Epithelial tumors of the appendix

INTRODUCTION — Appendiceal neoplasms comprise several histologic types, which are broadly characterized as the following:

●Epithelial neoplasms – These include invasive adenocarcinomas; low-grade appendiceal mucinous neoplasms (LAMNs) and high-grade appendiceal mucinous neoplasms (HAMN), which by definition, do not invade the lamina propria; and goblet cell adenocarcinomas (GCAs; previously called goblet cell carcinoids or adenocarcinoids) [1]. (See "Appendiceal mucinous lesions".)

●Neuroendocrine neoplasms – These include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) [2]. MiNEN typically show a combination of neuroendocrine carcinoma and adenocarcinoma, and these tumors are treated like high-grade neuroendocrine carcinomas. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms" and "Well-differentiated neuroendocrine tumors of the appendix".)

This topic will focus on the clinical presentation, staging workup, and treatment of epithelial neoplasms arising in the appendix, including GCAs. Evaluation and management of well-differentiated neuroendocrine appendiceal neoplasms and an overview of mucinous lesions arising in the appendix (including benign mucoceles) are presented separately. (See "Well-differentiated neuroendocrine tumors of the appendix" and "Appendiceal mucinous lesions".)

HISTOLOGIC SPECTRUM OF EPITHELIAL LESIONS — The literature regarding the classification of epithelial lesions of the appendix is confusing, particularly for mucinous lesions [3,4]. Mucinous appendiceal lesions are classified histologically as either nonneoplastic (mucoceles) or neoplastic epithelial lesions, which are subcategorized by histologic subtypes (serrated polyps, low-grade appendiceal mucinous neoplasms [LAMNs], high-grade appendiceal mucinous neoplasms [HAMNs], and invasive adenocarcinomas, which may be mucinous or non-mucinous). (See 'Histology and biologic behavior' below and "Appendiceal mucinous lesions", section on 'Pathology'.)

Goblet cell adenocarcinomas (GCAs) are classified, staged, and treated as appendiceal adenocarcinomas [1,5,6]. Prognosis is somewhat worse than with a malignant neuroendocrine tumor, but overall, it is better than with appendiceal adenocarcinoma (table 1) [7,8]. (See 'Goblet cell adenocarcinoma' below.)

Peritoneal disease spread and pseudomyxoma peritonei — The term "pseudomyxoma peritonei" (PMP) refers to a clinical syndrome characterized by diffuse mucinous peritoneal involvement, often in association with a mucinous appendiceal lesion. PMP is not a histologically based term, and it is not used in the staging or histologic classification of appendiceal neoplasms [6].

Definition and evolution of terminology — The term PMP was originally applied to intraperitoneal mucinous spread originating from a ruptured cystadenoma (now called a LAMN) of the appendix. As the lesion grows and occludes the lumen, mucus accumulates and the appendix ruptures. The peritoneum is then seeded with mucus-producing cells, which continue to proliferate and produce mucus. The progressive accumulation of copious amounts of mucinous fluid gradually fills the peritoneal cavity, resulting in the characteristic "jelly belly" [9]. Inevitably, this condition progresses to intestinal obstruction, which is fatal without treatment. (See 'Treatment' below.)

Over the years, the term PMP began to be used more generally by some authors and clinicians to signify any peritoneal dissemination of a wide variety of mucin-producing invasive adenocarcinomas of the appendix, large and small bowel, lung, breast, pancreas, stomach, bile ducts, gallbladder, and fallopian tubes/ovary [10,11].

However, in our view and that of others, the term PMP should be limited to a pathologically and prognostically homogeneous group of cases characterized by histologically benign peritoneal mucin that is associated with a ruptured LAMN or, less commonly, a ruptured benign appendiceal mucocele [9,10,12]. The presence of intraperitoneal acellular mucin, without identifiable tumor cells in the disseminated peritoneal mucinous deposits, satisfies the definition of stage M1a (peritoneal) spread (table 2).

These cases (spread of intraperitoneal mucin from a ruptured LAMN or, less commonly, a benign mucocele) have been grouped using the descriptive term "disseminated peritoneal adenomucinosis" (DPAM) [13], as defined by the presence of abundant peritoneal extracellular mucin containing scant mucinous epithelium with little cytologic atypia or mitotic activity, with or without an associated appendiceal mucinous lesion. The term DPAM is in contrast to the term peritoneal mucinous carcinomatosis, which denotes the presence of peritoneal lesions that are composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma, with or without an associated primary mucinous adenocarcinoma. Peritoneal mucinous deposits from an appendiceal neoplasm containing tumor cells are staged as M1b in the American Joint Committee on Cancer (AJCC) staging classification (table 2). (See 'Staging workup' below.)

More recently, the Peritoneal Surface Oncology Group International (PSOGI) pathologic classification for PMP has introduced somewhat different terminology to classify PMP for the purposes of treatment selection: low-grade and acellular mucin PMP (which correspond to a ruptured LAMN and mucocele, respectively), and high-grade and signet ring cell PMP (which would correspond to peritoneal mucinous carcinomatosis) (table 3) [14,15].

Many pathologists have yet to incorporate this new terminology into their reports, and we prefer to categorize patients as having DPAM and peritoneal mucinous carcinomatosis for the purposes of treatment selection.

Although our narrow definition of PMP (as DPAM histology) creates a more homogeneous entity for the purpose of evaluating treatment efficacy, it makes comparison of published results difficult as these definitions have not been universally applied and accepted. Although some consider that disseminated mucin-producing adenocarcinomas of the appendix (peritoneal mucinous carcinomatosis) can be characterized as PMP, these types of peritoneal mucinous tumors have a worse natural history compared with the more indolent DPAM [16,17]. However, there is a spectrum of clinical behavior, with some entities having intermediate features. The prognostic differences between these histologic subgroups have been addressed in the following reports:

●In one series, the age-adjusted five-year survival for patients with DPAM was 84 percent, compared with 7 percent for those with peritoneal mucinous carcinomatosis and 38 percent for those with intermediate features [13].

