Appendiceal mucinous lesions

INTRODUCTION AND TERMINOLOGY — Although a distended, mucus-filled appendix is often called a mucocele, this term is ambiguous and best utilized to describe an imaging appearance rather than a pathologic entity as the underlying biology and behavior of appendiceal mucinous lesions are extraordinarily variable and can range from non-neoplastic to neoplastic.

While older literature on appendiceal mucoceles often failed to distinguish between benign and neoplastic lesions, the classification of appendiceal mucinous lesions has undergone significant refinement over the years [1]. In 2012, the Peritoneal Surface Oncology Group International (PSOGI) developed a consensus classification that has helped to resolve much of the confusion surrounding diagnostic terminology [2,3]. The PSOGI classification will be the reference point for this topic.

●Non-neoplastic appendiceal mucinous lesions

•Simple mucoceles, or retention cysts, are characterized by degenerative epithelial changes due to obstruction (eg, fecalith) and distention, without any evidence of mucosal hyperplasia or neoplasia. They are also referred to as inflammatory or obstructive mucoceles.

●Neoplastic appendiceal mucinous lesions

•Serrated polyps of the appendix, with or without dysplasia, resemble the serrated lesions of the colon but have differing molecular features. In the past, serrated lesions lacking dysplasia have been called "hyperplastic polyps" of the appendix if focal and "mucosal hyperplasia" if flat and circumferential or otherwise diffuse. Typically, serrated polyps of the appendix are not associated with fibrosis or thickening of the appendiceal wall or loss of the lamina propria.

•Mucinous appendiceal neoplasms are dysplastic mucinous tumors. These tumors demonstrate a pushing front with tongues of epithelium dissecting outward into the muscularis mucosae, but they are confined by the muscularis propria and lack an infiltrative growth pattern, destructive invasion, or a stromal desmoplastic reaction. These tumors can be classified as either low-grade appendiceal mucinous neoplasms (LAMNs) or as high-grade appendiceal mucinous neoplasms (HAMNs) if they have areas with high-grade cytologic features [2]. The World Health Organization classifies the majority of noninvasive epithelial appendiceal lesions as LAMNs [4].

•Mucinous adenocarcinomas of the appendix demonstrate frankly infiltrative invasion, features of which include tumor budding (discohesive single cells or clusters of up to five cells) and/or small, irregular glands, typically within a desmoplastic stroma characterized by a proteoglycan-rich extracellular matrix containing activated fibroblasts/myofibroblasts with vesicular nuclei. They can be classified as well, moderately, or poorly differentiated mucinous adenocarcinomas; the presence of signet ring cells automatically consigns the tumor to the poorly differentiated category [2,5]. Appendiceal adenocarcinomas may be mucinous or nonmucinous. Mucinous adenocarcinomas are defined as invasive glands containing high-grade cytologic atypica and extracellular mucin making up >50 percent of the cross-sectional area of lesion under the microscope [4]. (See "Epithelial tumors of the appendix", section on 'Adenocarcinoma'.)

Appendiceal neoplasms may perforate and spread to the peritoneal cavity. The term pseudomyxoma peritonei (PMP) is best used to describe the clinical syndrome of mucinous appendiceal neoplasm with diffuse peritoneal spread that includes abundant mucin production [3]. The prognosis of patients with PMP is determined by the degree of cellularity within the mucin (eg, acellular, low-grade histologic features, high-grade histologic features, and signet ring cells (table 1)). (See "Epithelial tumors of the appendix", section on 'Peritoneal disease spread and pseudomyxoma peritonei'.)

This topic will review the epidemiology, clinical manifestations, diagnosis, pathology, and management of appendiceal mucinous lesions. Nonmucinous tumors of the appendix are discussed in other UpToDate topics. (See "Epithelial tumors of the appendix" and "Well-differentiated neuroendocrine tumors of the appendix".)

Other causes of ileocecal lesions, including tuberculosis, typhlitis, actinomycosis, carcinoid tumors, and lesions due to nonsteroidal anti-inflammatory drugs (NSAIDs), are discussed separately. (See "Neutropenic enterocolitis (typhlitis)" and "Abdominal actinomycosis" and "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts" and "NSAIDs: Adverse effects on the distal small bowel and colon".)

EPIDEMIOLOGY — Appendiceal mucinous neoplasms are rare, with an estimated 3500 cases diagnosed annually in the United States [6]. Appendiceal mucinous lesions (both benign and neoplastic) have a slight female predominance and are usually diagnosed in patients in their 50s and 60s [5,7].

The risk for occult appendiceal mucinous neoplasms is greater for patients who present with complicated appendicitis than the general population. In one study of 17 patients who underwent interval appendectomy for complicated appendicitis, five patients were found to have a mucinous neoplasm [8].

CLINICAL MANIFESTATIONS — Appendiceal mucinous lesions are usually discovered incidentally during radiologic or endoscopic evaluation for unrelated complaints [9-11] or in the pathologic specimen of an appendectomy (picture 1).

Clinical features — Patients are often asymptomatic or have nonspecific symptoms. The most frequent symptom is acute or chronic right lower quadrant abdominal pain. An abdominal mass is occasionally palpable. Less frequently, patients can present with intermittent colicky pain and gastrointestinal bleeding associated with intussusception of the mucocele; intestinal obstruction from mass effect; genitourinary symptoms due to obstruction of the right ureter; rarely, an acute abdomen from mucocele rupture; or sepsis [7,12,13].

Mucinous lesions that are due to hyperplasia (serrated polyps) or retention cysts (simple mucoceles) are not associated with recurrence once they rupture. By contrast, rupture of neoplastic mucinous lesions of the appendix, such as low-grade appendiceal mucinous neoplasms (LAMNs), high-grade appendiceal mucinous neoplasms (HAMNs), or mucinous adenocarcinomas, can lead to progressive intraperitoneal spread and accumulation of both mucinous ascites and neoplastic cells, resulting in a clinical syndrome referred to as pseudomyxoma peritonei (PMP) [14]. The clinical features of PMP are discussed separately. (See "Epithelial tumors of the appendix", section on 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)'.)

