local extension and dissemination. In a study of appendiceal epithelial neoplasms with positive lymph nodes, we found 15 of 25 patients had an initial symptom of acute appendicitis.⁸ Appendicitis was the initial symptom of 112 of 476 patients with negative lymph nodes or no lymph nodes detected within the specimen. This was a significant difference in the presentation of lymph node positive and lymph node negative appendiceal neoplasms (p=0.0006).#

Increasing abdominal girth was seen in 23% of patients and a new hernia seen in 14% of patients. An ovarian cystic tumor seen in 30% of women was caused by entrapment of adenomatous epithelial cells within a ruptured corpus hemorrhagicum as a site for adherence of tumor cells.⁹#

There is a distinctive pattern of dissemination within the peritoneal cavity. We have suggested that the principles of fluid hydrodynamics and gravity control the distribution (Fig. 1).#

The movement by peristalsis of the bowel, especially near continuous peristalsis of the small bowel, spares these structures. Sections of the bowel less mobile because of a lack of mesentery are less spared. The antrum of the stomach and the ileocecal valve region are fixed to the retroperitoneum, and the rectosigmoid colon is fixed within the pelvis causing greater volumes of mucinous neoplasm to accumulate. Tumor that accumulates on small bowel is often polypoid.¹⁰#

Patients with appendiceal epithelial neoplasms show a great variation in survival. Fig. 2 shows a composite graph of the survival of these mucinous appendiceal malignancies at The Memorial Sloan-Kettering Cancer Center, the Massachusetts General Hospital, and the Mayo Clinic in Rochester. If palliative surgery plus systemic chemotherapy are needed for treatment few patients are cured of this process even though the median survival is between 5 and 10 years.^11–13#

Ronnett et al. classified mucinous appendiceal neoplasms into 3 groups: the least aggressive neoplasms were designated disseminated peritoneal adenomucinosis (DPAM), the more aggressive were designated peritoneal mucinous adenocarcinoma (PMCA).⁵ Yan et al. classified the PMCA group into well-differentiated, moderately differentiated, and poorly differentiated cancer.¹⁴ When survival was assessed using the Ronnett criteria and a uniform treatment plan, these subtypes were associated with statistically different survival (Figs. 3–5). Patients treated by cytoreductive surgery plus perioperative chemotherapy and a favorable histology had a 70% survival at 20 years.¹⁵#

The Ronnett criteria help predict the outcome following cytoreductive surgery with intraperitoneal chemotherapy. However, problems remain in the use of this histological system as a prognostic indicator. First, discordant features occur indicating a lack of consistency between the histopathology of the primary appendiceal neoplasm and the peritoneal surface malignancy. In the original Ronnett et al. report, there were 3 cases with DPAM primary tumors and PMCA noted in the peritoneal surface lesions. There were 109 patients in this study for a 2.8% rate of discordance.⁵ In the study by Young et al. from the Massachusetts General Hospital, there were 3 patients with low-grade appendiceal mucinous neoplasms (LAMN) as a primary tumor and mucinous appendiceal cancer (MACA) in the peritoneal lesions. There were 107 patients in the study showing a 2.9% incidence of discordance.¹³ In the study of Yan et al., 2 cases showed DPAM in the primary appendiceal cancer with PMCA in the peritoneal lesions. Four cases showed PMCA in the primary lesion and DPAM in the peritoneal lesions. There were 46 patients in this study for a 13% incidence of discordance.¹⁴ The anatomic site to determine prognosis has not been clarified by any of the groups describing the discordant features.#

We studied the histologic appearance of peritoneal surface tumors in patients with mucinous carcinomatosis. 5-fluorouracil and mitomycin C given intraperitoneally induced marked changes in the histological appearance of the carcinomatosis in the most superficial 2mm of the peritoneal surface.¹⁶#

We also see transitions from less aggressive to more invasive histologic types over time in association with multiple surgical interventions. Yan and colleagues determined that 68% of 19 patients who failed reoperative treatment of their appendiceal neoplasm demonstrated transition from a less aggressive to a more aggressive histologic subtype.¹⁴#

Mohamed et al. showed that some patients who repeatedly showed DPAM histology may succumb to a rapidly progressive peritoneal surface disease despite this benign appearing histology. Eleven of 500 cases had a rapidly fatal progression of DPAM subtype of mucinous appendiceal malignancy. These patients died despite multiple reoperations and intraperitoneal chemotherapy.¹⁷#

The appendix has a significant cancerous predisposition. The cancer types and patterns of disease dissemination are varied; differences in patterns of dissemination and mucinous epithelial tumor subtypes influence the management of this disease. Appendiceal mucinous neoplasms should be considered a distinct disease with a unique natural history. Although much progress has been made, greater knowledge regarding the gross and microscopic pathology of this disease and the surgical implications of these findings are needed.#