Neoplastic Appendix

Amy E. Noffsinger

Appendiceal tumors constitute less than 0.4% of all intestinal neoplasms. Pathologically, they resemble their small and large intestinal counterparts. The most significant difference between appendiceal and intestinal neoplasms is in the frequency of specific tumor types arising in these sites, with the appendix having a higher incidence of neuroendocrine tumors than carcinomas (1). Neuroendocrine tumors are discussed in Chapter 17. Although even small appendiceal tumors may obstruct the appendiceal lumen leading to acute appendicitis, most neoplasms remain asymptomatic, and the diagnosis of neoplasia is seldom made prior to surgical resection. The WHO classification of appendiceal tumors is shown in Table 9.1 (2).

▪ POLYPS

Appendiceal polyps include both serrated and nonserrated types. Most nonserrated adenomas involve the appendiceal mucosa in a circumferential fashion (Fig. 9.1). Less commonly, they grow as a localized lesion resembling their more common colonic counterparts (Fig. 9.2). Serrated polyps may demonstrate associated cytologic dysplasia or may have none.

Localized Nonserrated Adenomas

Isolated sessile or pedunculated nonserrated adenomas resembling their colonic counterparts occur, but it is difficult to assess their incidence because these lesions tend to remain asymptomatic, and most pathologists do not open the appendix along its long axis. These adenomas affect patients of all ages, including children (3); median patient age is the mid-50s (4). Adenomas occur in younger individuals in association with familial polyposis. Patients with appendiceal adenomas may have additional primary tumors at other sites including colon, breast, kidney, ovary, and gallbladder (4,5,6), although whether these represent true associations rather than chance occurrences is not known.

Isolated adenomas are generally discovered incidentally in appendices removed for other reasons. They may also be detected at the time of colonoscopy if they prolapse through the appendiceal orifice into the cecum. Larger sessile adenomas produce appendicitis by obstructing the appendiceal lumen. They may also lead to formation of diverticula (Fig. 9.3). Histologically, isolated appendiceal adenomas resemble their colonic counterparts (Fig. 9.4). Sporadic adenomas may be tubular, tubulovillous, or villous in architecture and contain varying degrees of dysplasia. Simple appendectomy represents adequate treatment for patients with adenomas that do not contain an invasive cancer.

Serrated Polyps

Mixed hyperplastic-adenomatous polyps, traditional serrated adenomas, and sessile serrated adenomas/polyps (SSA/P) can develop in the appendix. As with traditional adenomas, the histologic features of these lesions resemble their colonic counterparts (discussed in Chapter 14) (Fig. 9.5). Recent evidence, however, suggests that appendiceal serrated polyps may differ biologically from those arising in the colon, and therefore, the terminology used in the colon may not be appropriate for serrated appendiceal lesions (7,8). Recently proposed terminology for appendiceal serrated polyps is summarized in Table 9.2.

Serrated polyps without cytologic dysplasia represent approximately 60% of serrated appendiceal polyps (8) and comprise the morphologic equivalents of colonic hyperplastic polyps and SSA/P (7). Those lesions that resemble colonic hyperplastic polyps often involve only a portion of the circumference of the appendix, while those resembling SSA/P are most often circumferential (9). These lesions uncommonly result in appendiceal luminal dilation and are often unsuspected at the time of gross examination of the appendix (7). Histologically, they are characterized by superficial
luminal serrations and variable crypt dilation, branching, or transverse basal extension of the crypts. By definition, cytologic dysplasia is absent. Recent studies suggest that these lesions differ from their colonic counterparts in that they more frequently harbor mutations in KRAS than in BRAF (7,8). There appears to be essentially no risk of progression of these lesions to disseminated appendiceal neoplasia or invasive adenocarcinoma (7).

TABLE 9.1 WHO CLASSIFICATION OF EPITHELIAL (NONNEUROENDOCRINE) APPENDICEAL TUMORS

Premalignant Lesions
	Adenoma
		Tubular
		Villous
		Tubulovillous
	Dysplasia (intraepithelial neoplasia), low grade
	Dysplasia (intraepithelial neoplasia), high grade
Serrated Lesions
	Hyperplastic polyp
	Sessile serrated adenoma/polyp
	Traditional serrated adenoma
Carcinoma
	Adenocarcinoma
	Mucinous adenocarcinoma
	Low-grade appendiceal mucinous neoplasm
	Signet-ring cell carcinoma
	Undifferentiated carcinoma
Adapted from Carr NJ, Sobin LH: Adenocarcinoma of the appendix. In: Bosman FT, Carneiro F, Hruban RH, et al. (eds). WHO Classification of Tumours of the Digestive System, 4th ed. Lyon, France: IARC, 2010, pp 199-225.

