Pathogenesis

Appendiceal adenomas show frequent KRAS mutations^25–27 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.

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.

Natural History

Appendiceal adenomas are benign lesions, and they are cured by appendectomy.

Treatment

Simple appendectomy is considered sufficient treatment for adenomas. In some cases, the margin of resection is denuded with intraluminal mucin or has residual dysplasia. Several authorities advise that additional surgery be considered in patients with a positive margin.^5,34

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

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.

Box 28.2

Histologic Features of Ruptured Diverticular Disease of the Appendix That Assist in Distinguishing Diverticular Disease from Low-Grade Appendiceal Mucinous Neoplasm (LAMN)

1. Multiple diverticula, many of which are intact

2. Mucosal hyperplastic changes with preserved crypt structure and lamina propria

3. Chronic inflammation and fibrosis

4. Mucosal neuromatous change

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).

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 adenocarcinomas^29,48 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 ovaries^67,70 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

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 grade^4,57,69 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

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). This is the appearance of classic PP. Peritoneal mucinous tumors with high-grade cytologic atypia of the neoplastic epithelium and more complex architecture are usually associated with mucinous adenocarcinomas of the appendix and are more appropriately termed peritoneal mucinous adenocarcinoma (see Fig. 28.14).^13,79 Progression from low grade to high grade has been described in patients after failure of cytoreduction and chemotherapy treatment.^93,94

Ronnett and co-workers separated peritoneal mucinous tumors into two categories based on cytologic and architectural features.⁷⁹ They proposed the term disseminated peritoneal adenomucinosis (DPAM) for “noninvasive” mucinous implants derived from an appendiceal “adenoma” (i.e., LAMN) that contains scant strips of nonstratified mucinous epithelium with minimal to moderate atypia, at most focal tufting, and no significant mitotic activity. In contrast, peritoneal tumors characterized by more abundant epithelium arranged as glands, nests, or individual cells and with marked cytologic atypia were classified as peritoneal mucinous carcinomatosis (PMCA). These peritoneal tumors are derived from an appendiceal or intestinal mucinous adenocarcinoma and are characterized by the presence of parenchymal organ invasion and lymph node metastases in the primary site.⁶ Five- and 10-year survival rates were 75% and 68% for patients with DPAM and 14% and 3% for patients with PMCA, respectively. These authors also described an intermediate category for tumors that are mostly DPAM but also contain focal areas of well-differentiated adenocarcinoma.⁷⁹ Initially, these patients appeared to have an intermediate prognosis, but additional follow-up showed that their tumors behaved similarly to PMCA.⁹⁵

In contrast, a study of 101 patients with PP by Bradley and co-workers found that patients with DPAM and intermediate-grade peritoneal mucinous tumors had a similar outcome and had a better prognosis than those with high-grade peritoneal tumors.⁹⁶ Because they found no difference in outcome between patients with DPAM and those with intermediate-grade histology (or well-differentiated adenocarcinoma), they argued that DPAM is equivalent to well-differentiated mucinous adenocarcinoma. As a result, they proposed a two-level classification: (1) mucinous carcinoma peritonei, low grade, and (2) mucinous carcinoma peritonei, high grade. They found that the histology of the primary appendiceal tumor was not predictive of behavior, because “ruptured adenomas” behaved similarly to well-differentiated invasive adenocarcinomas.

Although these studies support grading of peritoneal mucinous tumors, the appropriate nomenclature for peritoneal mucinous neoplasia remains controversial. The WHO discourages use of the term DPAM because the concept of a ruptured adenoma with dissemination of adenomatous epithelium cannot be reconciled with the low-grade malignant behavior of PP.¹⁰

Treatment

The treatment of PP has not been standardized. Surgical tumor debulking was the mainstay of therapy for decades, but most patients had disease recurrence that required repeated surgical debulking procedures until, eventually, adhesions precluded additional surgery and the patient succumbed to the tumor.^97,98 Survival rates for patients who underwent debulking have been reported to be 86% at 2 years, 53% to 67% at 5 years, and 32% at10 years.^97,99