Laboratory findings — Laboratory findings for appendiceal mucinous lesions are nonspecific but may include anemia or elevated levels of tumor markers (eg, carcinoembryonic antigen [CEA], CA 19-9, and CA-125) in patients with neoplastic mucinous lesions [15,16]. Although there is a paucity of information, the available data suggest that tumor markers are elevated in the majority of patients with advanced appendiceal mucinous tumors, and the levels correlate with treatment outcomes [17-20]. Thus, tumor markers should be measured upon diagnosis of appendiceal mucinous neoplasm and routinely repeated to monitor disease progression. (See 'Post-treatment surveillance' below and "Epithelial tumors of the appendix", section on 'Utility of tumor markers'.)

Imaging — Radiologic studies, in particular abdominal computed tomography (CT) and ultrasound, can diagnose an appendiceal mucocele but cannot definitively distinguish between non-neoplastic and neoplastic lesions. However, certain characteristics may be suggestive. As examples, neoplastic mucinous lesions are generally larger than retention cysts. The presence of soft tissue thickening, wall calcifications, and wall irregularity, but not an increase in wall thickness, is suggestive of a neoplasm [21]. The presence of ascites with hypodense peritoneal implants and scalloping of the liver surface suggests the intraperitoneal spread of neoplastic cells rather than peritoneal mucin alone [22,23]. (See "Epithelial tumors of the appendix", section on 'Radiographic studies'.)

Cross-sectional imaging of the abdomen and pelvis with CT or magnetic resonance imaging (MRI) should be performed upon diagnosis of an appendiceal mucinous neoplasm to evaluate the primary tumor and assess for intraperitoneal spread of disease and repeated regularly after resection to monitor for recurrence. In some patients (eg, those with moderate- to high-grade adenocarcinomas), chest CT may also be required. (See 'Post-treatment surveillance' below.)

●Abdominal CT scan – The typical abdominal CT finding in a patient with an appendiceal mucocele is a low-attenuation, well-encapsulated round or tubular cystic mass in the right lower quadrant adjacent to the cecum (image 1). An isolated, focal, distal appendiceal dilatation with a segment of morphologically normal appendix proximally has been strongly associated with underlying neoplastic appendiceal mucoceles [24]. The presence of mural curvilinear calcifications, especially eggshell in appearance, is strongly suggestive of an underlying appendiceal neoplasm [25]. Other neoplastic features include diameter >2 cm and absence of periappendiceal stranding.

●Abdominal MRI scan – When performed according to special peritoneal protocols and interpreted by an expert body MRI radiologist, MRI can detect extraluminal mucin and has been shown in some studies to be superior to CT in detecting peritoneal disease [26].

●Abdominal ultrasound – On abdominal ultrasound, an appendiceal mucocele has the appearance of an ovoid cystic mass with or without acoustic shadowing due to mural calcification. Ultrasound may demonstrate variable internal echogenicity depending upon the consistency of the mucocele [22]. Nodular enhancing lesions in the wall of the mucocele are suggestive of an underlying malignancy rather than a benign mucocele [27]. The "onion skin sign" seen on ultrasound of the lower abdomen appears to be specific for diagnosis of a mucinous appendiceal lesion [28,29].

●Abdominal radiographs – Abdominal radiographs may demonstrate a soft tissue mass in the right lower quadrant with curvilinear or punctate calcification.

●Barium enema – A barium enema may demonstrate a smooth cecal filling defect without contrast filling of the appendix or associated ulceration [9].

●As the neoplastic appendiceal mucinous lesions are highly mucinous, positron emission tomography (PET) imaging is not recommended, due to the high likelihood of a false negative finding [30].

Colonoscopy — Appendiceal mucinous lesions may be found incidentally on colonoscopy performed for colorectal cancer screening or evaluation of symptoms. As appendiceal mucinous lesions are extrinsic or submucosal, on colonoscopy they can produce a smooth indentation of the cecal lumen or have the appearance of a glossy, rounded, protruding mass arising from the appendiceal orifice moving in and out of the latter with respiration (picture 2) [10,31]. On colonoscopy, the appendiceal orifice may be seen in the center of a mound-like elevation of the cecal wall (volcano sign) [9]. Inflammatory exudate may be seen extruding from the appendiceal orifice [32]. When probed with the biopsy forceps, the lesion may be firm in consistency or soft, collapsing with a central indentation (cushion sign) [9,11]. As the overlying mucosa is normal, mucosal biopsies are not diagnostic.

As appendiceal mucinous lesions usually present endoscopically as submucosal tumors, appendiceal abnormalities are seen infrequently with colonoscopy and rarely yield a diagnostic biopsy [33]. Nevertheless, when an appendiceal mucocele is detected by imaging, colonoscopy can be used to evaluate for other colonic lesions and to determine if involvement of the cecum has occurred, which would be consistent with local invasion from an adenocarcinoma. Additionally, 13 to 42 percent of patients diagnosed with appendiceal neoplasms also have synchronous colonic lesions [14,33].

An endoscopic ultrasound (EUS) can also be performed to help exclude other submucosal lesions (eg, lipomas, neuroendocrine tumors, and lymphangiomas) [34]. EUS can detect the cystic nature of the mucocele, which appears anechoic or hypoechoic [34]. In addition, stromal invasion, suggestive of a mucinous adenocarcinoma, may also be seen on EUS [11]. (See "Endoscopic ultrasound for the characterization of subepithelial lesions of the upper gastrointestinal tract", section on 'Endosonographic findings'.)

For patients with an incidentally detected appendiceal mucinous lesion on colonoscopy with or without endoscopic ultrasound, an abdominal CT should be performed to confirm the diagnosis and exclude other etiologies [35]. (See 'Differential diagnosis' below.)

DIAGNOSIS — Appendiceal mucinous lesions are often discovered incidentally during radiologic or endoscopic evaluation for unrelated complaints such as abdominal pain.

If an appendiceal mucinous lesion is confined to the appendix, we perform appendectomy for definitive pathologic diagnosis. Given the challenges with cytological diagnosis of these highly mucinous lesions and the concern over peritoneal spread, biopsy of the primary mucinous appendiceal lesions should be avoided [36].

Unfortunately, many patients with appendiceal mucinous lesions present with peritoneal dissemination, in which case the diagnosis is usually established by percutaneous biopsy of one of the peritoneal lesions. (See 'Disseminated peritoneal disease' below.)