●In another retrospective multicenter series of 2298 patients presenting with PMP and undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), the five-year survival rate for patients with DPAM was 81 percent, compared with 59 percent for those with peritoneal mucinous carcinomatosis and 78 percent for those with intermediate features [18].

●In another report of 265 patients with isolated peritoneal spread from an appendiceal malignancy who uniformly underwent CRS and HIPEC, five-year survival was significantly better for the acellular mucin PMP and low-grade PMP subgroups (according to PSOGI terminology [14]) than for the high-grade and signet ring cell cancer subtypes (five-year overall survival 90, 63, 40, and 0 percent, respectively) [15].

The clinical presentation, radiographic evaluation, and treatment of PMP (DPAM histology) and the treatment of isolated intraperitoneal dissemination of mucinous peritoneal carcinomatosis from an appendiceal adenocarcinoma (including signet ring cell cancers) or GCA are discussed below. (See 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)' below and 'Cytoreductive surgery and heated intraperitoneal chemotherapy' below and 'Recurrent or metastatic disease' below.)

EPIDEMIOLOGY OF APPENDIX LESIONS — Neoplasms of the appendix are rare. Data from the Surveillance, Epidemiology, and End Results (SEER) database and other data sources suggest that the incidence of appendiceal tumors was approximately 0.12 to 2.6 per million people per year in the last century [19-22], but it rose to as high as 0.97 per 100,000 population in the early 2000s; the reason for the increase is not clear [23]. Appendiceal malignancies account for only approximately 0.5 of 1 percent of intestinal neoplasms [24].

Most mucinous appendiceal lesions are diagnosed incidentally at the time of appendectomy. A malignancy is found in approximately 1 percent of appendectomy specimens [19,25]. The distribution of tumor types within the appendix appears to be changing over time:

●In some older reports, well-differentiated neuroendocrine tumors (NETs) accounted for over 50 percent of neoplasms arising in the appendix (table 4) [19,26].

●More recently, mucinous epithelial lesions seem to be more common:

•In a large series of appendiceal tumors derived from the SEER database of the National Cancer Institute (NCI) between 1973 to 2003, the most frequent histology was mucinous adenocarcinoma, followed by intestinal-type adenocarcinoma; NETs ("malignant carcinoid") comprised only 11 percent (table 1) [7]. The difference in natural history of these different histologies is illustrated by their differing five-year disease-specific survival rates.

•In another large contemporary surgical series, well-differentiated NETs accounted for 18 percent of the unexpected histopathologic findings in appendectomy specimens; low-grade mucinous neoplasms and simple mucoceles (also termed retention cysts) accounted for nearly one-half of the cases [25].

ADENOCARCINOMA

Clinical presentation — The majority of appendiceal adenocarcinomas are diagnosed in appendectomy specimens. In contrast to other appendiceal neoplasms, which are often asymptomatic, the majority of patients with adenocarcinomas present with a picture of acute appendicitis [27]. Patients may also present with ascites, an abdominal mass, or generalized abdominal pain. In less than 20 percent of cases, the cancer is found incidentally at surgery for other reasons [28].

Histology and biologic behavior — Appendiceal adenocarcinomas fall into one of three separate histologic types. The most common mucinous type produces abundant mucin, the less common intestinal or colonic type closely mimics adenocarcinomas found in the colon, and the least common, signet ring cell adenocarcinoma, is quite virulent and associated with a poor prognosis (table 1) [7].

Intestinal-type tumors typically manifest as a focal mass without mucocele formation. Although they have a poorer prognosis in many series [29-31], others suggest that this is the case only if the disease is locoregionally advanced at presentation [22]. Some series report that intestinal-type tumors have a higher frequency of nodal metastases [32], others suggest that the incidence of nodal metastases is not significantly different (table 5) [22], and still other reports suggest a higher frequency of nodal metastases with mucinous adenocarcinomas [27].

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 pseudomyxoma peritonei (PMP) rather than other presentations of distant metastatic disease [33]. (See 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)' below.)

In general, appendiceal adenocarcinomas possess a nearly identical phenotype and immunophenotype to those of conventional colonic adenocarcinomas [34,35]. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Appendix cancer' and "Pathology and prognostic determinants of colorectal cancer", section on 'Immunohistochemistry'.)

Staging workup — Most adenocarcinomas are diagnosed postoperatively, and thus, staging procedures mostly concern postoperative rather than preoperative staging, unless there are suspected or evidenced distant metastases at the time of presentation.

There are no specific guidelines from either the National Comprehensive Cancer Network (NCCN) or the European Society for Medical Oncology (ESMO) as to the appropriate staging workup for an appendiceal adenocarcinoma. Consistent with guidelines from the American Society of Colon and Rectal Surgeons (ASCRS) [36], we perform the same staging workup as for colon cancer, including computed tomography (CT) scan of the chest, abdomen, and pelvis, and a full colonoscopy to exclude synchronous malignancies. Thirteen to 42 percent of patients with a primary epithelial appendiceal lesion have concurrent colorectal neoplasia [37,38]. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical staging evaluation'.)

