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. There is a female predominance. Abdominal pain that mimics acute appendicitis is the most common clinical presentation. Less often, an appendiceal adenoma manifests as an abdominal mass or as intussusception of the appendix. 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, but whether this represents more than a chance association is uncertain.

Pathogenesis

Appendiceal adenomas show frequent KRAS mutations and infrequent loss of chromosome 5q. However, one study of four adenomas found no loss of heterozygosity of the adenomatous polyposis coli ( APC ) or deleted in colorectal carcinoma ( DCC ) genes, and abnormal nuclear accumulation of β-catenin, a sign of APC loss of function, has not been found in adenomas. Adenomas are microsatellite stable and lack BRAF mutations.

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. The wall may be thin and fibrous, and after evacuation of the mucus, the inner surface appears granular or corrugated. 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 ). 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 .

Villous adenoma. Low-power view shows a villous mucinous epithelial proliferation confined to the appendiceal mucosa with absence of the normal lymphoid compartment.

Villous adenoma. High-power view of the villi shows that they are composed of mucinous epithelial cells with abundant intracytoplasmic mucin. The nuclei show mild nuclear hyper­chromasia and pseudostratification, consistent with low-grade dysplasia.

Cystadenoma. The appendix is dilated with mucin in the lumen, and the mucosal-based tumor is partly flattened and partly composed of short villi.

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, 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 ).

Appendiceal adenoma with high-grade dysplasia. The appendix mucosa is replaced by a highly atypical mucinous epithelial proliferation.

Localized tubular adenomas of the type that occur in the colon are rare in the appendix. However, they may occur in patients with familial adenomatous polyposis. 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

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.

Clinical Features

LAMNs usually manifest in the sixth decade of life, although the age range is broad (20 to 89 years). As with adenomas, there is a predilection for females. Presentation with an abdominal mass or with an ovarian metastasis is relatively common. In fact, diagnosis of the ovarian tumor may predate discovery of the appendiceal tumor. Other presentations include abdominal pain or distention. Rarely, a ruptured LAMN manifests with mucin in a hernia sac. A retrocecal LAMN can manifest as a retroperitoneal mass or as pseudomyxoma extraperitonei. Approximately 15% to 20% of LAMNs are found incidentally in patients undergoing surgery for unrelated conditions.

Pathogenesis

LAMNs show frequent KRAS mutations. Loss of chromosome 5q has been described, but one study of 31 LAMNs found no loss of heterozygosity of the APC or DCC genes. LAMNs have not been shown to demonstrate microsatellite instability or features of the mutator pathway, such as BRAF mutations. A recent study found GNAS mutations in 50% of 32 LAMNs. 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, 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. 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. The wall may be thin or fibrotic, hyalinized, and calcified ( Fig. 28.5 ). 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. Infrequently, the appendix may be completely encased in mucin or fused to a right ovarian tumor. The appendix lining may be smooth, granular, or corrugated with intervening smooth areas, similar to adenomas. Focal outpouchings of the lumen filled with mucin have been described.

Gross specimen of a low-grade appendiceal mucinous neoplasm shows cystic transformation of the appendix with marked thickening of the wall.

(From Misdraji J. Epithelial neoplasms and other epithelial lesions of the appendix [excluding carcinoid tumours]. Curr Diagn Pathol . 2005;11:60-71.)

On microscopic examination, these tumors show a villous or flat, neoplastic, mucinous epithelium, often associated with atrophy of lymphoid tissue, similar to adenomas. 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. 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, 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. 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. 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. Dystrophic calcification is common, particularly in areas with mucin.

Low-grade appendiceal mucinous neoplasm demonstrates submucosal fibrosis and marked mural hyalinization with a nodular hyalinized scar ( lower right ).

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. 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 ).

Low-grade appendiceal mucinous neoplasm. The mucinous neoplasm lines hyalinized or fibrotic stroma, and the muscularis mucosae is absent.

Low-grade appendiceal mucinous neoplasm dissecting through the muscularis propria ( upper left ) and merging with dissecting mucin and fibrosis on the appendiceal surface ( lower right ).

Low-grade appendiceal mucinous neoplasm. The luminal tumor breaches the appendiceal wall; although it may be interpreted to have “ruptured,” it actually may represent pushing invasion with perforation of the wall.

Appendiceal mucinous neoplasms and peritoneal metastasis usually express keratin 20, and approximately 25% to 40% coexpress keratin 7. CDX2 and MUC2 are expressed in almost 100% of appendiceal mucinous tumors and PP. In contrast, MUC1 is typically negative in adenomas (although it may be positive in adenocarcinomas). MUC5AC and MUC6 are variably expressed in these tumors and therefore are not of diagnostic value.

Differential Diagnosis

Retention Cyst

Retention cysts are caused by obstruction of the appendiceal lumen, 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. 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 ). 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. 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.

Retention cyst of the appendix with dilatation of the appendiceal lumen. A, The mucosa is atrophic, but mucosal architecture is still evident in the form of crypts and lamina propria. B, In this example, the cyst lining is composed of an attenuated layer of epithelial cells.

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 ). 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.

Ruptured appendiceal diverticulum. The appendiceal mucosa herniates through the muscularis propria, with extravasation of mucin outside the appendix. The mucosa shows architectural disarray, compatible with reactive changes. Together, these changes are often misinterpreted as a ruptured low-grade appendiceal mucinous neoplasm (LAMN).

