Epithelial Neoplasms of the Appendix
Joseph Misdraji
Mucinous Epithelial Tumors
Nomenclature
The classification, nomenclature, and histologic criteria of mucinous epithelial tumors in the appendix have been the source of considerable controversy. These tumors may be confined to the mucosa, in which case they are often classified as “adenomas,” but they may also penetrate deeply into, or through, the appendiceal wall and disseminate to the peritoneal cavity, resulting in a clinical syndrome known as pseudomyxoma peritonei (PP). The exact nature (benign versus malignant, invasive versus noninvasive) of these tumors when they disseminate to the peritoneum is controversial. Based purely on morphologic evaluation of tissue, some authorities interpret these lesions as ruptured adenomas with dissemination of adenomatous epithelium.1–6 Arguments in favor of this theory refer to the presence of low-grade cytologic features in the appendix and in the peritoneum, the lack of destructive invasion in the appendix, and the appearance of tumor in the peritoneum, which shows tumor coating surfaces of organs without definite evidence of stromal invasion. Others, including members of the American Joint Committee on Cancer (AJCC) and the World Health Organization (WHO), consider peritoneal dissemination to represent a cardinal feature of malignancy and classify these appendiceal tumors as adenocarcinomas.7–11 Arguments in favor of this theory include the facts that other mucinous tumors in humans can also be deceptively bland; direct organ invasion does occur in the ovary and spleen in some circumstances; and, most importantly, classification of these lesions as a ruptured benign adenoma does not account for the progressive biologic behavior of the tumor once it has spread to the peritoneum. These authorities suggest that “rupture” actually represents “pushing” or “broad front” invasion of a true carcinoma.
Because the criteria for invasion in appendiceal tumors are not well defined, and in order to account for the possibility of pushing invasion, various terms have been proposed for this group of epithelial tumors, particularly those that dissect into the wall and disseminate to the peritoneum. Some authors have proposed the term “mucinous tumor of uncertain malignant potential” for tumors that appear to push deeply into the appendix wall but do not show dissemination beyond the appendix.12 Others have proposed the term “low-grade appendiceal mucinous neoplasm”13 for the entire spectrum of these tumors, including those that show peritoneal dissemination. Pai and colleagues14 classified tumors that are associated with extraappendiceal mucin as “low-grade mucinous neoplasm with low risk of recurrence” if the mucin located outside the appendix was acellular or “low-grade mucinous neoplasm with high risk of recurrence” if it contained neoplastic epithelium. A comparison of the classification systems used for these tumors is presented in Table 28.1. In the most recent WHO classification of appendiceal tumors, the term low-grade appendiceal mucinous neoplasm (LAMN) is used for low-grade mucinous tumors that reveal pushing invasion, and mucinous adenocarcinoma is used for high-grade appendiceal tumors and ones with conventional features of tissue invasion (Box 28.1).10
Table 28.1
Classifications of Low-Grade Appendiceal Mucinous Neoplasms of the Appendix
| Pathologic Features | Carr and Sobin* | Misdraji et al.† | Pai and Longacre‡ | World Health Organization§ |
| Tumors without Invasion (Intact Muscularis Mucosae) | ||||
| Adenoma | LAMN | Adenoma | Adenoma | |
| Tumors with Pushing Invasion | ||||
| Tumor confined to the appendix | Mucinous tumor of uncertain malignant potential | LAMN | Adenoma? | LAMN |
| Tumor with acellular mucin outside the appendix | Mucinous tumor of uncertain malignant potential | LAMN | Low-grade mucinous neoplasm with low risk of recurrence | LAMN |
| Tumor with extraappendiceal tumor | Mucinous adenocarcinoma | LAMN | Low-grade mucinous neoplasm with high risk of recurrence | LAMN |
| Tumors with Infiltrative Invasion | ||||
| Infiltrative-type invasion of the wall, with or without desmoplasia, regardless of stage | Invasive mucinous adenocarcinoma | Invasive mucinous adenocarcinoma | Invasive mucinous adenocarcinoma | Invasive mucinous adenocarcinoma |
* Data from Carr NJ, McCarthy WF, Sobin LH. Epithelial noncarcinoid tumors and tumor-like lesions of the appendix: a clinicopathologic study of 184 patients with a multivariate analysis of prognostic factors. Cancer. 1995;75:757-768.