Utility of tumor markers — A variety of serum markers have been associated with gastrointestinal tract tumors, particularly carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and cancer antigen 125 (CA-125). For example, in the case of colorectal cancer, CEA is useful for prognostication at the time of initial diagnosis and for post-treatment surveillance as a means of detecting disease recurrence in those who have undergone potentially curative resection. In addition, when levels of serum tumor markers are elevated, serial assay is useful for monitoring response to therapy. In general, tumor markers are not useful diagnostically. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Role of tumor markers' and "Post-treatment surveillance after colorectal cancer treatment", section on 'Carcinoembryonic antigen' and "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Assessing treatment response' and "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Tumor markers' and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

There is a paucity of information on the utility of serum tumor markers in appendiceal malignancies relative to the more common gastrointestinal tract tumors. However, the available data suggest that tumor markers (most commonly CEA, CA 19-9, and CA-125) are elevated in the majority of patients with advanced appendiceal mucinous tumors and adenocarcinomas, and that in this setting, levels correlate with treatment outcomes [39-43].

If initially elevated, serial assay of tumor markers such as CEA, CA 19-9, or CA-125 may be useful in the post-treatment follow-up of patients with advanced disease; in one report, elevations in tumor markers predated radiographic evidence of disease recurrence by up to nine months following cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) [39].

There are no definitive data for use of tumor markers in surveillance after curative-intent surgery for appendiceal adenocarcinomas; however, extrapolation of data from colorectal cancer is reasonable in this setting. (See "Post-treatment surveillance after colorectal cancer treatment", section on 'Carcinoembryonic antigen'.)

Staging system and prognosis — Compared with the earlier 2010 edition, the most recent Tumor, Node, Metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC; eighth edition, 2017) contains many changes to the T stage definitions (including a category for low-grade appendiceal mucinous neoplasms [LAMNs] that invade or push into the muscularis propria) and to the N stage definitions (which now harmonize with the categories for colorectal cancer), adopts a three-tiered grading system for mucinous grading, revises stage IVa disease to include intraperitoneal acellular mucin as M1a disease, and classifies peritoneal mucinous deposits from an appendiceal neoplasm containing tumor cells as M1b disease (table 2) [6]. (See "Pathology and prognostic determinants of colorectal cancer", section on 'Appendix cancer'.)

The natural history and prognosis of appendiceal adenocarcinomas differ from those of adenocarcinomas arising in other large bowel sites (table 6) [44]. Five-year survival rates for 931 cases of appendiceal carcinoma diagnosed between 1991 and 2000 and stratified according to stage (using the 2010 version) are presented in the table (figure 1) [45]. Perforated tumors do not seem to be associated with a higher recurrence risk, while the presence of nodal metastases is a strong indicator of recurrence risk (78 versus 4 percent at five years in one series [46]).

However, prognosis also varies according to histologic subtype (table 1) [7], a distinction that is not evident in most series that stratify according to disease stage.

Treatment

Stage I to III disease — Considerations for local treatment for patients with stage I to III (table 2) appendiceal adenocarcinoma include a decision as to optimal local surgery and, for stage II and III disease, whether or not adjuvant therapy should be recommended.

Local treatment — The majority of appendiceal adenocarcinomas are diagnosed in appendectomy specimens. For most patients, we suggest right hemicolectomy rather than simple appendectomy alone. This recommendation is consistent with guidelines from the ASCRS [36]. Others disagree, advocating simple appendectomy alone for all unruptured, completely resected mucinous adenocarcinomas that are well differentiated, given their minimal risk for nodal involvement and the propensity for peritoneal dissemination compared with non-mucinous adenocarcinomas. (See "Appendiceal mucinous lesions", section on 'Completely resected adenocarcinoma'.)

For all patients, we suggest not pursuing prophylactic oophorectomy in females with apparently local or locoregional appendiceal adenocarcinomas if the ovaries are grossly normal. (See 'Ruptured tumors and the role of routine oophorectomy' below.)

The optimal treatment for most non-metastatic, unruptured, completely resected appendiceal adenocarcinomas that are found incidentally in an appendectomy specimen is debated. Several retrospective series that are uncontrolled for stage suggest that survival is better with hemicolectomy as compared with simple appendectomy [24,27-30,47]. Given the low likelihood of nodal metastases, some authors and consensus groups advocate a simple appendectomy for well-differentiated adenocarcinomas that invade no deeper than the submucosa [48,49], and advocate a hemicolectomy for more deeply invasive (or higher-grade) tumors. Others, citing the high risk of lymph node positivity in appendiceal adenocarcinomas, even those that are small in size, advocate a right hemicolectomy for all cases [50]. Consensus-based guidelines from the ASCRS advocate right hemicolectomy for all appendiceal adenocarcinomas [36].

The role of complete hemicolectomy is especially debated in patients with completely resected, unruptured, well-differentiated mucinous adenocarcinomas. Proponents argue that an oncologic right hemicolectomy affords proper lymphadenectomy for staging purposes. Opponents argue that the use of right hemicolectomy for appendiceal cancer is largely based on studies of intestinal-type tumors [24], and that a number of studies have demonstrated extremely low rates of lymph node involvement for well-differentiated (and in some cases, moderately well-differentiated [51]) mucinous adenocarcinomas [48,52-54]. 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 [52]. Given these data, we consider that an acceptable approach following an appendectomy for a localized, well-differentiated mucinous adenocarcinoma (assuming negative resection margins) invading no deeper than the submucosa is to do nothing further. (See "Appendiceal mucinous lesions", section on 'Completely resected adenocarcinoma'.)

Ruptured tumors and the role of routine oophorectomy — At nonspecialized centers, initial surgery for an apparently ruptured appendiceal mucinous lesion should be limited to appendectomy or right hemicolectomy (if the rupture is contained by the right colon and mesentery), peritoneal washing with fluid cytology, 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. More extensive surgery aimed at clearing peritoneal mucinous disease (ie, formal CRS) should only be conducted by surgeons with extensive experience with peritoneal malignancies after the return of final pathology. (See "Appendiceal mucinous lesions", section on 'Ruptured lesions' and 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)' below and 'Cytoreductive surgery and heated intraperitoneal chemotherapy' below.)