Sugarbaker and colleagues^54,84,85,100 pioneered an aggressive treatment approach that uses peritonectomies to achieve complete cytoreduction and hyperthermic intraoperative peritoneal chemotherapy (HIPEC), supplemented by additional cycles of early postoperative intraperitoneal chemotherapy (EPIC). The cytoreduction procedures include peritonectomies as well as resection of affected organs. Women require hysterectomy and bilateral salpingo-oophorectomy.¹⁰¹ Using this aggressive approach, they achieved 5- and 10-year survival rates of 71.9% and 54.5%, respectively.⁵⁴ Other groups have reported similar survival rates by using cytoreduction surgery and HIPEC/EPIC. In particular, long-term (10-year) survival has been reported to be better in some studies.^102–104

Several factors have been associated with success in the management of PP. One of the most important is the need to achieve complete cytoreduction, which is accomplished in 40-91% of cases.^101,104 In one study, patients who had complete cytoreduction had a 5 and 10 year survival rate of 87% and 74%, respectively, whereas those in which complete cytoreduction could not be achieved, and thus underwent debulking only, had 34% and 23% 5 and 10 year survival rates.¹⁰⁴ In this regard, the experience of the surgeon may play a role, with specialized centers achieving better survival statistics.^102,103 Extensive involvement of the small bowel or mesentery predicts a high likelihood of incomplete cytoreduction. Tumor grade is a factor that affects outcome.^102,103 Patients with low-grade peritoneal disease (DPAM) show improved survival compared with those with peritoneal carcinomatosis, with 5-year survival rates of 86% and 50%, respectively.¹⁰⁰

Some authors remain skeptical of such aggressive treatment, given the high associated morbidity and mortality of these procedures.^98,101 Similar survival rates have been achieved by using less aggressive debulking surgery, particularly for patients with low-grade histology and complete cytoreduction.^98,99,105

Clinical Features

Serrated polyps in the appendix are most often detected as an incidental finding or in patients with presenting symptoms of acute appendicitis.^7,8,15,107 They often affect older adults, and they are found in men and women equally.²⁹ They may also be seen in appendices with invasive cancer and probably represent a precursor lesion in some of those tumors (Fig. 28.18).^29,108 Studies have been inconsistent regarding an association between serrated neoplasia of the appendix and concomitant colorectal neoplasms.^29,109

Pathogenesis

Mucosal hyperplasia is occasionally seen in appendices that have been inflamed, obstructed, or ulcerated, presumably as a reaction to prior inflammation. Hyperplastic, serrated proliferations in this setting may not be neoplastic. However, there is evidence that a small proportion of appendiceal cancers develop through the serrated pathway of carcinogenesis, indicating that many serrated lesions are neoplastic. For instance, in a large study of serrated polyps of the appendix, Yantiss and colleagues²⁹ found reduced MLH1 and MGMT expression across the entire spectrum of serrated lesions, although loss of MLH1 immunoreactivity was not accompanied by MSI-H. In their study, most serrated polyps in the appendix had either BRAF (29%) or KRAS (34%) mutations. Among the nondysplastic serrated polyps, the prevalence of BRAF mutation was less than in colorectal serrated lesions. BRAF mutations were less common in dysplastic serrated polyps and in invasive carcinomas arising in serrated polyps than in nondysplastic polyps. This finding suggests that the biologic potential of BRAF in the appendix is limited. Also of interest is the fact that most BRAF mutations were present in only a minor portion of the DNA (usually ≤25%). In contrast, most polyps with KRAS mutations showed alterations in more than 25% of extracted DNA, and most of these were dysplastic polyps, indicating that KRAS mutations may be more important in the biology of appendiceal serrated neoplasms. Finally, in four cancers that developed within serrated polyps, a clear relationship between the molecular changes in the serrated lesion and those in the carcinoma was not established. None of the serrated polyps adjacent to carcinomas harbored BRAF mutations. In addition, most carcinomas also lacked BRAF mutations, except for one case in which a BRAF mutation was identified in a small portion of DNA in the carcinoma but not in the associated serrated polyp.