† Data from Misdraji J, Yantiss RK, Graeme-Cook FM, et al. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol. 2003;27:1089-1103.
‡ Data from Pai RK, Beck AH, Norton JA, Longacre TA. Appendiceal mucinous neoplasms: clinicopathologic study of 116 cases with analysis of factors predicting recurrence. Am J Surg Pathol. 2009;33:1425-1439.
§ Data from Carr NJ, Sobin LH. Adenocarcinoma of the appendix. In: Bosman FT, Carneiro F, Hruban RH, Theise ND, eds. WHO Classification of Tumours of the Digestive System. Lyon: International Agency for Research on Cancer (IARC); 2010:122-125.
LAMN, Low-grade appendiceal mucinous neoplasm.
Adenoma
Clinical Features
Adenomas typically occur in patients in their fifth decade of life, but the age range is wide, with cases reported in patients between 18 and 87 years of age.3,5,8,15 There is a female predominance.3,5,8,15 Abdominal pain that mimics acute appendicitis is the most common clinical presentation.5,8 Less often, an appendiceal adenoma manifests as an abdominal mass or as intussusception of the appendix.5,8,16–24 Approximately half of the cases are discovered in asymptomatic patients, particularly in women who have undergone an appendectomy during gynecologic surgery. Occasionally, a patient with adenoma in the appendix has concomitant colonic adenocarcinoma,5,8,15 but whether this represents more than a chance association is uncertain.
Pathogenesis
Appendiceal adenomas show frequent KRAS mutations25–27 and infrequent loss of chromosome 5q.25,28 However, one study of four adenomas found no loss of heterozygosity of the adenomatous polyposis coli (APC) or deleted in colorectal carcinoma (DCC) genes,27 and abnormal nuclear accumulation of β-catenin, a sign of APC loss of function, has not been found in adenomas.29,30 Adenomas are microsatellite stable and lack BRAF mutations.27,29
Pathology
Grossly, an appendix with an adenoma may be unremarkable, or it may be dilated with tenacious mucin. The serosa is typically smooth unless there are adhesions, but gross mucin is absent.8 The wall may be thin and fibrous, and after evacuation of the mucus, the inner surface appears granular or corrugated.8 Microscopically, these tumors are by definition confined to the mucosa, show intact muscularis mucosae, and contain no mucin in the wall or outside the appendix. The tumor consists of a proliferation of mucinous epithelial cells, often with atrophy of the lymphoid tissue (Fig. 28.1). The tumor is usually composed of slender villi with scant lamina propria; the villi are lined by mucinous epithelial cells, often with abundant intracytoplasmic mucin (Fig. 28.2).1,12,13 The glands may have straight luminal edges, or they may have luminal serration that raises the suspicion of a serrated epithelial neoplasm (see later discussion). In some cases, mucin accumulation leads to cystic dilatation of the appendix. In these cases, one may see a flat, undulating, or short villous pattern of the neoplastic epithelium (Fig. 28.3). These findings in the appendix are often termed cystadenoma.
The tumors are graded as either low or high. Most tumors are low grade. They show nuclear enlargement, elongation, hyperchromasia, pseudostratification, rare mitoses, and apoptotic nuclear debris,8,13,31 but the nuclei are limited to the basal portion of the cell. High-grade dysplasia reveals large pleomorphic nuclei, prominent nucleoli, increased mitotic figures, and full-thickness nuclear pseudostratification (Fig. 28.4).
Localized tubular adenomas of the type that occur in the colon are rare in the appendix.32,33 However, they may occur in patients with familial adenomatous polyposis.7,12 The histologic appearance of these polyps is identical to those that occur in the colon, and these may be low or high grade as well.
Differential Diagnosis
Retention Cyst
In cystic tumors, attenuation and denudation of the lining may make distinction between an appendiceal adenoma and a retention cyst difficult. In this case, multiple sections, and deep cuts of each section, may be necessary to detect (or exclude) the presence of neoplastic epithelium. Cysts larger than 2 cm are likely neoplastic. Examination of the lining may reveal residual villi focally that indicate a neoplasm. Convincing low-grade dysplasia with nuclear pseudostratification, nuclear enlargement, apoptotic debris, and infrequent mitoses also warrant a diagnosis of cystadenoma.