Routine oophorectomy has been proposed at the time of colectomy because the ovaries are a common organ for metastases [29,30,47,55]. Resection of ovaries that are involved with metastatic spread is clearly beneficial [56]. As an example, in the Mayo series, females who underwent resection of ovarian metastases had a 31 percent five-year survival rate [29]. However, no series has shown an improvement in survival with prophylactic oophorectomy, and this approach has not been widely adopted. Routine oophorectomy should only be considered as part of the cytoreduction procedure in females with peritoneal disease, not in other (prophylactic) settings [36].

Adjuvant therapies — For patients with resected node-positive appendiceal adenocarcinoma, we suggest a three- to six-month course of adjuvant oxaliplatin-containing chemotherapy, extrapolating from data showing the efficacy of adjuvant fluorouracil (FU) and oxaliplatin-based chemotherapy for node-positive colon cancer. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

●Chemotherapy – A role for adjuvant chemotherapy for adenocarcinoma of the appendix has not been definitively established. The rarity of this disease has precluded the performance of randomized studies, and few institutions see sufficient numbers of patients to report series of homogeneously treated patients. There are no published recommendations for or against from expert groups.

The best available data come from an analysis of 11,871 patients with appendiceal adenocarcinoma reported to the National Cancer Database (NCDB) between 1985 and 2006 [53]. Overall, 50 percent of the patients had mucinous adenocarcinomas, 40 percent had non-mucinous tumors, and 10 percent had signet ring cell cancers. In multivariate analysis, among the patients with stage I to III disease (tumor >2 cm, directly invading adjacent organs, or node positive), the use of adjuvant chemotherapy was associated with a significant survival benefit, both in those with mucinous (hazard ratio [HR] for death 0.79, 95% CI 0.69-0.90) and non-mucinous tumors (HR 0.84, 95% CI 0.75-0.95). The survival benefit was observed for both stage II and III tumors.

Despite the lack of robust data, many medical oncologists extrapolate from data showing the efficacy of adjuvant FU and oxaliplatin-based chemotherapy for node-positive colon cancer, particularly for patients with intestinal-type (non-mucinous) appendiceal adenocarcinomas. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

For patients with stage II disease (table 2), considerations for offering or recommending adjuvant therapy are similar to those in stage II colon cancer: higher risk features (T4, perforation, inadequate nodal sampling, lymphovascular or perineural invasion, or poorly differentiated histology) would lead us to favor adjuvant therapy, while good-risk disease (T3, N0, adequate nodal sampling, well- or moderately differentiated histology) should lead to a discussion that covers the lack of definitive data for adjuvant therapy, the risks of therapy, and the likelihood of a small, if any, benefit over surgery alone. (See "Adjuvant therapy for resected stage II colon cancer", section on 'Higher-risk stage II disease'.)

The optimal duration of chemotherapy depends on the regimen and disease stage. If a fluoropyrimidine alone is administered, six months of treatment is standard. For an oxaliplatin-based regimen, a longer duration (ie, six versus three months) provides little incremental benefit, especially for stage III disease, and clearly increases the risk of treatment-related neuropathy. Decision making must be individualized. These issues are addressed in detail elsewhere. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Duration of therapy' and "Adjuvant therapy for resected stage II colon cancer", section on 'Duration of chemotherapy'.)

●Radiation therapy – The benefit of adjuvant radiation therapy (RT) is also uncertain; as with chemotherapy, randomized trials have not been conducted. One small retrospective study suggested that postoperative external beam RT improves local control and survival for patients with locally advanced but non-metastatic disease (14 of 15 had clinical bowel perforation, and seven [47 percent] had microscopic residual disease after surgery) [57]. Five of 10 patients failed locally after surgery alone; by contrast, only one of five failed locally after postoperative RT.

Stage IV (metastatic) disease

Systemic chemotherapy — The utility of systemic chemotherapy for metastatic appendiceal adenocarcinoma has not been systematically studied. As a result, much is unknown. Treatment commonly incorporates agents and regimens that are used for advanced colorectal cancer, such as FOLFOX (oxaliplatin plus leucovorin and infusional FU) with or without bevacizumab, CAPOX (capecitabine plus oxaliplatin), FOLFIRI (irinotecan plus leucovorin and infusional FU), and single-agent fluoropyrimidines. There are no comparative data, and the choice of regimen is empiric. Given the low potential for well-differentiated mucinous appendiceal adenocarcinomas to respond to conventional cytotoxic chemotherapy, at many institutions, these patients are referred for CRS/HIPEC if they are otherwise appropriate candidates. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" and 'Cytoreductive surgery and heated intraperitoneal chemotherapy' below.)

●Cytotoxic chemotherapy – Historically, appendiceal adenocarcinomas (particularly mucinous adenocarcinomas) have been considered refractory to intravenous FU-based chemotherapy, although the available data are conflicting:

•A report from MD Anderson Cancer Center included 54 patients with surgically unresectable neoplasms of appendiceal origin who were not candidates for CRS/HIPEC and who received at least two courses of chemotherapy [58]. Several different regimens were used, although the majority (84 percent) received capecitabine or FU, with or without a platinum drug. Clinical benefit was achieved in 30 patients (55 percent), with a median progression-free survival duration of 7.6 months. There were two complete responses, 11 partial responses (objective response rate 24 percent), and 17 cases of prolonged stable disease (32 percent). Median overall survival was 55 months, reflective of the predominance of well-differentiated tumors in this cohort.

•Benefit for combination chemotherapy was also shown in a retrospective analysis of 78 patients with metastatic poorly differentiated or signet ring appendiceal adenocarcinoma who were treated with a variety of regimens [59]. The overall response rate was approximately 45 percent, and median progression-free and overall survival durations were 6.9 and 20.4 months, respectively.