Abnormal nuclear localization of β-catenin is a reflection of loss of APC function, part of the canonical adenoma–carcinoma sequence in the colorectum. To date, studies have failed to demonstrate abnormal nuclear localization of β-catenin in serrated lesions in the appendix.^29,30

Pathology

As in the colon, distinction among the various serrated lesions in the appendix is difficult given the morphologic overlap.

Hyperplastic Polyp/Diffuse Mucosal Hyperplasia

Mucosal hyperplasia in the appendix may be localized and polypoid (hyperplastic polyp) or diffuse and nonpolypoid. In the appendix, hyperplastic polyps are unusual, whereas nonpolypoid mucosal hyperplasia is relatively more common.⁷ In some cases, mucosal hyperplasia can involve large portions of the appendix or the entire circumference of the lumen. Grossly, an appendix with mucosal hyperplasia is usually unremarkable, but the lumen may be slightly dilated with mucinous material, and the mucosa may appear grossly thickened, with minute papillary areas.⁸ Histologically, mucosal hyperplasia shows elongation of crypts with delicate papillary structures and glandular infolding, producing a serrated luminal contour.^8,107 The glands are lined by mucinous cells that differentiate progressively toward the surface, with columnar cells having apical mucin vacuoles alternating with goblet cells.^8,29,107,108 The crypts taper down to a preserved proliferative zone with regular cells containing small, round nuclei.¹⁰⁸ Mitoses are largely restricted to the basal area.^8,107 A prominent basement membrane may be seen, and the muscularis mucosae is intact.^7,8 Essentially, these tumors appear similar histologically to hyperplastic polyps that occur in the colon (see Chapter 22) (Fig. 28.19).⁸

Sessile Serrated Adenoma/Polyp

In comparison to hyperplastic polyps, sessile serrated adenoma/polyps (SSA/Ps) show architectural and cytologic atypia and abnormal crypt proliferation. The latter is characterized by displacement of the proliferative zone into the more superficial portions of the crypts. SSA/Ps demonstrate architectural distortion characterized by basal crypts that are branched or grow in a horizontal fashion.²⁹ This results in boot-shaped or inverted T-shaped crypts. Other features include prominent serration and dilatation of the crypts, particularly at the base of the mucosa; fewer neuroendocrine cells; dystrophic goblet cells; increased mitotic figures; and mild nuclear atypia (Fig. 28.20).²⁹ SSA/Ps may develop cytologic dysplasia; these polyps are often designated as “mixed polyps” when they show areas that resemble hyperplasia or SSA/P and other areas with cytologic dysplasia.²⁹ Dysplasia may be of the conventional (adenomatous, intestinal) type or serrated. In either case, dysplastic epithelium shows enlarged ovoid nuclei, increased nucleus-to-cytoplasm (N : C) ratio, hyperchromaticity, nuclear debris, infrequent mitoses, and pseudostratification.²⁹ High-grade dysplasia shows micropapillary epithelial infolding or cribriform architecture with increased nuclear irregularity, nucleoli, hyperchromasia, loss of nuclear polarity, and increased mitoses (Fig. 28.21).²⁹

Traditional Serrated Adenoma

Traditional serrated adenoma (TSA) was originally described in 1990 by Longacre and Fenoglio-Preiser.¹¹⁰ These tumors show a villous growth pattern with complex serration, epithelial cells with abundant eosinophilic cytoplasm and elongated nuclei, and little or no proliferative activity (Fig. 28.22). Conventional dysplasia may also develop in TSAs. One report of 10 serrated adenomas in the appendix (defined by the presence of serrated fronds in more than 50% of dysplastic structures) showed invasive carcinoma in 4, suggesting that TSAs in the appendix may be more aggressive than those that occur in the colon.¹⁰⁸ However, in a large series by Yantiss and co-workers,²⁹ a strong association between TSAs and adenocarcinoma was not seen.

