The classification of appendiceal mucinous tumors is controversial and terminology used for them inconsistent, particularly when they lack overtly malignant features but are associated with extra-appendiceal spread. We reviewed 107 appendiceal mucinous neoplasms and classified them as low-grade appendiceal mucinous neoplasm (LAMN) (n = 88), mucinous adenocarcinomas (MACAs) (n = 16), or discordant (n = 3) based on architectural and cytologic features. LAMNs were characterized by a villous or flat proliferation of mucinous epithelium with low-grade atypia. Thirty-nine tumors were confined to the appendix, but 49 had extra-appendiceal tumor spread, including 39 with peritoneal tumor characterized by mucin pools harboring low-grade mucinous epithelium, usually dissecting in a hyalinized stroma. Eight of the 16 MACAs lacked destructive invasion of the appendiceal wall and eight showed an infiltrative pattern of invasion. Extra-appendiceal tumor spread was present in 12 MACAs (four peritoneum, seven peritoneum and ovaries; one ovaries only). In MACAs with an infiltrative pattern, peritoneal tumor consisted of glands and single cells in a desmoplastic stroma. The peritoneal tumor in the remaining cases consisted of mucin pools that contained mucinous epithelium with high-grade atypia and, in some cases, increased cellularity compared with that seen in peritoneal spread in cases of LAMN. Three cases were classified as discordant because the appendiceal tumors were LAMNs but the peritoneal tumors were high-grade. Follow-up was available for 49 LAMNs, 15 MACAs, and 2 discordant cases. None of the patients with LAMNs confined to the appendix experienced recurrence (median follow-up 6 years). LAMNs with extra-appendiceal spread were associated with 3-, 5-, and 10-year survival rates of 100%, 86%, and 45%, respectively. Patients with MACA had 3- and 5-year survival rates of 90% and 44%, respectively (p = 0.04). The bulk of peritoneal disease correlated with prognosis among patients with MACA (p = 0.04) and, to a lesser degree, among patients with LAMNs (p = 0.07). We conclude that: 1) appendiceal mucinous neoplasms can be classified as either low-grade mucinous neoplasms or mucinous adenocarcinoma based on architectural and cytologic features; 2) tumors that can be confidently placed in the low-grade group (which requires rigorous pathologic evaluation of the appendix) and are confined to the appendix are clinically benign in our experience to date; 3) low-grade tumors confined to the appendix are morphologically identical to those with extra-appendiceal spread (except for the usual identification of breach of the wall in the latter cases) and the same designation is appropriate for the appendiceal neoplasia in each situation; 4) the long-term outlook for patients with low-grade tumors and peritoneal spread is guarded with just over half dying of disease after 10 years; 5) appendiceal mucinous tumors with destructive invasion of the appendiceal wall, complex epithelial proliferations, or high-grade nuclear atypia generally pursue an aggressive clinical course and should be classified as mucinous adenocarcinomas; 6) peritoneal tumor can be classified as involvement by LAMN or MACA, and this distinction is of prognostic significance; 7) bulky peritoneal tumor worsens prognosis; and 8) LAMNs associated with high-grade peritoneal tumor behave as adenocarcinoma.
The classification of mucinous tumors of the appendix is controversial when they lack overtly malignant features and are associated with peritoneal spread which, when grossly evident as mucinous aggregates, carries the clinical descriptive term “pseudomyxoma peritonei” (PP). 28 Although there is general agreement that noninvasive mucinous neoplasms confined to the mucosa are clinically benign, that morphologically similar lesions (“cystadenomas”) may be associated with extra-appendiceal disease and may be fatal has resulted in confusion. Controversy has centered on whether peritoneal involvement by the appendiceal tumor, by definition, warrants a diagnosis of adenocarcinoma. Some investigators maintain that peritoneal involvement by low-grade mucinous tumor may result from a ruptured appendiceal adenoma and does not mandate a diagnosis of carcinoma, 1,8,21,23,25,27,36 whereas others regard epithelial proliferation outside the appendix as adenocarcinoma, regardless of the morphology of the appendiceal or peritoneal tumor. 3,4,10
Many patients with appendiceal mucinous tumors have associated ovarian mucinous tumors, and such cases are frequently sent to us in consultation with questions about the relationship between the appendiceal and ovarian tumors. 39 As a result, we have encountered a large number of cases of appendiceal mucinous tumors. In our experience, the majority of these tumors associated with PP have low-grade cytologic atypia and lack destructive invasion of the appendiceal wall; they have been previously referred to by one of us and others as “borderline tumor of the appendix.”39 Occasional appendiceal tumors, although not invasive of the appendiceal wall, show greater cytologic atypia and more cellular and atypical epithelium in the peritoneal mucin and have been designated by us in our practice as mucinous adenocarcinomas (MACAs), as are frankly invasive MACAs. However, studies correlating the biologic behavior with the varied histologic features of these tumors based on large numbers of cases are few. We reviewed 107 cases of appendiceal mucinous tumors, and peritoneal tumor when present, and separated them into low-grade appendiceal mucinous neoplasm (LAMN) and MACA based upon their architectural and cytologic features in an effort to define the histologic spectrum of appendiceal mucinous tumors and to determine features of prognostic significance.