•The only published phase II trial in advanced unresectable peritoneal carcinomatosis of appendiceal origin suggested activity for capecitabine combined with mitomycin [60]. After six months, 3 of the 23 patients whose disease was progressive at baseline had a sustained reduction in the volume of mucus, one of whom also had a reduction in the solid component of the disease; nine others (41 percent) had stabilization of tumor growth. Two patients with initially unresectable disease were able to undergo potentially curative CRS after chemotherapy. Thus, of 39 assessable patients, 15 (38 percent) appeared to benefit from treatment. Overall, therapy was reasonably well tolerated. Only 6 percent of cycles were complicated by grade 3 or 4 toxicity (all hand-foot syndrome), and cumulative hematologic toxicity related to mitomycin was not observed. This regimen has fallen out of favor given other options such as FOLFOX or FOLFIRI.

•Benefit for systemic chemotherapy was also supported by a retrospective review of 112 patients who received systemic chemotherapy for advanced recurrent or metastatic appendiceal carcinoma at eight NCCN member institutions [61]. The most commonly used regimens were FOLFOX with (n = 39) or without bevacizumab (n = 37), FOLFIRI (n = 15), and a single-agent fluoropyrimidine. Among the 99 patients evaluable for best response, the objective response rate was 39 percent, and stable disease was achieved by an additional 36 percent. Median progression-free and overall survival durations were 1.2 and 2.1 years, respectively. Patients with non-mucinous or high-grade tumors had worse progression-free and overall survival.

●Benefit of biologic agents

•The role of therapies targeting the epidermal growth factor receptor (EGFR; eg, cetuximab and panitumumab), which are approved for treatment of patients with metastatic colorectal cancer who lack a mutation in RAS or BRAF, is not well studied in this disease. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'Impact of RAS status on the use of EGFR inhibitors'.)

Few data are published on the benefits of targeting vascular endothelial growth factor (VEGF). (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Efficacy and toxicity of bevacizumab and biosimilars'.)

•The benefit of adding a biologic agent to the chemotherapy backbone was addressed in an analysis of 130 patients with unresectable appendiceal epithelial neoplasms; 59 received the VEGF inhibitor bevacizumab, six received an agent targeting the EGFR, and 65 received no biologic agent at all [62]. The addition of bevacizumab (but not an anti-EGFR agent) significantly improved median progression-free and overall survival. However, interpretation of these data is limited by the fact that a far greater number of patients who did not receive a biologic agent received fluoropyrimidine monotherapy alone (39 versus 5 percent), and fewer received combination chemotherapy with FOLFOX/CAPOX (32 versus 76 percent) or FOLFIRI (8 versus 19 percent).

●Mucinous adenocarcinomas – There are conflicting data as to whether systemic chemotherapy is beneficial for advanced mucinous adenocarcinomas.

•In one of the studies cited above, patients with non-mucinous and higher-grade tumors had worse outcomes with systemic chemotherapy [61]. Others note histologic evidence to support a response to chemotherapy in patients with mucinous peritoneal carcinomatosis [63].

•On the other hand, two separate retrospective analyses of data derived from the NCDB suggest differential responsiveness to chemotherapy according to histology and grade:

-In an early analysis of 5049 patients with stage IV appendiceal adenocarcinoma reported to the NCDB between 1985 and 2006, systemic chemotherapy did not improve overall survival for patients with well-differentiated mucinous tumors, whereas it was beneficial for those with non-mucinous tumors and with moderately or poorly differentiated mucinous tumors [53].

-A similar conclusion was reached in a later analysis of 639 patients with stage IV, well-differentiated, mucinous appendiceal adenocarcinoma reported to the NCDB between 2004 and 2015 [64]. Five-year overall survival rates for patients receiving no chemotherapy versus those receiving chemotherapy were 53 versus 61 percent. After adjusting with the Cox proportional hazards model, systemic chemotherapy was not associated with overall survival.

One problem with evaluating response to chemotherapy is accurate response assessment, especially in patients with highly mucinous tumors. This can be illustrated by a prospective study of 34 consecutive patients with mucinous peritoneal carcinomatosis who received neoadjuvant treatment with FOLFOX (table 7) or CAPOX [63]. By radiographic (CT) assessment, 22 patients (65 percent) were thought to have stable disease, seven (20 percent) were thought to have progression, and five (15 percent) were thought to have a partial response. However, intraoperative findings were consistent with progressive disease in 50 percent of cases, while 29 percent of patients had histologic evidence to support some response to therapy. Thus, short of randomized clinical trial data, there remains uncertainty regarding the benefit of systemic chemotherapy, particularly for well-differentiated mucinous appendiceal adenocarcinomas, and decisions should be individualized by patient, with a short reassessment interval to determine effectiveness. These patients should be referred for consideration of CRS/HIPEC if they are otherwise appropriate candidates. (See 'Cytoreductive surgery and heated intraperitoneal chemotherapy' below.)

Cytoreductive surgery and heated intraperitoneal chemotherapy

Patient selection — The optimal selection factors for CRC and HIPEC in patients who have peritoneal dissemination from an advanced appendiceal adenocarcinoma (ie, peritoneal mucinous carcinomatosis) have not been established, and there is no consensus on this issue. In our view, this approach is best suited to patients with a good performance status who have no or limited (ie, easily resectable) extraperitoneal disease after an initial period of systemic chemotherapy and who have small-volume peritoneal disease that is likely to be successfully cytoreduced (leaving behind deposits <2.5 mm) with surgical debulking. Although patients with signet ring cell carcinomas have a less favorable long-term outcome than do those with other histologies, signet ring cell histology should not be considered an absolute contraindication to CRS/HIPEC, as selected patients may benefit from this approach [65,66]. Laparoscopy is frequently utilized to determine disease burden and estimate the likelihood of complete cytoreduction, especially in patients with high-grade disease [67].