Low-Grade Appendiceal Mucinous Neoplasm
Distinction between a mucinous adenoma and a LAMN rests on evaluation of the muscularis mucosae, which is intact in a mucinous adenoma and is breached by epithelium in a LAMN (see later discussion).
Serrated Polyp of the Appendix
Mucinous adenomas can have serrated glandular lumina that can mimic serrated polyps of the appendix (discussed later).
Natural History
Appendiceal adenomas are benign lesions, and they are cured by appendectomy.
Low-Grade Appendiceal Mucinous Neoplasm
Clinical Features
LAMNs usually manifest in the sixth decade of life, although the age range is broad (20 to 89 years).13,35 As with adenomas, there is a predilection for females.14 Presentation with an abdominal mass or with an ovarian metastasis is relatively common.8,13,35 In fact, diagnosis of the ovarian tumor may predate discovery of the appendiceal tumor. Other presentations include abdominal pain or distention.13,14 Rarely, a ruptured LAMN manifests with mucin in a hernia sac.36–38 A retrocecal LAMN can manifest as a retroperitoneal mass or as pseudomyxoma extraperitonei.39–44 Approximately 15% to 20% of LAMNs are found incidentally in patients undergoing surgery for unrelated conditions.13,14
Pathogenesis
LAMNs show frequent KRAS mutations.25–27,45 Loss of chromosome 5q has been described,25,28 but one study of 31 LAMNs found no loss of heterozygosity of the APC or DCC genes.27 LAMNs have not been shown to demonstrate microsatellite instability or features of the mutator pathway, such as BRAF mutations.27,29 A recent study found GNAS mutations in 50% of 32 LAMNs.45 Activating GNAS mutations cause constitutive activation of adenylate cyclase and elevated cyclic adenosine monophosphate (cAMP) levels. In cell lines, this was associated with increased expression of the mucins MUC2 and MUC5AC,45 raising the intriguing possibility that GNAS mutations play a role in the prominent mucin production that is a hallmark of LAMNs and PP.
Bibi and colleagues showed that N-cadherin expression is increased in appendiceal mucinous tumors and PP, whereas E-cadherin expression is reduced in tumors relative to normal mucosa.46 They also showed vimentin expression in these tumors. They suggested that a shift in cadherin phenotype and vimentin expression may reflect an epithelial-mesenchymal transition state in which epithelial cells switch to mesenchymal phenotype, a process that presumably promotes metastasis.
Pathology
Appendices with LAMNs may appear grossly unremarkable, or they may be cystically dilated and filled with tenacious mucin.8,13,35,47 The wall may be thin or fibrotic, hyalinized, and calcified (Fig. 28.5).8,13 When calcifications are extensive, they can lead to the development of a thin-walled appendix with a hard, gritty texture, often referred to as “porcelain appendix.” Rupture with mucin present in the wall or on the serosal surface may be evident grossly.8,13,35 Infrequently, the appendix may be completely encased in mucin or fused to a right ovarian tumor.13,35,47 The appendix lining may be smooth, granular, or corrugated with intervening smooth areas, similar to adenomas.8 Focal outpouchings of the lumen filled with mucin have been described.35
On microscopic examination, these tumors show a villous or flat, neoplastic, mucinous epithelium, often associated with atrophy of lymphoid tissue, similar to adenomas.1,12,13 In villous tumors, the villi are typically filiform and contain scant lamina propria. The epithelium contains abundant cytoplasmic mucin that may compress nuclei. Cells with small, compressed nuclei may appear deceptively benign or even non-neoplastic.1 The villi are usually straight, but occasionally there is variable degree of luminal serration. These cases may resemble hyperplastic polyps or a serrated neoplasm (see later discussion). Mucin accumulation may be extensive; cystic dilatation may develop in these cases, usually in association with attenuation of the lining epithelium. The epithelium may be flat, forming a single layer of epithelium, or undulating. Denudation of the epithelium is common in these tumors,1 particularly in those with attenuated epithelium, and the distinction between a LAMN and a retention cyst can be difficult (see later discussion). In some cases, the entire appendiceal mucosa is denuded of epithelium. In these cases, extensive sampling may be needed to identify rare foci of neoplastic epithelium.7,8 The tumors are composed of columnar cells that are rich in mucin and display low-grade nuclear atypia consisting of nuclear elongation, hyperchromasia, pseudostratification, inconspicuous nucleoli, occasional mitoses, and apoptotic nuclear debris.8,13,31 High-grade tumors are classified as mucinous adenocarcinoma (see later discussion).