Differential diagnosis — The differential diagnosis of a radiographic appendiceal mucocele includes appendicitis, nonmucinous appendiceal neoplasms (eg, leiomyoma, fibroma, neuroma, neuroendocrine tumor, lipoma, nonmucinous adenocarcinoma of the appendix), and a mesenteric or duplication cyst [9,10]. These often can be differentiated from an appendiceal mucinous lesion by their appearance on abdominal CT scan. As an example, the presence of periappendiceal inflammation or abscess is suggestive of acute appendicitis and is not typically seen with appendiceal mucinous lesions [21-23,27], granted that up to 30 percent of patients with complicated appendicitis can have mucinous tumors [8].

PATHOLOGY — The course and prognosis of appendiceal mucinous lesions are dictated by their histologic subtypes [37]. Hence, the pathology and staging of these lesions are discussed before their treatment. (See 'Treatment' below.)

Appendiceal mucinous lesions are classified histologically as either non-neoplastic or neoplastic epithelial lesions, and the neoplasias are subcategorized by histologic subtypes. Accurate histologic diagnosis requires a rigorous evaluation of the entire appendiceal specimen. Especially important when evaluating a neoplastic lesion is examination of the entire appendiceal wall for evidence of epithelial invasion, a feature that differentiates adenocarcinomas from all other mucinous lesions. Microscopic identification of this critical feature may be challenging, however, as evidence of overt invasion of the appendiceal wall may be lacking, and fibrotic attenuation of the mural layers is seen instead, with or without mucin extension into the wall. The current pathological classification schemes for neoplastic lesions take into account both the variations in the histopathological appearance of the epithelium of the lesion and the pattern of mural involvement [2,38,39].

Non-neoplastic appendiceal mucinous lesions — These consist of simple mucoceles (also known as "retention cysts" or "inflammatory mucoceles") and are not neoplasms.

Simple mucoceles are also known as retention cysts because their etiology is believed to be related to chronic luminal obstruction with secondary cystic expansion of the appendix distal to the level of obstruction due to continued mucin secretion by the mucosal epithelium. The epithelial lining of the simple mucocele is normal (lacking dysplasia) but may show flattening secondary to increased intraluminal pressure or abundant intracellular mucin content. Increased intraluminal pressure also may lead to complete effacement of the mucosal epithelium and/or mucin extrusion into or through the wall resulting in mucin pools without epithelium.

Causes of obstruction include fecalith formation in the lumen, endometriosis involving the appendix, or any other chronic local process that leads to focal scarring. These abnormalities have no known predisposition toward neoplastic transformation. Since low-grade appendiceal neoplasms can have features that overlap with those of simple mucoceles, such as focal epithelial flattening, epithelial effacement, or mucin extrusion into the wall or extramural tissue, it is important to examine the entire appendix microscopically to definitively rule out a true neoplasm.

Neoplastic appendiceal mucinous lesions — These lesions include serrated polyps (which are hyperplastic lesions with a unique architecture, with or without dysplasia), hyperplastic polyps, low-grade appendiceal mucinous neoplasms (LAMNs), high-grade appendiceal mucinous neoplasms (HAMNs), and mucinous adenocarcinomas.

The histopathologic terminology and classification of mucinous neoplasms of the appendix have long been controversial. In 2012, the Peritoneal Surface Oncology Group International (PSOGI) developed a consensus classification that has helped to resolve much of the confusion surrounding diagnostic terminology [2,3]. The PSOGI classification will be the reference point for this discussion. It is well recognized; however, many lesions have mixed histopathological features.

Serrated lesions and hyperplastic polyps of the appendix — Despite the PSOGI clarifications, serrated polyps of the appendix, with or without dysplasia, remain incompletely studied and are not always classified as neoplasms. Due to the lack of certainty about their biological nature, it has been suggested that these lesions should be classified indefinitively as serrated "polyps," either with or without epithelial dysplasia, rather than using the term "adenoma," a term that would more specifically classify them as benign neoplasms [3]. In the past, serrated lesions lacking dysplasia have been called "hyperplastic polyps" of the appendix if focal and "mucosal hyperplasia" if flat and circumferential or otherwise diffuse.

Historically, these "hyperplasias" were considered to be reactive in nature because most lesions, but not all, of this type lack cytological atypia/dysplasia. They typically involve the mucosa circumferentially and may have a tufted luminal epithelial architecture, which, on cross section of the appendix, gives the mucosa the appearance of being serrated or "saw toothed." The crypt epithelium also may be tufted.

The discovery that similar-appearing lesions in the colorectum are, indeed, mutated and constitute an early phase in the serrated adenoma pathway suggested the possibility that serrated lesions of the appendix also are neoplastic in nature. Molecular studies have shown that these appendiceal lesions contain mutations in specific oncogenes. As an example, appendiceal serrated lesions are most often KRAS mutated but lack the BRAF mutations that characterize their lookalike lesions in the colon (ie, sessile serrated adenomas). (See "Overview of colon polyps", section on 'Sessile serrated lesions' and "Molecular genetics of colorectal cancer".)

Accordingly, the 2019 World Health Organization classification of tumors of the appendix contains a category of appendiceal serrated lesions and polyps and defines serrated lesions as mucosal epithelial polyps that are characterized by a serrated (sawtooth or stellate) architecture of the crypt lumen [40]. Polyps that lack this architectural pattern and lack dysplasia are referred to as hyperplastic polyps. A table illustrating the histologic and molecular features of appendiceal serrated lesions and polyps is provided (table 2).

It is worth noting that the appendiceal neoplasms defined as "adenomas" are those that resemble colonic adenomas of the APC tumor suppressor pathway and are classified as tubular, tubulovillous, or villous adenomas. They are uncommon in the appendix and do not cause gross luminal dilatation (mucoceles).