A more extensive discussion of selection factors for CRS/HIPEC in patients with peritoneal surface malignancies is included below. (See 'Patient selection' below.)

Given that adenocarcinoma of the appendix often fails with isolated intraperitoneal spread [57], it would seem intuitive that an aggressive approach that includes surgical removal of all intraabdominal and pelvic disease (CRS) and the administration of HIPEC might control growth of peritoneal disease. This rationale is the same as that applied to the treatment of PMP. However, in contrast to classic PMP, which is caused by peritoneal dissemination from a ruptured benign mucocele or LAMN, aggressive CRS/HIPEC is less likely to produce lasting benefit for peritoneal carcinomatosis from an invasive adenocarcinoma, and patient selection is critical. (See 'Definition and evolution of terminology' above and 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)' below.)

Efficacy

●Randomized trials – Only one prospective controlled trial has been completed. This Dutch trial randomly assigned 105 patients with peritoneal carcinomatosis from appendiceal (n = 18) or colorectal (n = 87) cancer without evidence of other metastases to CRS (aiming to achieve deposits ≤2.5 mm) with HIPEC followed by systemic chemotherapy or to systemic chemotherapy alone without debulking [68]. Only palliative surgery was permitted in the control patients, and they received FU and leucovorin given weekly until progression. In the experimental group, after CRS, the abdominal cavity was perfused for 90 minutes with isotonic dialysis fluid containing mitomycin and heated to 41°C. After HIPEC, anastomoses were completed, and the abdomen was closed. Systemic chemotherapy similar to the control arm was started six weeks after CRS/HIPEC.

After a median follow-up of 22 months, median survival (the major endpoint) was significantly longer in the HIPEC group (22.4 versus 12.6 months, p = 0.032). This same difference was maintained in a later analysis at a median follow-up of eight years (median disease-specific survival 22.2 versus 12.6 months), although only nine patients remained alive, five without disease recurrence [69]. Treatment-related morbidity was high, and mortality was 8 percent in the HIPEC group, mostly related to bowel leakage. The study has been criticized because the experimental group differed from controls not only in the use of HIPEC but also in surgical debulking. It is possible that the important treatment was the CRS, and the HIPEC made little difference. Furthermore, the trial was performed without oxaliplatin or irinotecan, and the overall survival differences might have been smaller had these more active agents been used for systemic therapy. However, other data support the independent contribution of HIPEC when added to CRS compared with CRS alone in patients with primary appendiceal mucinous adenocarcinomas [70].

●Other data – Several institutions have published their experience with this approach for populations that consist exclusively of peritoneal mucinous carcinomatosis from an appendiceal adenocarcinoma; results from CRS/HIPEC for combined populations with disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis are presented below (see 'Outcomes' below):

•In a report from Australia, 46 patients with peritoneal metastases from mucinous or non-mucinous appendiceal adenocarcinoma underwent CRS/HIPEC using mitomycin and/or early postoperative chemotherapy with intraperitoneal FU [71]. Median survival for the entire group was 56.4 months, and the three-year overall and disease-free survival rates were 59 and 30 percent, respectively.

•The most recent update of Sugarbaker's experience with mucinous carcinoma of the appendix and peritoneal seeding included 501 patients treated with CRS/HIPEC over a 17-year period [32]. Peritoneal tumor spread was present at initial diagnosis in 418, while it was confirmed at reoperation in 83. At the time of last follow-up, 236 remained free of disease recurrence, and the 5- and 10-year overall survival rates were 72 and 54 percent, respectively. These numbers are difficult to interpret given the lack of information on histologic tumor grade.

•Another retrospective analysis included 282 patients with peritoneal mucinous carcinomatosis of appendiceal origin treated with CRS; most had HIPEC [72]. Before undergoing the procedure, 39 percent received systemic chemotherapy. Intraoperatively, a complete CRS was achieved in 82 percent, despite a high peritoneal cancer index (PCI) of 14 (as assessed by the Dutch simplified PCI) [73]. (See 'Patient selection' below.)

Most received HIPEC using mitomycin. Major postoperative morbidity occurred in 25 percent of patients, and the 60-day mortality rate was 1.1 percent. At a median follow-up of approximately two years, 202 patients remained alive, 82 without evidence of disease. The three- and five-year rates of overall survival were 67 and 53 percent, respectively. The corresponding rates of progression-free survival were 45 and 32 percent, respectively. Outcomes were better among those whose postoperative completeness of cytoreduction score was 0 (no visible residual disease) than among those with visible residual tumor, even as small as 2.5 mm.

•Although there are few comparator trials, at least some data from a single multicenter randomized trial suggest that long-term physical and functional outcomes may be better if the HIPEC perfusion uses oxaliplatin instead of mitomycin, while survival outcomes and complication rates were similar. Additional data are needed before it can be concluded that any one chemotherapy drug is better than another for the HIPEC perfusion [74].

●Signet ring histology – Outcomes tend to be worse for patients with signet ring cell histology [15,65,66,75-77]. As an example, in one report of 151 patients undergoing CRS/HIPEC for high-grade mucinous carcinoma peritonei with (n = 65) or without (n = 86) signet ring cell histology, progression-free survival at three and five years was better in the absence of signet ring cells (59 versus 48 percent and 31 versus 14 percent, respectively) [65]. Overall survival was also better, but in those with signet ring cell histology, a five-year survival of 25 percent was achieved, which improved to 51 percent if lymph nodes were negative.