The appendiceal wall in LAMNs may show alterations of the muscularis mucosae and even extensive effacement of normal appendiceal landmarks in some cases. Fibrosis and hyalinization of the wall are common. In some cases, the hyalinized tissue in the wall is nodular (Fig. 28.6), and this may represent evidence of prior episodes of mucin leakage and subsequent tissue repair.13 Dystrophic calcification is common, particularly in areas with mucin.1,47
One distinctive feature of LAMN is the pattern of invasion of the underlying appendiceal wall. Neoplastic epithelium, mucin, or a combination of both may dissect into or through the wall of the appendix, lying very close to the serosa.35 Fibrosis of the appendiceal wall may result in growth of neoplastic epithelium along fibrotic or hyalinized stroma rather than atop normal lamina propria and muscularis mucosae (Fig. 28.7). Tumor dissecting into the wall may resemble involvement of preexisting diverticula, but, in contrast to true diverticular involvement, tumor involving the wall lacks lamina propria (Fig. 28.8). LAMNs typically do not invade in a conventional manner, with production of desmoplastic stroma combined with an infiltrative and irregular glandular proliferation. Tumors that invade and perforate the appendix may appear similar to a ruptured adenoma, but in the new WHO classification, as discussed earlier, any tumor with mucin or epithelium within or outside the wall of the appendix should be classified as LAMN, not an adenoma (Fig. 28.9).
Appendiceal mucinous neoplasms and peritoneal metastasis usually express keratin 20, and approximately 25% to 40% coexpress keratin 7.46,48 CDX2 and MUC2 are expressed in almost 100% of appendiceal mucinous tumors and PP.46,48–51 In contrast, MUC1 is typically negative in adenomas (although it may be positive in adenocarcinomas).48 MUC5AC and MUC6 are variably expressed in these tumors and therefore are not of diagnostic value.48
Differential Diagnosis
Retention Cyst
Retention cysts are caused by obstruction of the appendiceal lumen,5 although the cause of the obstruction may not be readily apparent. Retention cysts are relatively uncommon lesions. They only rarely attain a size larger than 2 cm in greatest diameter.7 Appendices larger than 2 cm in diameter are usually neoplastic (either adenomas or LAMNs). Retention cysts may be fibrotic and chronically inflamed and may show extensive epithelial denudation similar to adenomas and LAMNs. The mucosa may be atrophic but retain some semblance of crypt architecture with lamina propria, or it may be composed of a single layer of attenuated cuboidal epithelium (Fig. 28.10).3,12 In these cases, the appendix should be submitted in its entirety for microscopic evaluation to detect or exclude a neoplasm. Any atypicality, such as nuclear enlargement, elongation, hyperchromaticity, or mitoses, particularly if atypical, should raise suspicion for a neoplasm. In particular, villous epithelial proliferations are not consistent with a retention cyst and indicate a neoplasm. Retention cysts may also rupture and result in the presence of mucin in the peritoneal cavity.12 However, unlike PP resulting from a neoplasm, the mucin in these cases is usually confined to the localized area of rupture and does not continue to accumulate after appendectomy. Microscopic examination of the mucin may demonstrate varying degrees of tissue reaction and organization, showing granulation tissue in various degrees of development and mesothelial hyperplasia. Epithelial cells are not present in peritoneal mucin in cases of ruptured retention cyst. Therefore, its presence should exclude this diagnosis, unless contamination of mucin with epithelium occurred as a technical complication of specimen prosection.