LAMN — LAMN is the term of consensus to describe a true neoplasm with dysplastic epithelium that produces abundant mucin and characteristically exhibits expansile growth with a "pushing" border, which may or may not cause loss of the muscular components of the wall and mural fibrosis [41]. LAMNs always lack overt infiltrative epithelial invasion of the appendiceal wall and are confined by the muscularis propria. Mucin dissection through the appendiceal wall may be seen, but the mucin pools are acellular. The low-grade epithelial dysplasia of LAMN is characterized by mildly enlarged hyperchromatic nuclei with minimal mitotic activity. Although by definition LAMNs do not invade, their expansile growth may push and thin the appendiceal wall until the appendix ruptures, and the resultant spillage of cellular or acellular mucin may lead to pseudomyxoma peritonei (PMP).

HAMN — HAMNs are distinguishable from LAMNs only by the degree of epithelial dysplasia present. High-grade dysplastic changes may include cribriform growth, nuclear stratification to the surface of the epithelium, piling up of epithelial cells with high-grade features enlarged, hyperchromatic and pleomorphic nuclei, and abundant atypical mitotic activity [41]. HAMNs do not look innocuous, but they lack the aggressive features of an overt malignancy. Specifically, like LAMNs, they lack infiltrative invasion. Because HAMN is a newly created pathologic category, there are limited data on the behavior of HAMNs, and this is a highly controversial area. Although HAMNs may appear to have a more aggressive course than LAMNs, currently their clinical management is closer to that of LAMNs than that of mucinous adenocarcinomas [2]. The PSOGI recommended that though an unequivocal focus of high-grade dysplasia is sufficient for a diagnosis of HAMN [2], it may be more prudent to report the percentage of high-grade dysplasia present since the clinical significance of small foci of high-grade dysplasia is unknown. (See 'Additional treatment based on pathology' below.)

Mucinous adenocarcinoma — Adenocarcinoma of the appendix has been classified into two different pathological types: mucinous and nonmucinous (intestinal or colonic type) [39]. However, the distinction between them is somewhat arbitrary: if 50 percent or more of the tumor mass in any microscopic section is composed of extracellular mucin, the tumor is classified as mucinous.

The defining feature of adenocarcinomas of the appendix is their infiltrative invasion pattern, typically with a marked desmoplastic stromal reaction [39]. Mucinous adenocarcinomas are graded according to a three-tiered system (well, moderately, or poorly differentiated), but the presence of signet ring cells automatically consigns the tumor to the poorly differentiated category. In contrast to the higher-grade malignancies, well-differentiated mucinous adenocarcinomas may be more likely to produce peritoneal spread with a clinical picture of PMP rather than other presentations of distant metastatic disease, whereas the higher-grade tumors are more likely to produce both distant metastasis and peritoneal carcinomatosis [3]. (See "Epithelial tumors of the appendix", section on 'Adenocarcinoma'.)

STAGING — The 8^th edition American Joint Committee on Cancer (AJCC) staging manual provides guidelines for staging both low-grade appendiceal mucinous neoplasms (LAMNs) and adenocarcinomas (table 3). The role of acellular mucin or mucinous epithelium outside the appendix is also addressed and included in the staging guidelines.

LAMNs that are confined to the appendiceal wall without invasion or loss of the muscularis propria are classified as Tis(LAMN). This is to reflect the excellent outcome for confined LAMNs. The T1 and T2 stages are not used for LAMNs. LAMNs that demonstrate involvement with either acellular mucin or mucinous epithelium of the subserosa or serosa are classified as T3 or T4a, respectively. Acellular mucin involving the appendiceal serosa or mesoappendix is classified as T4a, while mucin involvement of distant peritoneal sites is classified as M1. In order to address the improved outcome for cases in which peritoneal dissemination is limited to acellular mucin only, these cases are classified as M1a. Other metastatic categories are M1b, which refers to metastases confined to the peritoneum only, and M1c, which refers to metastases outside the peritoneum.

In contrast to LAMNs, high-grade appendiceal mucinous neoplasms (HAMNs) are staged not as in situ tumors but as invasive adenocarcinomas (T1 to T4), because of their higher risk of recurrence. However, this area is controversial, and the clinical significance of a diagnosis of HAMN, as opposed to LAMN, remains unclear.

TREATMENT

Initial surgery — We recommend surgical resection of all localized appendiceal mucinous lesions for both diagnostic and therapeutic purposes. Because there are no reliable criteria to exclude malignant lesions, surgery should be pursued even for a benign-appearing appendiceal mucocele on imaging studies [42-45]. Surgical removal of the lesion will also prevent potential rupture in the future, which could cause pseudomyxoma peritonei (PMP) if the lesion is neoplastic.

Localized disease — For most localized appendiceal mucinous lesions, we perform a standard appendectomy. The decision to perform a more extensive resection than appendectomy is usually made intraoperatively but occasionally can be planned in patients with a complicated radiographic mucocele with involvement of the terminal ileum or cecum and in patients with known adenocarcinoma with mesenteric or adjacent organ involvement.

To ensure a complete resection of the lesion at appendectomy, we strive to include a cuff of the cecum with the appendiceal specimen without encroaching on the ileocecal valve. Either an open or laparoscopic approach can be utilized, depending on surgeon experience.

If the base of the appendix is involved in the disease process so that a clear margin cannot be achieved by stapling, a partial cecectomy (with preservation of the ileocecal valve), ileocecectomy (resecting the ileocecal valve), or right colectomy can be performed at the surgeon's discretion, with the ultimate goal of achieving a clear margin.

Some authors advocate resecting the mesoappendix with the specimen so that the regional lymph nodes can be analyzed [46]. Similarly, if a right hemicolectomy is performed to achieve a negative resection margin, it should follow oncologic principles with high ligation of the ileocolic pedicle at its origin. However, more extensive lymphadenectomy or routine right hemicolectomy performed solely to increase lymph node yield is not necessary for low-grade appendiceal mucinous neoplasms (LAMNs) or high-grade appendiceal mucinous neoplasms (HAMNs) of the appendix, which, unlike high-grade mucinous or nonmucinous appendiceal cancers, rarely involve the lymph nodes [47].

We do not perform intraoperative frozen section during resection of appendiceal mucinous lesions, as the pathologies of these lesions are most often complex and unlikely to be diagnosed based upon a single frozen section.