On occasion, it is difficult to distinguish serrated lesions of the appendix from adenomas or LAMNs that show serrated crypt architecture. In contrast to adenomas and LAMNs, which often show slender villi with scant lamina propria, most serrated lesions show crypts separated by lamina propria and lack villous architecture (although TSAs can be villous). Complex serration favors a serrated lesion. Tumors that are associated with PP are LAMNs, because the available evidence indicates that serrated lesions do not spread to the peritoneum as PP.

Metastatic Carcinoma

Occasionally, an appendiceal NET (particularly the L cell variant) can be mistaken for a metastatic carcinoma, such as metastatic breast carcinoma. Attention to the nuclear chromatin pattern, bland nuclear features, and low mitotic activity in NETs helps avoid this diagnostic pitfall.

Tubular carcinoid tumors can have a small nested appearance similar to goblet cell carcinoid tumors. However, in goblet cell carcinoids, most cells are of the goblet cell type, whereas goblet cells are absent or infrequent in tubular carcinoids. Tubular carcinoid tumors are not typically associated with abundant extracellular mucin and are typically much smaller than goblet cell carcinoid tumors. They do not grow circumferentially around the appendiceal lumen.

Natural History

Tubular carcinoid tumors are invariably benign.

Treatment

Appendectomy is curative for tubular carcinoid.

Clinical Features

Goblet cell tumors most often affect patients in the fifth decade of life, and the sex distribution is equal.¹⁶⁰ The tumors are usually diagnosed incidentally in patients with clinical symptoms of appendicitis.^161,162 Females may have ovarian metastases at presentation.^163–169

Pathogenesis

Isaacson demonstrated that many goblet cell tumors show staining for immunoglobulin A, secretory component, and lysozyme, all of which are features of intestinal crypt cells, and proposed the term “crypt cell carcinoma.”¹⁵⁸ Others have also noted similarity between the tumor nests and normal crypts. These observations raised theories regarding the derivation of these tumors and whether they represent proliferation of pluripotential crypt cells or are simply neoplasms that retain the capacity to differentiate into crypt-like units.^153,157,158

Ultrastructural and molecular studies have shown that the pathogenesis of goblet cell tumors shares features with both conventional NETs and adenocarcinomas. Electron microscopic studies have provided evidence of both mucin production and neuroendocrine differentiation (electron-dense granules) in the same cells.^{136,170–173} van Eeden and colleagues¹⁷⁴ showed absent staining for TP53 and nuclear β-catenin expression, normal DPC4 expression, and rare KRAS mutations in 16 goblet cell tumors, similar to conventional carcinoid tumors. However, they also found expression of CEA and cytokeratin 7 (CK7), similar to adenocarcinomas and unlike conventional carcinoid tumors. Goblet cell tumors were also marked with an antibody against the transcription factor Atoh1/Math1, which is involved in the differentiation of intestinal stem cells toward progenitor cells with a secretory phenotype.

Some molecular studies have demonstrated a greater degree of similarity between goblet cell tumors and conventional carcinoid tumors. Stancu and colleagues¹⁶⁰ found allelic loss of chromosomes 11q, 16q, and 18q as frequently in goblet cell tumors as in ileal carcinoids. They also found absent KRAS, CTNNB1 (β-catenin), and DPC4 mutations and no TP53 overexpression by immunohistochemistry. These findings are similar to the molecular features of conventional carcinoid tumors. Ramnani and associates¹⁷⁵ were also unable to detect mutations of KRAS in 22 goblet cell tumors. They found mutations of TP53 in 25% of goblet cell tumors and in 44% of classic carcinoid tumors of the appendix.