Ruptured Appendiceal Diverticulum
Appendiceal diverticula may, on occasion, rupture and cause release of mucin into the wall and onto the serosa, which may raise concern for a mucinous neoplasm (Fig. 28.11).52 In addition, hyperplastic and reactive changes of the epithelium within the diverticula may be confused with a neoplastic process. An everted diverticulum, or fragments of diverticular lining on the serosa, may be confused with localized PP. There are some features that pathologists can use to differentiate ruptured diverticulum from a mucinous neoplasm (Box 28.2). In patients with appendiceal diverticular disease, the appendix often shows several diverticula, and in these cases, the finding of intact diverticula assists the pathologist in establishing a correct diagnosis of benign diverticular disease. Hyperplastic and reactive changes show architectural alterations that are more pronounced in the superficial rather than the basal portions of the mucosa. Gland serration, crypt disarray, and hyperplastic changes with abundant mucin-producing cells are usually located in the upper half of the mucosa. Non-neoplastic crypts are normally separated by lamina propria and show little or no crowding. In contrast, typical LAMNs show back-to-back crypts with scant lamina propria and elongated, slender villi that protrude into the lumen of the appendix. The nuclei in some neoplasms are larger and show elongation, hyperchromaticity, and mitoses. One other helpful hint is that appendices with diverticula often show transformation of the lamina propria into neural tissue, termed “mucosal neuroma” (Fig. 28.12). This may result from the effects of obstruction.
Natural History
The prognosis of LAMN is highly dependent on the presence or absence of neoplastic epithelium outside the appendix.8,13,14 For instance, LAMNs that are confined to the appendix, without extraappendiceal mucin, are almost always cured by appendectomy, similar to adenomas. LAMNs associated with acellular mucin in the peritoneal cavity confined to the right lower quadrant carry a low risk of recurrence or progression to PP. In a multiinstitutional study by Yantiss and associates,53 the authors collected 65 patients with ruptured appendiceal mucinous tumors, all of whom had at least 6 months of follow-up. Of the 50 patients with acellular mucin in the right lower quadrant, only 2 (4%) had local recurrence after 56 and 92 months of follow-up. In contrast, 15 tumors were associated with clusters of low-grade neoplastic epithelium within the extraappendiceal mucin. Five of these cases (33%) recurred as diffuse PP within 24 to 87 months, and 1 patient died of disease at 60 months. Pai and colleagues14 studied 116 patients with mucinous tumors and came to similar conclusions. They had follow-up for 14 patients with acellular mucin in the right lower quadrant; 1 (7%) of these patients had a recurrence during the follow-up period. Three (75%) of 4 patients with extraappendiceal mucin with neoplastic epithelium limited to the right lower quarter had a recurrence. From these studies, it can be concluded that appendiceal mucinous tumors with extraappendiceal acellular mucin in the right lower quadrant only rarely recur but that tumors with extraappendiceal mucin with neoplastic epithelium recur more often. Therefore, evaluation of the appendix specimen for extraappendiceal mucin and neoplastic epithelium should be performed, in total, for all cases.
In contrast, LAMNs with diffuse (nonlocalized) peritoneal seeding of neoplastic epithelium and mucin have a rather progressive clinical course that frequently results in death of the patient unless managed aggressively (see Pseudomyxoma Peritonei).
Treatment
Simple appendectomy is considered sufficient treatment for LAMNs that are confined to the appendix if the tumor is removed in total with a negative proximal margin. Given the possibility of peritoneal recurrence in patients with ruptured LAMNs, those with acellular mucin on the periappendiceal serosa should be followed closely to ensure that localized or diffuse PP does not develop. Radiographic imaging of the abdomen and pelvis is often the preferred method of surveillance. Tumors that have spread to the right lower quadrant have a higher risk of recurrence, but the appropriate management for these patients is controversial. Right hemicolectomy offers no additional benefit over appendectomy alone for patients with LAMN, even those with extraappendiceal mucin and neoplastic epithelium.54,55 Tumors that have disseminated widely throughout the peritoneal cavity are treated either by debulking or, more aggressively, with multiple peritonectomies and heated intraperitoneal chemotherapy (see Pseudomyxoma Peritonei).