Ruptured lesions — As rupture of an appendiceal mucinous lesion may result in peritoneal dissemination of neoplastic cells, careful handling and resection of the lesion during surgery is paramount [42,48,49]. After the appendix is resected, it should be placed in a retrieval bag before being extracted. The operative note should specify whether the appendix is intact when it is placed into the bag as it can rupture during the extraction process. If a lesion has ruptured but the rupture is walled off, a right hemicolectomy may be performed if the surgeon deems it possible to remove the contained rupture with such a procedure. However, more extensive surgery aimed at clearing peritoneal mucinous disease (ie, formal cytoreductive surgery) should only be conducted by surgeons with extensive experience with peritoneal malignancies after the return of final pathology.

Thus, at nonspecialized centers, the initial surgery for a ruptured appendiceal mucinous lesion (that is localized) should be limited to an appendectomy/ileocecectomy/right hemicolectomy, careful inspection of the abdominal cavity with documentation, and biopsy of any suspicious peritoneal lesions. In addition, the abdomen and surgical wounds should be thoroughly cleaned by irrigation to minimize tumor cell implantation [46]. The patient with gross peritoneal spread of mucin (M1a/b according to American Joint Committee on Cancer [AJCC] staging) should then be referred to a specialized center for further evaluation and management depending on the final pathology.

Peritoneal washing with fluid cytology is not standard for appendiceal neoplasm, as there is no evidence that its result impacts treatment decisions or survival [50].

Disseminated peritoneal disease — Patients with radiographically apparent disseminated peritoneal disease do not require appendectomy for diagnosis. The diagnosis is usually established by percutaneous biopsy of one of the peritoneal lesions, with the resulting histologic grade being utilized to guide the initial therapeutic approach. The appendix will be resected at the time of definitive operation (ie, cytoreductive surgery), unless the patient presents with appendicitis that cannot be managed with antibiotics. (See "Epithelial tumors of the appendix", section on 'Stage IV (metastatic) disease'.)

Additional treatment based on pathology — Advanced-stage, ruptured, and/or metastatic appendiceal mucinous neoplasms may require additional surgical treatment beyond appendectomy. Candidacy for one or more such treatments depends on the final pathology of the appendix and any intraoperative findings of disseminated peritoneal disease. The surgical options include:

●Completion right hemicolectomy with lymphadenectomy

●Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) to treat peritoneal disease

This area of practice is not standardized and is actively evolving. Therefore, patients requiring additional surgical treatments should be presented at a multidisciplinary setting, such as a tumor board, and possibly referred to a center specializing in treating peritoneal surface malignancies. This subject is discussed elsewhere. (See "Epithelial tumors of the appendix", section on 'Aggressive cytoreduction and heated intraperitoneal chemotherapy'.)

Simple mucoceles and serrated polyps — Appendectomy is curative for patients with a non-neoplastic mucinous neoplasm, such as a simple mucocele or retention cyst, or a serrated polyp of the appendix. Such lesions are not associated with recurrence even if they rupture. Therefore, no additional treatment or surveillance is necessary.

LAMN and HAMN

Completely resected LAMN or HAMN — Patients with an LAMN or HAMN that is confined to the appendix, has not ruptured, and is completely resected by appendectomy do not require a completion right hemicolectomy.

The management of a microscopically positive margin after appendectomy for an unruptured LAMN is controversial, with some guidelines recommending reexcision by either cecectomy or ileocecectomy [51] while others recommend against a completion right colectomy [50]. The controversy is at least partially fueled by a lack of high-quality evidence; only limited retrospective data demonstrate that involvement of the appendectomy margin by neoplastic epithelium or acellular mucin does not predict recurrence of disease even without further surgery [52]. Given the lack of conclusive data, the authors of this topic favor either observation or cecectomy/ileocecectomy after discussion of risks and benefits, but not completion right colectomy.

Appendectomy alone is also sufficient treatment for nonperforated HAMNs, so long as the entire surgical specimen has been evaluated histologically to exclude the presence of associated invasive adenocarcinoma [50].

T4a LAMN or HAMN — Patients who do not have distant peritoneal mucinous disease but do have either cellular or acellular mucin on the serosal surface of the appendix or the mesoappendix are staged as T4a by the 2017 AJCC staging manual (table 3). Such patients are described as having "perforation with extra-appendiceal mucin or neoplastic cells" by the Chicago consensus LAMN management pathway [51].

For these patients, the risk for subsequent PMP is typically higher than without perforation. Actual rates of recurrence vary greatly between studies due to the small sample sizes. Most (but not all [53]) studies show that patients with just acellular mucin deposits on the visceral peritoneal surface of the appendix have a recurrence rate of 3 to 7 percent [54], while for those with cellular mucin outside of the appendix, the risk is higher and ranges from 33 to 78 percent [37,55-59].

There is no consensus on how best to manage patients with T4a LAMNs/HAMNs. Although the presence of cells outside of the appendix increases the risk for a recurrence, right hemicolectomy appears to offer no additional benefit over appendectomy alone [1,55]. At most institutions, such patients are followed with regular imaging and tumor markers for evidence of PMP. Once PMP is detected, CRS and HIPEC are then performed to treat PMP.

●At one center, expectant observation of 30 asymptomatic patients with low-grade tumor and no or limited disease on imaging resulted in five-year overall and progress-free survival of 95 and 82 percent, respectively; two patients required CRS for progression on imaging [60]. (See 'Post-treatment surveillance' below.)

●In another series of 30 patients with LAMN (70 percent perforated, 93 percent with extra-appendiceal mucin), six patients (20 percent) developed PMP at 12.4 months after appendectomy detected by serial imaging; four patients underwent CRS and HIPEC [61].

Another option for patients with T4a LAMN is diagnostic laparoscopy in 6 to 12 months, which may discover peritoneal disease earlier than imaging surveillance [62]. However, the impact on survival of this more aggressive approach has not been demonstrated, and given the added risk of an additional surgery, the authors favor serial radiographic imaging.  

Although some centers offer "preemptive" CRS/HIPEC for T4a LAMN [63,64], and the Chicago consensus lists both surveillance and intraperitoneal chemotherapy as options for such patients [51], the preemptive CRS/HIPEC approach is not supported by high-quality evidence, and we do not offer it.