FIG. 9.1 Circumferential adenoma. A: Gross appearance of a cross-section of a circumferential appendiceal villous adenoma. Note the long fingerlike villiform structures in the center of the photograph. B: Low-power histologic features of the lesion demonstrated in A showing the villous architecture. The lesion is confined to the mucosa and no evidence of invasive malignancy was seen in this lesion.

In contrast, serrated polyps of the appendix with cytologic dysplasia carry a significant risk for associated invasive adenocarcinoma. These polyps are often circumferential and may morphologically resemble either colonic SSA/P with cytologic dysplasia or TSA (7,8,9). In one study, invasive adenocarcinoma was identified in 17% of cases (most of which were TSA) and was most often nonmucinous histologically (7).

Unlike their colorectal counterparts, serrated lesions of the appendix more frequently harbor mutations in KRAS. In one study (7), KRAS mutation was found in 52% of appendiceal serrated polyps, and there was no significant difference in the presence of KRAS mutations in serrated lesions with and without cytologic dysplasia. In the same study, BRAF mutations were found in only 4% of appendiceal serrated neoplasms. In another study, BRAF mutations were found in a larger proportion of appendiceal serrated neoplasms but were still less common than described in their colonic counterparts (8). As in the colon, KRAS and BRAF mutations were mutually exclusive. This finding suggests that the serrated neoplasia pathway described for colonic serrated polyps may not be applicable to appendiceal lesions.

FIG. 9.2 Adenoma. A: Polyp within the lumen of the appendix (arrow). A piece of paper has been slipped under the polyp to distinguish it from the surrounding normal mucosa. B: Small whitish adenomatous polyp (arrow) in the appendix of a patient who underwent an ileocolectomy for a carcinoma of the cecum.

Appendiceal Mucinous Neoplasms

Appendiceal mucinous neoplasms comprise a spectrum of tumors, the classification of which has been controversial, although a recent consensus paper has been published, which may help to standardize the terminology used in describing these lesions (10) (Table 9.3). Historically, most of the debate was focused on the group of mucinous neoplasms with low-grade cytologic atypia, now referred to as low-grade appendiceal mucinous neoplasms (LAMN). These lesions have an innocuous gross and microscopic appearance, pushing rather than infiltrative invasion, and in some circumstances rupture the appendiceal wall, ultimately disseminating throughout the peritoneal cavity to produce pseudomyxoma peritonei (PMP). Predicting which appendiceal mucinous tumors will likely result in PMP is a difficult challenge with which pathologists are commonly faced.

FIG. 9.3 An appendiceal diverticulum can be seen arising in association with a low-grade mucinous neoplasm, which can be seen in the far upper right aspect of the photograph.

Low-Grade Appendiceal Mucinous Neoplasms

LAMN, often referred to previously as mucinous cystadenomas (a term that is no longer favored) (10), arise in both males and females, although a female predilection has been reported (11). Patients range in age from 27 to 77 years, with an average age of 53 years and a median age of 64 years (12). Approximately 20% of patients have a metachronous or synchronous colonic adenocarcinoma (13). Some patients develop acute appendicitis because the mucin accumulation obstructs the appendiceal lumen (Fig. 9.6). Patients also develop abdominal pain, nausea and vomiting, and, sometimes, a palpable right lower quadrant mass, perforation, or intussusception (Fig. 9.7). Other patients present with PMP or with what appears to be an ovarian tumor.

LAMN can produce large amounts of mucus converting the appendix into a sausage-shaped, cystic or spherical, mucusfilled mass (Fig. 9.6); the average diameter is 2.2 cm with a range of 0.3 to 9 cm (14). Diverticula are often present and there may be areas of rupture. There may also be grossly visible mucus on the serosal surface of the appendix. Mural calcification may produce the gross pattern of a “porcelain appendix.”