Adenocarcinoma
Clinical Features
Adenocarcinomas of the appendix are uncommon; Collins found an incidence of 0.082% among 50,000 appendectomy specimens.56 There is an increased incidence among men in some series4,57–64 but not in others.65–68 Patients are usually in their fifth to seventh decade of life at presentation57,59–61,66,68 and usually are seen with symptoms of acute appendicitis. Less common modes of presentation include a palpable mass, obstruction, gastrointestinal (GI) bleeding, and symptoms related to metastases.3,4,59–62,64–67,69–71
Pathogenesis
Appendiceal adenocarcinomas show frequent allelic loss of chromosome 18q but less frequent mutations of SMAD4 (DPC4), suggesting that tumor suppressor genes located on 18q may play a role in their pathogenesis.72 Studies have found frequent mutations of KRAS.27,29,45,73 A recent study found absent GNAS mutations in three mucinous adenocarcinomas.45 Studies have been mixed with regard to TP53. Some have reported absent TP53 expression,27,73 whereas others have reported TP53 expression in most adenocarcinomas29,48 or TP53 mutations in approximately 75% by gene sequencing.48 Mutations in CTNNB1 (β-catenin) were not found in a series of 28 appendiceal adenocarcinomas,72 and no loss of heterozygosity for APC or DCC was detected in another series of 6 adenocarcinomas.27 Although mucinous carcinomas in the right colon are frequently associated with defective DNA mismatch repair and microsatellite instability,74–76 most appendiceal adenocarcinomas studied to date have been microsatellite stable.27,73 However, in one study, four adenocarcinomas arising in the background of serrated lesions29 showed loss of the mismatch repair gene MLH1 and reduced expression of O-6-methylguanine-DNA methyltransferase (MGMT), with high microsatellite instability (MSI-H) in one tumor. A second tumor showed reduced MGMT expression. One tumor showed two different KRAS mutations and a BRAF mutation, indicating genetic instability in this tumor. In another study of nine appendiceal adenocarcinomas, a single case showed absent expression of MSH2 and MSH6, and none showed absent MLH1 expression.77
Pathology
Grossly, appendiceal carcinomas can be polypoid, ulcerating, or infiltrative.62,63,71 Obstruction of the lumen may result in cystic dilation of the appendix. The proximal third of the appendix is involved more often than the distal portions.58,66,69
The classification of carcinomas is indicated in Box 28.1. They are classified as adenocarcinoma not otherwise specified, mucinous adenocarcinoma, LAMN (see prior discussion), signet ring cell adenocarcinoma, or undifferentiated carcinoma.10 Mucinous adenocarcinoma accounts for approximately 40% of all appendiceal adenocarcinomas.60 The histology of invasive mucinous adenocarcinoma of the appendix is similar to that of mucinous adenocarcinoma occurring elsewhere in the colon. These tumors show irregular pools of mucin of various sizes and shapes infiltrating the wall of the appendix and associated with cytologically malignant glandular epithelium, the latter usually arranged as strips, clusters, or complex glandular structures (Fig. 28.13). Mucinous cystadenocarcinomas may rupture and metastasize to the peritoneum or ovaries67,70 or, less commonly, they may metastasize via a hematogenous route.3,54,61,73 Peritoneal metastasis may reveal large volumes of extracellular mucin.31 Histologically, peritoneal metastasis resembles that occurring in LAMNs, except that the mucin is more cellular and the neoplastic epithelium shows a greater degree of architectural complexity and higher-grade cytologic atypia (Fig. 28.14). In this circumstance, the peritoneal metastasis is termed peritoneal mucinous adenocarcinoma.6 Other organs may be affected, such as small or large bowel, liver, or ovary.6,79
Nonmucinous appendiceal carcinomas show a range of morphologic features of the invasive component. For instance, the tumors may resemble colonic adenocarcinomas by revealing malignant glands lined by neoplastic columnar epithelium with dirty necrosis. Some tumors are composed of well-differentiated tubular glands lined by cuboidal shaped cells without dirty necrosis, and with only a mild amount of extracellular mucin, reminiscent of pancreaticobiliary adenocarcinomas. Adenocarcinomas arising in the background of serrated polyps may have serrated gland morphology, with or without extracellular mucin (see Serrated Tumors of the Appendix).29
Signet ring cell adenocarcinomas are rare in the appendix. These tumors are associated with a poor prognosis because of rapid dissemination within the peritoneal cavity.80,81 The histology is similar to that of signet ring cell adenocarcinomas at other sites in the GI tract (Fig. 28.15). They are composed of single cells, clusters, and/or sheets of signet ring cells, some with extracellular mucin. Some tumors show areas reminiscent of goblet cell carcinoid tumor, suggesting that the adenocarcinoma arose from the latter (see Goblet Cell Carcinoid).7
Differential Diagnosis
Low-Grade Appendiceal Mucinous Neoplasm versus Mucinous Adenocarcinoma
The distinction between LAMN and mucinous adenocarcinoma is based on evaluation of the characteristics of the “invasive” component and on the cytologic features of the neoplastic epithelium. LAMNs show prominent fibrosis of the wall with “pushing” invasion. Mucinous adenocarcinomas usually show conventional patterns of invasion, exhibiting irregular pools of mucin harboring high-grade epithelium in complex architectural configurations or irregularly shaped glands with a desmoplastic stromal response. LAMNs, by definition, are low-grade tumors, whereas mucinous adenocarcinomas may be low or high grade.