Metastatic (M1a/b) LAMN or HAMN — Patients who are found to have peritoneal mucin (ie, M1a/b disease (table 3)) at the time of initial surgery should be referred to a center specializing in management of peritoneal surface malignancies for possible CRS/HIPEC. Although LAMN is a noninvasive neoplasm, peritoneal dissemination of mucinous disease predisposes patients to future recurrences and PMP. Given the predilection for peritoneal dissemination and indolent biologic behavior of LAMN with peritoneal involvement (stage IVA disease), CRS with HIPEC should be considered as the initial treatment modality for such stage IVA patients [65-67]. (See "Epithelial tumors of the appendix", section on 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)'.)

The American Society of Colon and Rectal Surgeons clinical practice guidelines (2019) suggested appendectomy with cytoreduction of the periappendiceal peritoneum for those with acellular mucin limited to the right lower quadrant, but also HIPEC for those with cellular mucin because of a higher risk of peritoneal involvement [50]. The extent of such "limited" CRS, however, was not defined.

The Chicago consensus LAMN management pathway subdivides M1a/b LAMN into three categories: acellular mucin (local only: right lower quadrant [RLQ]), acellular mucin (widespread), and cellular mucin [51]. CRS and HIPEC are unequivocally recommended for the latter two categories of patients. For those whose peritoneal diseases are limited to the right lower quadrant, it is possible that such limited disease has been resected at the time of appendectomy. In that case, both observation and intraperitoneal chemotherapy are options for further management. Patients with limited RLQ peritoneal disease that is not completely resected have the options of observation versus CRS/HIPEC [68]. We do not suggest performing more than appendectomy and peritoneal biopsy during the initial operation for mucinous appendiceal lesions. Formal CRS is best reserved for specialists after the final pathology is available [68]. (See 'Ruptured lesions' above.)

The treatment of PMP is beyond the scope of this discussion and is presented elsewhere. (See "Epithelial tumors of the appendix", section on 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)'.)

Mucinous adenocarcinoma of appendix

Completely resected adenocarcinoma — It is controversial whether patients with an unruptured, completely resected mucinous adenocarcinoma of the appendix (MACA) by an appendectomy should undergo a completion right hemicolectomy.

The proponents argue that an oncologic right hemicolectomy affords proper lymphadenectomy for staging purposes. The opponents argue that the use of right hemicolectomy for appendiceal cancer is largely based on studies of intestinal-type tumors [47,69] and that a number of studies have demonstrated extremely low rates of lymph node involvement for well-differentiated mucinous adenocarcinomas [70-72]. Furthermore, in a study evaluating appendiceal carcinomas from the Surveillance, Epidemiology, and End Results (SEER) database, no difference in survival was seen for those patients undergoing an appendectomy compared with a right hemicolectomy (p = 0.59) [72]. In a separate study of over 500 patients with low-grade mucinous appendiceal carcinoma from the SEER database, the overall rate of lymph node spread was 7.3 percent, but right hemicolectomy was not associated with any survival advantage over appendectomy [73]. Given these data, an acceptable approach following an appendectomy for a localized well-differentiated mucinous adenocarcinoma (assuming negative resection margins) is to do no further surgery.

Our approach is to observe patients with well-differentiated (G1) MACA and offer completion right hemicolectomy to the others (G2/G3). In a study of over 1000 patients with mucinous appendiceal neoplasms, the incidence of positive lymph nodes in patients with G1, G2, and G3 disease was 10, 23, and 41 percent, respectively [74].

For MACA, T4a means the tumor has invaded the visceral peritoneum, T4b means the tumor has invaded other organs or structures, and M1 means peritoneal (M1a/b) or extraperitoneal (M1c) disease (table 3). This is in contrast to LAMN, which technically does not invade, and for which T4a means mucin is present on the outside of the appendix due to rupture and M1 means that the mucin has spread further in the abdomen. For MACA, the T stage of the primary tumor (eg, T4a) does not factor into clinical decision making as it does for LAMN, but the histology does, and the T stage matters for prognosis. Instead, the pivotal decision point for MACA is the presence of peritoneal disease, extraperitoneal disease, or neither, as discussed below.

Metastatic adenocarcinoma — Patients with mucinous peritoneal carcinomatosis (M1a/b (table 3)) should be referred to a specialized center for possible CRS/HIPEC if their performance status would permit more advanced surgery [75]. The goal of CRS is eradication of gross disease, and when this goal is achieved, CRS is often combined with HIPEC for the potential additive benefit of reducing recurrence [76]. Patients with a well-differentiated (G1) MACA have better prognosis than those with a moderately (G2) or poorly differentiated MACA (G3) [70,71]. The treatment of peritoneal carcinomatosis also depends on whether complete cytoreduction is predicted and whether extraperitoneal disease is present, as detailed in the Chicago consensus appendiceal adenocarcinoma management pathway [51].

The use of CRS, systemic chemotherapy, and the role of heated intraperitoneal chemotherapy following CRS to treat MACA are discussed in a separate, dedicated topic. (See "Epithelial tumors of the appendix", section on 'Stage IV (metastatic) disease'.)

Exclusion of a concurrent malignancy — An association between appendiceal mucinous lesions and other tumors involving the gastrointestinal tract, ovary, endometrium, breast, and kidney has been reported [13,42,44,48,77-80]. A concurrent colorectal lesion can be found in approximately 20 percent of patients with appendiceal mucinous lesions. Colonoscopy should therefore be performed pre- or postoperatively. Similarly, careful examination of the ovaries is imperative at the time of surgery [81,82].

POST-TREATMENT SURVEILLANCE — Post-treatment surveillance, which typically constitutes cross-sectional imaging (abdominal and pelvic CT or MRI) and tumor markers, should be tailored to recurrence risk based on pathology and the completeness of surgical resection. Given the lack of data addressing post-treatment surveillance, the recommended intervals for imaging are based on expert opinions [50].

Simple mucoceles or serrated polyps — Such non-neoplastic lesions are not associated with recurrence even if they rupture. Therefore, no surveillance is necessary following appendectomy.

Completely resected LAMN — If a nonperforated low-grade appendiceal mucinous neoplasm (LAMN) of the appendix is removed without fracturing the tumor or spilling mucin, and there are no cells or mucin outside of the appendix on the pathology specimen, there is in theory no risk of recurrence, and specific follow-up or surveillance is not needed [83]. However, the practical concern with a nonperforated LAMN relates to the rare but possible risk of prior rupture that has healed and is thus not appreciated at histopathologic assessment. This represents the reason why Tis(LAMN) is restricted to only those lesions that are confined by the muscularis propria and thus should not have this risk.