LAMN may not be appreciated at the time of gross examination of the appendix, especially if there is a coexisting acute appendicitis. Therefore, if a tumor is found, the pathologist should carefully reexamine the appendix for areas of perforation, serosal mucin accumulations, and invasive carcinoma, since these modify the patient’s prognosis and treatment if identified. Perforation sites and serosal mucin deposits should be sampled; the entire tumor should be submitted to rule out invasion. The proximal margin of resection

should be identified and submitted for histologic examination, although a recent study found that involvement of the appendectomy margin in LAMN confined to the appendix did not predict disease recurrence (15).

FIG. 9.4 Adenoma of the appendix. A: The epithelium resembles that seen in colonic adenomas. The adenomatous epithelium demonstrates the typical picket-fenced arranged nuclei and the presence of immature goblet cells as evidenced by the small goblet cell collections. B: Another area of the tumor demonstrating marked goblet cell dystrophy.

FIG. 9.5 Serrated adenoma/polyp of the appendix. A: Low-power photomicrograph showing that the lesion involves the full circumference of the distal appendix. B: Histologically, appendiceal serrated adenoma/polyps resemble their colonic counterparts.

TABLE 9.2 PROPOSED CLASSIFICATION OF SERRATED APPENDICEAL LESIONS

Proposed Nomenclature	Colorectal Counterpart
Serrated polyp without cytologic dysplasia	Hyperplastic polyp
	Sessile serrated adenoma/polyp without cytologic dysplasia
Serrated polyp with cytologic dysplasia	Sessile serrated adenoma/polyp with cytologic dysplasia
	Traditional serrated adenoma

TABLE 9.3 MUCINOUS NEOPLASMS OF THE APPENDIX

Features	Consensus Terminology (10)	Synonyms Previously in Use
Mucinous neoplasm with low-grade cytologic features and no evidence of infiltrative invasion of the appendiceal wall	Low-grade appendiceal mucinous tumor (LAMN)	Mucinous cystadenoma, mucinous tumor of uncertain malignant potential, low-grade mucinous tumor with low/high risk of recurrence
Mucinous neoplasm with architectural features of LAMN but with high-grade cytologic features	High-grade appendiceal mucinous tumor (HAMN)	None
Mucinous neoplasm with infiltrative invasion of the appendiceal wall	Mucinous adenocarcinoma (well, moderate, poorly differentiated)
Mucinous carcinoma with ≤50% signet ring cells	Poorly differentiated mucinous adenocarcinoma with signet ring cells
Mucinous carcinoma with >50% signet ring cells	(Mucinous) Signet ring cell adenocarcinoma

Histologically, a circumferential proliferation of neoplastic mucinous epithelium replaces the normal epithelium. Usually, a single layer of tall crowded columnar adenomatous epithelium with basally located hyperchromatic, pseudostratified nuclei, and clear-to-eosinophilic cytoplasm lines the neoplastic glands (Fig. 9.8). The elongated nuclei lack nucleoli. Mitotic activity is usually low and usually limited to the base of the glands. The glands are usually tubular although a villous architecture may be present. More often, the epithelial proliferation produces an undulating pattern.

FIG. 9.6 Low-grade mucinous neoplasm with secondary appendicitis. A: Gross appearance of the unopened specimen with appendicitis as indicated by the serosal erythema and adhesions. B: Opened specimen demonstrating a mass at the base of the appendix. The distal portion of the appendix is filled with inspissated mucinous secretions. The dusky color at the base of the specimen in A and B correlates with the presence of acute appendicitis.

Most appendiceal mucinous neoplasms are low grade with minimal cytological atypia. However, some cases demonstrate moderate to marked atypia and abundant mitotic activity, and the term “high-grade appendiceal mucinous neoplasm” (HAMN) has been proposed for these lesions
(10). Areas of high-grade dysplasia appear as a disorderly proliferation of cells that lose their polarity (Fig. 9.9) and may exhibit a back-to-back glandular pattern that obliterates the intervening lamina propria. As in the colon, these changes remain confined to the area above the muscularis mucosae. Since the likelihood of an invasive carcinoma increases with the degree of dysplasia, these areas should be well sampled to rule out an invasive process.

FIG. 9.7 Ileocolectomy specimen from a patient with a large sessile nonmucinous adenoma of the distal appendix. The appendix has intussuscepted into the cecum. The arrows delineate the areas of the appendiceal adenoma. Normal-appearing appendix (NA) is present proximally.