Natural History
The reported 5-year survival rate for patients with appendiceal adenocarcinoma ranges from 18.7%57 to 55%.65 Patients with mucinous adenocarcinomas have a better prognosis than those with non-mucinous adenocarcinomas.65,66,70 Several studies have shown that histologic grade4,57,69 and Duke stage correlate with prognosis.4,65,66,69,70,82,83 Patients with peritoneal carcinomatosis have a poor prognosis.6,60,68,70
Treatment
Invasive adenocarcinoma of the appendix warrants treatment by right hemicolectomy, with lymph node dissection, to potentially achieve a cure.65,67,70,82 Most studies have shown that right hemicolectomy offers improved 5-year survival compared with appendectomy alone.31,59,65,67,82,83 Some authorities advocate oophorectomy in women, both for staging purposes and to remove a common site of metastasis.65,70 Treatment of patients with peritoneal spread depends on the resectability of the tumor. Patients whose tumors are resectable should be treated aggressively with peritonectomy and postoperative intraperitoneal chemotherapy.54,84,85
Pseudomyxoma Peritonei
The term pseudomyxoma peritonei refers to the accumulation of mucin within the peritoneal cavity. Historically, the term was used to describe mucin in the peritoneal cavity regardless of the presence or absence of neoplastic epithelial cells,1,47,86,87 but more recently, it has been reserved for cases in which neoplastic epithelial cells are present within the peritoneal mucin.8,88,89 This condition most often occurs as a result of peritoneal spread of a mucinous neoplasm from the appendix (Fig. 28.16) but has been described with mucinous tumors from other sites, including colon, ovary, gallbladder, pancreas, and urachus.
Clinical Features
Spread of mucinous neoplastic epithelium to the peritoneal cavity occurs most often in association with LAMN and mucinous adenocarcinomas. PP develops in approximately 20% of patients with a mucinous tumor of the appendix.90 PP typically manifests in the sixth to seventh decades of life, and in some series, women predominate over men.88,90,91 Along with the peritoneal cavity, the ovaries are commonly involved with tumor as well.35,88,90 Peritoneal mucinous deposits tend to accumulate in particular areas, such as the greater omentum, the undersurface of the right hemidiaphragm, the pelvis, the right retrohepatic space, the left abdominal gutter, and the ligament of Treitz.92 This so-called “redistribution phenomenon” occurs because tumor accumulates at anatomic locations where ascitic fluid is resorbed from the abdomen and in those areas most subjected to pooling in the abdomen.
Pathology, Nomenclature, and Outcome
The morphologic characteristics, particularly the degree of atypia of the neoplastic epithelium (grade), correlate with the grade and degree of “invasiveness” of the primary appendiceal tumor.6 Peritoneal tumors in patients with LAMN demonstrate abundant mucin; hyalinized, fibrotic stroma; and a variable quantity of strips of low-grade (or even non–neoplastic-appearing) mucinous epithelium (Fig. 28.17
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