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

Mucosal neuroma. The lamina propria contains a vaguely nodular neural proliferation. Mucosal neuromas are frequently seen in appendices with diverticula.

Natural History

The prognosis of LAMN is highly dependent on the presence or absence of neoplastic epithelium outside the appendix. 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, 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 colleagues 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. 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 ).

Clinical Features

Adenocarcinomas of the appendix are uncommon; Collins found an incidence of 0.082% among 50,000 appendectomy specimens. There is an increased incidence among men in some series but not in others. Patients are usually in their fifth to seventh decade of life at presentation 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.

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. Studies have found frequent mutations of KRAS . A recent study found absent GNAS mutations in three mucinous adenocarcinomas. Studies have been mixed with regard to TP53 . Some have reported absent TP53 expression, whereas others have reported TP53 expression in most adenocarcinomas or TP53 mutations in approximately 75% by gene sequencing. Mutations in CTNNB1 ( β-catenin ) were not found in a series of 28 appendiceal adenocarcinomas, and no loss of heterozygosity for APC or DCC was detected in another series of 6 adenocarcinomas. Although mucinous carcinomas in the right colon are frequently associated with defective DNA mismatch repair and microsatellite instability, most appendiceal adenocarcinomas studied to date have been microsatellite stable. However, in one study, four adenocarcinomas arising in the background of serrated lesions 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.

Pathology

Grossly, appendiceal carcinomas can be polypoid, ulcerating, or infiltrative. 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.

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. Mucinous adenocarcinoma accounts for approximately 40% of all appendiceal adenocarcinomas. 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 or, less commonly, they may metastasize via a hematogenous route. Peritoneal metastasis may reveal large volumes of extra­cellular mucin. 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 . Other organs may be affected, such as small or large bowel, liver, or ovary.

Invasive mucinous adenocarcinoma of the appendix. Pools of mucin harboring complex atypical epithelial groups dissect into and through the appendiceal wall, arising from a villous tumor in the appendix lumen.

A, This peritoneal mucinous adenocarcinoma is composed of pools of mucin harboring many groups of mucinous epithelium with complex, cribriform growth. B, High-power view of a cribriform epithelial group shows nuclear hyperchromasia and crowding, consistent with mucinous carcinoma.

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 ).

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. 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 ).

Appendiceal signet ring cell carcinoma. A, Low-power view shows a cellular neoplasm in the submucosa and muscularis with areas of extracellular mucin production and a predominance of single cells. B, High-power view shows that the tumor is composed of single cells, many with an eccentric mucin vacuole.

Differential Diagnosis

Natural History

The reported 5-year survival rate for patients with appendiceal adenocarcinoma ranges from 18.7% to 55%. Patients with mucinous adenocarcinomas have a better prognosis than those with non-mucinous adenocarcinomas. Several studies have shown that histologic grade and Duke stage correlate with prognosis. Patients with peritoneal carcinomatosis have a poor prognosis.

Treatment

Invasive adenocarcinoma of the appendix warrants treatment by right hemicolectomy, with lymph node dissection, to potentially achieve a cure. Most studies have shown that right hemicolectomy offers improved 5-year survival compared with appendectomy alone. Some authorities advocate oophorectomy in women, both for staging purposes and to remove a common site of metastasis. 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.

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. PP typically manifests in the sixth to seventh decades of life, and in some series, women predominate over men. Along with the peritoneal cavity, the ovaries are commonly involved with tumor as well. 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. 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. 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 ). Progression from low grade to high grade has been described in patients after failure of cytoreduction and chemotherapy treatment.

Peritoneal involvement by low-grade appendiceal mucinous neoplasm. A, Whole mount view shows that the peritoneal tumor is composed largely of pools of mucin dissecting fibrotic stroma. B, Low-power view shows that the tumor is composed of abundant mucin dissecting fibrotic stroma with scant low-grade mucinous epithelium. C, High-power view shows mucinous epithelium in the peritoneal tumor demonstrating low-grade nuclear atypia with mild nuclear pseudostratification.

Ronnett and co-workers separated peritoneal mucinous tumors into two categories based on cytologic and architectural features. 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. 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. Initially, these patients appeared to have an intermediate prognosis, but additional follow-up showed that their tumors behaved similarly to PMCA.

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. 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.

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. 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.

Sugarbaker and colleagues 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. Using this aggressive approach, they achieved 5- and 10-year survival rates of 71.9% and 54.5%, respectively. 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.

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. 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. In this regard, the experience of the surgeon may play a role, with specialized centers achieving better survival statistics. Extensive involvement of the small bowel or mesentery predicts a high likelihood of incomplete cytoreduction. Tumor grade is a factor that affects outcome. 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.

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

Clinical Features

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

Invasive carcinoma arising from a serrated epithelial proliferation in the appendix. In this example, the invasive tumor also shows serrated gland morphology.

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 colleagues 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.

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. 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. Histologically, mucosal hyperplasia shows elongation of crypts with delicate papillary structures and glandular infolding, producing a serrated luminal contour. The glands are lined by mucinous cells that differentiate progressively toward the surface, with columnar cells having apical mucin vacuoles alternating with goblet cells. The crypts taper down to a preserved proliferative zone with regular cells containing small, round nuclei. Mitoses are largely restricted to the basal area. A prominent basement membrane may be seen, and the muscularis mucosae is intact. Essentially, these tumors appear similar histologically to hyperplastic polyps that occur in the colon (see Chapter 22 ) ( Fig. 28.19 ).

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