FIG. 9.8 Low-grade mucinous neoplasm of the appendix. A: Gross photograph showing the presence of whitish papillary excrescences within the lumen of the appendix. Abundant mucoid material is present. B: A microscopic section through this lesion. The appendix is lined circumferentially by papillary proliferations of appendiceal epithelial cells. C: The prominent pencil-shaped nuclei characteristic of adenomatous epithelium are evident. Some of the cells contain abundant mucin, whereas others do not.

FIG. 9.9 High-grade dysplasia. The neoplastic cells have lost their polarity, and in this area, mucin production is reduced.

The nonneoplastic mucosa often appears atrophic and the usually prominent Peyer patches are often absent. Mucosal denudation is common (Fig. 9.10), either from compression by the intraluminal mucin or by ulceration due to coexisting appendicitis. The mucosal ulcers may produce a granulomatous reaction with subsequent mural fibrosis. The intraluminal mucin may compress the lining epithelium in such a way that the flattened epithelium may not be easily recognizable as being neoplastic.

FIG. 9.10 Wall of a ruptured low-grade mucinous neoplasm. A: Mucinous lakes dissect into the periappendiceal tissues. A prominent inflammatory infiltrate surrounds the edge of the mucinous lakes in the appendiceal fat. B: Higher magnification of the edge of the lesion showing fibrous tissue, benign, flattened epithelium, and inflammatory cells. Finding an area such as this in an appendix should prompt a search for a mucinous tumor in the remainder of the appendix.

A characteristic feature of LAMN is a pattern of “pushing” invasion into the underlying appendiceal wall (16). The muscularis propria of the appendix may be attenuated or even absent in some cases and is often hyalinized or fibrotic. Neoplastic epithelium growing along an underlying fibrotic stroma rather than lamina propria or muscularis mucosae is frequently seen in association with LAMN and is considered a sign of pushing invasion (16). Neoplastic epithelium may also extend through the wall via diverticula (Fig. 9.11). Tongues of epithelium may also extend through the wall without the usual features of infiltrating invasion as typifies mucinous adenocarcinomas. A desmoplastic stromal response or tumor budding are absent.

FIG. 9.11 Appendiceal low-grade mucinous neoplasm with secondary diverticulum formation. A villiform mucin-secreting epithelium lines the appendiceal lumen as well as the diverticulum. The wall of the appendix on the left-hand side of the picture has become markedly thinned due to dilation.

When the wall of the appendix is completely traversed by the tumor, mucin, with or without associated epithelial cells, may be seen on the appendiceal surface (Fig. 9.12). The serosa itself may show an acute or chronic serositis with inflammation and mesothelial hyperplasia. It is important to search these areas carefully for the presence of both mucin and epithelial cells and to report their presence if they are seen. The histological features of LAMN with and without extra-appendiceal spread are identical (with the exception of the identification of a breach in the appendiceal wall in the former). The mucus extravasation can be limited to the periappendiceal area, or it can spread over large areas of the peritoneal surface (see below). Noninvasive lesions that exhibit marked cytologic atypia or complex intraepithelial proliferations tend to have a higher proliferative rate than low-grade tumors, and if these lesions gain access to the peritoneal cavity, they tend to behave more aggressively than low-grade lesions.

The differential diagnosis of LAMN includes both malignant and benign entities. A LAMN that perforates the appendiceal wall may be confused with invasive adenocarcinoma. Adenocarcinomas show infiltrative invasion of the appendiceal wall, usually associated with stromal desmoplasia, individual invading cells, or small nests of cells. Tumor budding may also be seen and is not a characteristic of LAMN with perforation. When a mucinous neoplasm has disseminated to the peritoneal cavity, there is still debate as to whether the lesion should be classified as LAMN or as adenocarcinoma. The term LAMN, however, reconciles the cytologic features of these neoplasms with their propensity to disseminate to the peritoneum and is terminology that conforms to WHO recommendations (16).

FIG. 9.12 Low-grade mucinous neoplasm with rupture. Low-power magnification demonstrating a cross-section of the appendix distal to the tumor. The appendix shows central fibrous obliteration of the lumen. External to the appendiceal wall is a collection of mucin.

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