Although it is difficult to know whether CRS and/or the addition of HIPEC impacted survival, these long-term outcomes are far superior to any reported for a similar group of patients with peritoneal spread from appendiceal adenocarcinoma treated without CRS and HIPEC. Nevertheless, the possibility of selection bias cannot be discounted, since all of these are single-institution series representing highly selected patient populations. A randomized trial is warranted in which the only treatment variable is HIPEC.

The complications of CRS/HIPEC are addressed below. (See 'Complications' below.)

Contribution of initial (neoadjuvant) chemotherapy — For most patients with high-grade disease, we suggest a period of initial chemotherapy prior to CRS/HIPEC. Low-grade mucinous appendiceal neoplasms are generally considered indolent, and show little to no chemotherapy responsiveness [49]. (See 'Patient selection' below.)

Potential benefits of systemic chemotherapy before a planned CRS/HIPEC procedure include improved resectability and survival, and, perhaps more importantly, it may permit the natural history of the metastatic disease to declare itself. However, the available data concerning the actual benefits of neoadjuvant chemotherapy are scant and conflicting:

●In one report of patients undergoing CRS and HIPEC for moderately or poorly differentiated appendiceal adenocarcinoma, 73 percent of the total received neoadjuvant chemotherapy prior to CRS, but there was no difference in overall survival in those who received it versus those who did not [78].

●The same conclusion was reached in an analysis by the Sugarbaker group [75].

●In another retrospective series of 45 patients undergoing CRS/HIPEC for a high-grade appendiceal cancer, 26 got chemotherapy and 19 did not [79]. While 15 of the 26 had a response based on imaging, biomarkers, or both, there was no difference in PCI, completeness of cytoreduction score, operative blood loss, or major organ resection between those who received and those who did not receive three months of neoadjuvant chemotherapy. Major complications and length of hospital stay were similar between the two groups as well.

Post-treatment follow-up — There are no specific guidelines from either the NCCN or ESMO that address the components or optimal frequency of post-treatment surveillance. We generally follow recommended guidelines for resected colon cancer (table 8). (See "Post-treatment surveillance after colorectal cancer treatment".)

GOBLET CELL ADENOCARCINOMA — Histologically, goblet cell adenocarcinomas (GCAs; previously called goblet cell carcinoids or adenocarcinoids) have features of both adenocarcinomas and neuroendocrine tumors (NETs). They are more aggressive than NETs and are classified and staged as appendiceal carcinomas (table 2) [5,45].

Incidence and risk factors — Appendiceal GCAs have an approximate incidence of 0.01 to 0.05 per 100,000 per year, and they are very rare neoplasms [20,22,80]. The average age at presentation is 52 to 58 years, closer to the age at presentation of adenocarcinomas (approximately 60) than of appendiceal well-differentiated NETs (approximately 38) [22,81,82]. A sex predilection has not been in evidence, although a predisposition to affecting White populations is described [20,22]. The only potential risk factor described to date is schistosomiasis [83,84].

Clinical presentation — Affected patients most often present with acute or chronic abdominal pain; up to one-third are incidentally found at appendectomy [5,46,81,85,86]. In one series of 74 patients with a GCA, symptoms at diagnosis included the following [87]:

●Appendicitis – 32 percent

●Abdominal pain – 20 percent

●Abdominal distention – 18 percent

●Bowel obstruction – 10 percent

●Not specified/other – 20 percent

Patients who presented with a clinical picture of appendicitis were more frequently found to have a perforated tumor (80 percent), but they also more frequently had early stage (stage I or II) tumors (80 percent) [87].

Up to 40 percent of cases present with distant metastases to the peritoneum, liver, and/or ovaries (Krukenberg tumor) [81,86-88].

Histology — Appendiceal tumors exhibiting both neuroendocrine and glandular differentiation are uncommon and have caused difficulty in histologic classification, prediction of prognosis, and clinical management. The histologic hallmark of GCA is the focal presence of mucin-containing goblet-shaped epithelial cells, which may cluster in the lamina propria or submucosa of the appendix, leaving the mucosa itself relatively intact [5,82,83,89,90].

These tumors display a spectrum of histologic features and clinical behavior [5,91]. Tang reviewed 63 cases of appendiceal tumors exhibiting both neuroendocrine and glandular differentiation and classified them on the basis of histologic features (table 9) as typical GCA (Tang A, 48 percent of the total cases) or "adenocarcinoma ex goblet cell carcinoid" GCA [5]. They further subclassified the adenocarcinoma ex goblet cell carcinoid cases into signet ring cell type (Tang B, 41 percent of the cases) and poorly differentiated adenocarcinoma type (Tang C, 11 percent of the cases). Although most patients (63 percent) presented at an advanced clinical stage, their clinical outcomes could be differentiated by subclassification. The stage IV matched five-year survival rates were 100, 38, and 0 percent for Tang A, B, and C, respectively. Others have shown the stratification of outcomes based on histology among patients undergoing multimodality therapy for GCA that includes cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) [91]. (See 'Recurrent or metastatic disease' below.)

All GCAs stain positive on periodic acid-Schiff (PAS) staining for mucin and, thus, can be differentiated from appendiceal NETs. On immunohistochemical staining, there is pronounced expression of the neuroendocrine markers chromogranin A (CgA) and synaptophysin, and the expression of carcinoembryonic antigen (CEA) provides the hallmark marker that differentiates between a GCA and an appendiceal neuroendocrine neoplasm. Cytokeratin (CK) staining for CK20 and CK19 may assist in the differential diagnosis between appendiceal neuroendocrine neoplasms and adenocarcinomas [89,90,92].

Ki-67 immunostaining as a marker of proliferation increases with decreasing differentiation of appendiceal neoplasms, but a clear correlation between Ki-67 levels and clinical outcome has not been definitively shown [5,89,90,93-95].