T4a LAMN — For patients with either acellular or cellular mucin outside of the appendix (T4a) or a ruptured tumor, it is only intuitive that regularly scheduled imaging/tumor marker follow-up permits earlier detection of recurrent disease. In one report, pseudomyxoma peritonei (PMP) was detected much sooner in patients who were followed up regularly (median 14 versus 72 months [58]). Earlier detection presumably can lead to earlier treatment and better outcomes. Unfortunately, there is no consensus regarding the adequate follow-up schedule and duration after resection of an appendiceal mucinous neoplasm. Recommendations vary from imaging every six months [6] to two years [58].

We typically perform follow-up abdominal CT scan yearly for four years, then every two years until 10 years. Given the requirement for ongoing surveillance, young patients may undergo MRI (with diffusion weighted imaging) instead of CT scan to limit cumulative radiation exposure. Other authors perform diagnostic laparoscopy if imaging does not show recurrent disease after 12 months [62]. Laparoscopic inspection is more invasive but more sensitive than imaging, which may permit earlier detection of peritoneal recurrent disease. (See 'T4a LAMN or HAMN' above.)

Metastatic (M1a/b) LAMN or HAMN — Such patients with good performance status should be referred to specialized centers for consideration of cytoreductive surgery (CRS). Post-treatment surveillance is often dictated by individual centers' practices. As an example, the American Society of Colon and Rectal Surgeons clinical practice guidelines (2019) suggested baseline imaging at two months after cytoreductive surgery, then annually for ≥5 years for low-grade peritoneal disease [50].

Adenocarcinoma — Surveillance following treatment of a mucinous adenocarcinoma should be performed more frequently depending on grade and completeness of surgery. This is discussed elsewhere. (See "Epithelial tumors of the appendix", section on 'Adenocarcinoma'.)

PROGNOSIS — The clinical course and prognosis of appendiceal mucinous lesions are closely associated with their histology and presence and extent of peritoneal spread [70,71,84,85]. Simple retention cysts (mucoceles) and serrated polyps are benign lesions; survival is excellent (91 to 100 percent) after standard appendectomy [7,48,86]. Neoplastic lesions, such as low-grade appendiceal mucinous neoplasms (LAMNs) and high-grade appendiceal mucinous neoplasms (HAMNs), have excellent prognosis with complete resection, whereas mucinous adenocarcinomas have a more guarded prognosis dependent upon histologic grade and stage. Histopathologic features such as the presence of extra-appendiceal neoplastic epithelium, high-grade cytology, architectural complexity, and invasion are important predictors of recurrence [56].

LAMN — LAMNs confined to the appendix (Tis LAMN) rarely recur [56,84]. By contrast, overall three-year and five-year survival rates for LAMNs with extra-appendiceal spread are 91 to 100 percent and 79 to 86 percent, respectively [84]. The prognostic impact of acellular mucin outside the appendix (T4a disease) is less well determined, with risk of recurrence varying from 4.8 to 20.4 percent. In one study of 41 patients with LAMNs in which 46 percent had extra-appendiceal acellular mucin, the five-year relapse-free survival after complete resection was 95.2 percent with a median follow-up time of 58 months [87]. In a second study of 98 patients (median follow-up 2.6 years) with LAMNs in which 94 percent had extra-appendiceal acellular mucin, the five-year overall survival was 86 percent, with 20 patients demonstrating disease recurrence, of whom 5 died from disease [88].

HAMN — HAMNs are LAMNs in which there exists high-grade cytologic atypia. By definition, HAMNs are histologically grade 1. The prognosis of LAMNs and HAMNs appears similar, though limited data suggest that HAMNs may have a higher risk of recurrence than LAMNs [89,90].  

Adenocarcinoma — On the other hand, prognosis is worse for mucinous adenocarcinomas. In a series derived from the National Cancer Database (NCDB), the five-year overall survival for mucinous adenocarcinomas was 53.6 percent [71]. However, outcomes vary by stage and grade (figure 1), with five-year overall survival rates for localized stages I to III of 74.9, 63.2, and 51.1 percent for well-, moderately, and poorly differentiated tumors, respectively. For stage IV disease, the five-year overall survival rates for well-, moderately, and poorly differentiated tumors were 56.7, 31.5, and 11.3 percent, respectively. Similar findings are seen from the Surveillance, Epidemiology, and End Results (SEER) database with five-year cancer-specific survival for mucinous adenocarcinoma of well-, moderately, and poorly differentiated histology of 82, 64, and 50 percent for stages I to III, respectively and 71, 51, and 0 percent for stage IV, respectively [70]. However, appendiceal mucinous adenocarcinomas that spread to the peritoneum have a much better prognosis than do nonmucinous tumors [70,76]. (See "Epithelial tumors of the appendix", section on 'Staging system and prognosis'.)

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from delaying cancer treatment versus harm from COVID-19, minimizing the number of clinic and hospital visits to reduce exposure whenever possible, mitigating the negative impacts of social distancing on delivery of care, and appropriately and fairly allocating limited healthcare resources. Specific guidance for decision-making for cancer surgery on a disease-by-disease basis is available from the American College of Surgeons, from the Society for Surgical Oncology, and from others. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Appendiceal neoplasms".)

SUMMARY AND RECOMMENDATIONS

●Terminologies – Appendiceal mucinous lesions are a rare group of lesions characterized by a distended, mucus-filled or ruptured appendix. They may be non-neoplastic (simple mucoceles/retention cysts) or neoplastic lesions (serrated polyps, low-grade appendiceal mucinous neoplasms [LAMNs], high-grade appendiceal mucinous neoplasms [HAMNs], or mucinous adenocarcinomas of the appendix [MACAs]). (See 'Introduction and terminology' above.)

●Clinical features – Appendiceal mucinous lesions are usually discovered incidentally during radiologic or endoscopic evaluation for unrelated complaints or in pathologic specimens after an appendectomy. Patients are often asymptomatic or have nonspecific symptoms (eg, right lower quadrant abdominal pain). (See 'Clinical features' above.)