Goblet cell carcinoid tumors usually appear as an area of circumferential thickening of the appendix and may be recognized only on microscopic examination of the specimen. Tumor size averages 2 cm.¹⁶⁰ Microscopically, goblet cell carcinoids show circumferential infiltration of the appendix by discrete nests of mucinous cells that resemble goblet cells or, in cases in which the mucin compresses the nucleus to the edge of the cell, signet ring cells (Fig. 28.31).¹⁵⁶ The mucin within goblet-like cells stains positive with periodic acid–Schiff (PAS) or Alcian blue stain.¹⁵⁶ Admixed with goblet-like or signet ring–like cells are cells with eosinophilic cytoplasm and, occasionally, Paneth cells (Fig. 28.32).^{153,157,158,176,177}

Most tumor cell clusters lack central lumina.^156,177 Cell clusters that contain central lumina resemble intestinal crypts.^153,157 Nuclear pleomorphism is typically mild, and mitoses are infrequent. Perineural and intralymphatic invasion may be present.¹⁵⁶ Extracellular mucin pools harboring clusters of tumor cells are not an uncommon finding, but, unlike pure mucinous adenocarcinomas, the epithelium within pools of mucin usually remains clustered, without the formation of large cribriform-shaped units. Some cell clusters reveal preserved central lumina resembling “floating” crypts (Fig. 28.33).^153,177

The tumor typically does not elicit a stromal reaction. Subtle atypical changes may be seen in the overlying mucosa, consisting of goblet cell disarray and slight nuclear enlargement.³¹ Tumor cells may infiltrate the lamina propria diffusely without the appearance of a clear point of origin, or they may seem to arise from the crypts.¹⁷⁷ Immuno­histochemically, goblet cell carcinoid tumors are keratin and CEA positive.^153,171,176 They also express Cam 5.2, CK7, CK20, CDX2, and E-cadherin.¹⁷⁴ Silver stains show the presence of argentaffin and argyrophil cells; these can be numerous, but some cases show few or only rare positive cells.^{4,153,156,158,176–178} Similar results are obtained by immunohistochemistry for chromogranin and synaptophysin.^159,174,179 In some cases, small numbers of cells may be positive for glucagon, particularly in areas that resemble a tubular carcinoid tumor.¹⁵³

Mixed Adenoneuroendocrine Carcinoma (MANEC)

In 1990, Burke and colleagues defined carcinomatous growth patterns in goblet cell carcinoids as fused or cribriform glands, single-file structures, diffusely infiltrating signet ring cells, or sheets of tumor cells.¹⁵³ They also classified tumors as having carcinomatous growth patterns if they demonstrated compressed goblet cell nests with small glands and signet ring cells with little or no intervening stroma, or extracellular mucin pools harboring glandular epithelium that demonstrated gland fusion and lacked lumina (Box 28.4). Tumors lacking significant carcinomatous growth patterns (<25%) were designated goblet cell carcinoid. Tumors with greater than 50% carcinomatous growth pattern were classified as mixed carcinoid-adenocarcinoma. In Burke’s series, no tumor had between 25% and 50% carcinomatous growth patterns.

Box 28.4

Carcinomatous Growth Patterns in Mixed Adenoneuroendocrine Carcinomas

Fused or cribriform glands

Single-file structures

Diffusely infiltrating signet ring cells

Sheets of tumor cells

Compressed goblet cell nests with small glands and signet ring cells with little or no intervening stroma

Extracellular mucin pools harboring glandular epithelium with gland fusion and without lumina

From Burke AP, Sobin LH, Federspiel BH, et al. Goblet cell carcinoids and related tumors of the vermiform appendix. Am J Clin Pathol. 1990;94:27-35.