●Diagnostic evaluation – For patients with an incidentally detected appendiceal mucinous lesion on colonoscopy, an abdominal CT scan should be performed to confirm the diagnosis and exclude other etiologies. Tumor markers, including carcinoembryonic antigen (CEA), CA 19-9, and CA-125, should be measured upon diagnosis of an appendiceal mucinous neoplasm and routinely repeated to monitor disease progression. (See 'Laboratory findings' above and 'Imaging' above.)

●Initial treatment – Initial treatment of an appendiceal mucinous lesions is as follows:

•For most localized appendiceal mucinous lesions without evidence of peritoneal disease, we suggest initially performing a standard appendectomy, rather than more extensive procedures (Grade 2C). Either an open or laparoscopic approach can be utilized depending on surgeon preference. If the base of the appendix is involved in the disease process so that a clear margin cannot be achieved by stapling, a more extensive resection (eg, partial cecectomy, ileocecectomy, or right colectomy) may be performed. This is usually determined intraoperatively. Biopsy of an appendiceal mucinous lesion should be avoided given the risk of peritoneal spread and the limitations of cytological diagnosis. (See 'Localized disease' above.)

•As rupture of an appendiceal mucinous lesion may result in peritoneal dissemination of mucin and neoplastic cells, careful resection and handling of the specimen is paramount. More extensive surgery aimed at clearing peritoneal mucinous disease (ie, formal cytoreductive surgery) should be reserved for surgeons with extensive experience with peritoneal surface malignancies after review of the final pathology. (See 'Ruptured lesions' above.)

•Appendiceal mucinous lesions that present with peritoneal dissemination (radiographically) are usually diagnosed with percutaneous biopsy of one of the peritoneal lesions. In the absence of appendicitis, appendectomy can usually wait until the time of definitive cytoreductive surgery. (See 'Disseminated peritoneal disease' above.)

●Additional treatment – Additional treatment and surveillance after appendectomy is based on pathology. Our approach is as follows:

•For patients with a non-neoplastic mucinous abnormality (eg, simple mucocele or retention cyst or serrated polyp of the appendix), no additional treatment or surveillance is necessary. (See 'Simple mucoceles and serrated polyps' above.)

•For patients with LAMN or HAMN that is confined to the appendix, has not ruptured, and is completely resected, no additional treatment or surveillance is needed. Patients who have a microscopically positive proximal margin for LAMN after appendectomy may either be observed or undergo re-excision by a cecectomy or ileocecectomy. (See 'Completely resected LAMN or HAMN' above and 'Completely resected LAMN' above.)

•For LAMN or HAMN with periappendiceal mucin with or without cells (T4a LAMN by American Joint Committee on Cancer [AJCC] staging), we suggest not performing a completion right colectomy after appendectomy (Grade 2C). This includes patients who have margin involvement by neoplastic epithelium or acellular mucin after appendectomy. (See 'Completely resected LAMN or HAMN' above.)

•For patients with a well-differentiated (G1) MACA that is completely resected, we suggest not performing a completion right colectomy after appendectomy (Grade 2C). Studies have demonstrated extremely low rates of lymph node involvement for well-differentiated MACA. (See 'Completely resected adenocarcinoma' above and "Epithelial tumors of the appendix", section on 'Adenocarcinoma'.)

•For patients with a moderately (G2) or poorly (G3) differentiated MACA, we suggest performing a completion right colectomy after appendectomy (Grade 2C). A right colectomy permits harvesting of regional lymph nodes to complete the staging workup. (See 'Completely resected adenocarcinoma' above.)

•There is no consensus on the optimal subsequent therapy in patients with T4a LAMNs or HAMNs. For these patients, the risk of pseudomyxoma peritonei (PMP) is variable. At most institutions, such patients are followed with regular imaging and tumor markers for evidence of PMP. Once PMP is detected, patients should be referred to a center specializing in management of peritoneal surface malignancies for possible cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). (See 'T4a LAMN or HAMN' above and 'T4a LAMN' above and 'Adenocarcinoma' above and "Epithelial tumors of the appendix", section on 'Aggressive cytoreduction and heated intraperitoneal chemotherapy'.)

•Patients who have peritoneal mucin (ie, M1a/b disease) with LAMN or HAMN at the time of initial surgery are at risk for future recurrences and PMP. Such patients should be referred to a specialized center for management of peritoneal surface malignancies for possible CRS and HIPEC. The surveillance schedule following cytoreductive surgery varies according to individual centers' practice. (See 'Metastatic (M1a/b) LAMN or HAMN' above.)

•Patients with metastatic MACA, especially metastatic higher-grade (moderately or poorly differentiated) MACA, are less likely to have PMP and more likely to have peritoneal carcinomatosis and other distant metastases. Depending on the patient's performance status, whether complete cytoreduction is predicted, and whether extraperitoneal disease is present, such patients may be treated with CRS/HIPEC, systemic chemotherapy, or palliation. This is further discussed in another topic. (See 'Metastatic adenocarcinoma' above and "Epithelial tumors of the appendix", section on 'Stage IV (metastatic) disease'.)

●Exclude a concurrent malignancy – Colorectal cancer and other tumors involving the gastrointestinal tract, endometrium, ovary, breast, and kidney have been reported in patients with appendiceal mucinous lesions. Careful examination of the ovaries should be performed at the time of surgery. Colorectal cancer should also be excluded by pre- or postoperative colonoscopy. (See 'Colonoscopy' above and 'Exclusion of a concurrent malignancy' above.)

●Prognosis – Survival is excellent after standard appendectomy for non-neoplastic appendiceal mucinous lesions. Completely resected LAMNs rarely recur. Patients with only acellular mucin deposits on the visceral peritoneal surface of the appendix have a recurrence rate of 3 to 7 percent, while for those with cellular mucin outside of the appendix, the risk is higher and ranges from 33 to 78 percent. The prognosis of MACA is generally worse but is dependent upon the stage and grade of the tumor (figure 1). (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Louis-Michel Wong Kee Song, MD, FRCP(C), and Norman E Marcon, MD, FRCP(C), who contributed to an earlier version of this topic review.