In 2008, Tang and co-workers¹⁵⁹ proposed a classification of goblet cell carcinoid tumors (Table 28.2) that distinguishes pure goblet cell carcinoid tumor from carcinomas that arise in association with them (carcinoma ex goblet cell carcinoid, signet ring type or poorly differentiated type). By definition, these two carcinomas should contain, at minimum, focal areas in the tumor that are recognizable histologically as goblet cell carcinoid tumors. As described earlier, pure goblet cell carcinoids are characterized by the presence of cohesive, well-formed, round or oval goblet cell clusters with well preserved and uniform goblet cells and low-grade cytologic features (low N : C ratio, no or only mild pleomorphism, low mitotic rate). In contrast, adenocarcinoma ex goblet cell carcinoid, signet ring cell type demonstrates partial or near-complete loss of goblet cell clustering as a major criterion. Tumors consist of signet ring cells with hyperchromatic and irregular nuclei that infiltrate in the form of disorganized single cells, cells arranged in a single-file pattern, or tumor clusters with irregular shapes and jagged contours (Fig. 28.34). Adenocarcinoma ex goblet cell carcinoid, poorly differentiated carcinoma subtype, is defined as a goblet cell carcinoid tumor with at least one focus (occupying at least 1 low-power field or 1 mm²) that is indistinguishable from a conventional poorly differentiated or undifferentiated adenocarcinoma (Fig. 28.35). These carcinomatous areas resemble conventional gland-forming adenocarcinomas of the GI tract, or consist of sheets of malignant cells with or without signet ring cell features, or show morphologic features of a high-grade neuroendocrine carcinoma or undifferentiated carcinoma. In their study, tumors in this group showed positive staining for TP53 and MUC1 but absent MUC2 expression, suggesting progression of the goblet cell tumor.

Table 28.2

Classification of Goblet Cell Tumors of the Appendix

Goblet cell carcinoid

1. Well-formed round or oval goblet cell clusters 2. Cohesive tumor cell clusters 3. Well-preserved and uniform goblet cells 4. Low-grade cytology 5. No stromal desmoplastic reaction

Carcinoma (e.g., goblet cell carcinoid, signet ring cell type)

1. Partial or near-complete loss of goblet cell clustering

2. Signet ring cells with irregular, hyperchromatic nuclei

3. Tumor infiltrating as disorganized single cells, cells arranged in a single-file pattern, or tumor clusters with irregular shapes and jagged contours

Carcinoma (e.g., goblet cell carcinoid, poorly differentiated type)

1. A focus occupying at least one low-power field or 1 mm² that is indistinguishable from a poorly differentiated or undifferentiated adenocarcinoma

2. Carcinomatous areas resembling gland-forming adenocarcinoma, confluent sheets of malignant cells with or without signet ring cell features, high-grade neuroendocrine carcinoma, or undifferentiated carcinoma

From Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008;32:1429-1443.

Conventional Adenocarcinoma versus Pure Goblet Cell Carcinoid Tumor

Occasionally, the glandular profiles in pure goblet cell carcinoid tumors can be focally dilated and irregular, or they can form strips or incomplete glands, in which case distinction from a primary mucinous adenocarcinoma or another variant of adenocarcinoma may be difficult. Furthermore, immunohistochemistry for neuroendocrine markers can be misleading, because some pure goblet cell carcinoid tumors stain weakly, focally, or not at all, and some adenocarcinomas contain areas of neuroendocrine cell differentiation. Glandular differentiation with columnar cells, strips of glandular epithelium, and cribriform glands favors a diagnosis of adenocarcinoma. A precursor lesion in the lumen of the appendix (adenoma) suggests an adenocarcinoma because goblet cell tumors do not usually have a recognizable precursor lesion, although the two may coexist as a collision tumor.¹⁸⁰ As mentioned earlier, the presence of a discrete area of the tumor that shows goblet cell carcinoid features is sufficient for a diagnosis of carcinoma ex goblet cell carcinoid.

Metastatic Adenocarcinoma versus Pure Goblet Cell Carcinoid Tumor

Some metastatic adenocarcinomas to the appendix can assume a nested appearance, mimicking goblet cell carcinoid tumor. For instance, metastatic breast carcinoma, prostate cancer, pancreatic acinar cell carcinoma, and other tumors can assume this morphologic appearance. However, metastatic tumors usually show a higher degree of cytologic atypia and more frequent mitoses.