Staging workup — As with appendiceal adenocarcinomas, most GCAs are diagnosed postoperatively in appendectomy specimens, and thus, diagnostic procedures mostly concern postoperative rather than preoperative staging, unless there are suspected or evidenced distant metastases at the time of presentation [5,82,85]. These tumors are worked up in a manner more similar to mucinous appendiceal adenocarcinomas than NETs.

Cross-sectional imaging (helical contrast-enhanced computed tomography [CT] or magnetic resonance imaging [MRI]) should be used to rule out locoregional or distant metastases [96]. A role for somatostatin-receptor-based imaging is not established. The sensitivity of somatostatin-receptor-based imaging decreases with less neuroendocrine differentiation (and therefore, less somatostatin receptor expression), such as in the case of GCAs, and in general, cross-sectional imaging tends to be more sensitive and more useful in these cases [86,96-98]. Somatostatin-receptor-based imaging might be considered on a case-by-case basis in settings where curative resection is not completely assured, or when distant metastases are suspected and cross-sectional imaging is not definitive. When somatostatin-receptor-based imaging is chosen, in general, positron emission tomography (PET) with newer somatostatin-receptor-targeting radiotracers, such as gallium Ga-68 DOTATATE or gallium Ga-68 DOTATOC, is more sensitive than somatostatin receptor scintigraphy with indium-111 pentetreotide (OctreoScan). (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

Tumor markers — In contrast to well-differentiated appendiceal NETs, serum levels of CgA are of no value for the detection or monitoring of GCA [85,96]. Other tumor markers, such as CEA, carbohydrate antigen 19-9 (CA 19-9), and cancer antigen 125 (CA-125), are elevated in up to 80 percent of patients and are of potentially greater value for post-treatment surveillance, although none of these has been prospectively validated for this indication. (See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Assay of tumor markers'.)

Staging system and prognosis — The most recent Tumor, Node, Metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC; eighth edition, 2017) uses the staging classification for appendiceal carcinomas to stage mixed-histology tumors such as GCAs (table 2).

The following data are available regarding prognosis:

●The five-year survival rates according to disease stage at presentation in two single-institution series totaling 131 patients were as follows [81,87]:

•Stage I – 100 percent

•Stage II – 76 and 87 percent

•Stage III – 22 and 40 percent

•Stage IV – 14 and 18 percent

●Stage-stratified outcomes from a retrospective review of data on 2552 patients derived from the National Cancer Database (NCDB) were as follows [99]:

•Stage I – 91 percent

•Stage II – 91 percent

•Stage III – 57 percent

•Stage IV – 19 percent

One possible reason for the better outcomes in stage III disease in this cohort is that 41 percent of those with stage III disease received adjuvant chemotherapy.

●Others report five-year overall survival of 87 percent for the combined population with stage I, II, and III disease [100].

In general, prognosis is worse than with malignant NETs but better than with appendiceal adenocarcinoma (table 1) [7,8]. Of all the tumor types listed in the table, GCAs have the lowest frequency of regional nodal metastases (7 and 17 percent in two series [22,87]), but the risk of nodal positivity is correlated with T stage. As an example, in a multi-institutional series of 88 cases of confirmed GCA, the rates of lymph node metastases at hemicolectomy for T2, T3, and T4 tumors were 0, 15, and 24 percent, respectively [100].

The rate of nodal metastases may be higher with signet ring or poorly differentiated histology (8 of 23, 35 percent); adenocarcinomas ex goblet cell carcinoid were node positive in one series [87]. (See 'Histology' above.)

GCAs also have the potential to spread intraperitoneally, even in the absence of nodal metastases [22,101]. In the McCusker series, which included 227 GCAs, 51 percent either had spread through the serosa or had mesoappendiceal invasion, while 14 percent extended to other organs or the peritoneum [22]. The intraperitoneal metastatic deposits are typically adenocarcinoma rather than NET. Patients with isolated peritoneal spread may be candidates for aggressive CRS with HIPEC. (See 'Recurrent or metastatic disease' below.)

Treatment

Localized disease — Given the higher risk of metastases with an appendiceal GCA compared with an appendiceal NET, we suggest that most patients, even those with T1 or T2 favorable-histology tumors, undergo complete right hemicolectomy within three months of initial appendectomy if the patient is fit for additional surgery. We suggest not pursuing prophylactic oophorectomy in females with apparently local or locoregional appendiceal adenocarcinomas if the ovaries are grossly normal.

The optimal surgical treatment for GCAs is debated. Some suggest simple appendectomy for localized low-grade tumors with a low proliferative index [102], while others advocate right hemicolectomy for all GCAs, regardless of pathologic features, because of the high risk of metastatic disease [85,96,100,103,104]. Still others suggest right colectomy only if the tumor is >2 cm in size, is poorly differentiated, involves the base of the appendix, is associated with nodal metastases, or has atypical histologic features [26,81,82,101,105-107].

There are no randomized trials to inform clinical practice. The benefit of right colectomy has been addressed in the following reports:

●A year 2004 meta-analysis evaluating the role of right hemicolectomy in appendiceal GCA included 13 studies and 100 patients [102]. The authors concluded that there was no clear benefit for right hemicolectomy and supported the use of appendectomy alone for localized cases invading no deeper than the muscularis propria (≤T2) with no cecal involvement and low-grade histology (<2 mitotic figures per 10 high-power fields [HPF]). The poor quality of the studies in this analysis renders this conclusion less than definitive.

●A single-center retrospective analysis of 57 patients also failed to demonstrate a specific benefit for performing a complete right hemicolectomy [81].

●Another single-center analysis of 74 patients undergoing potentially curative treatment for GCA also failed to demonstrate an impact of right hemicolectomy on disease-free survival, even in patients with tumor size >2 cm [87]. Nevertheless, these authors concluded that appendectomy alone should be considered only if comorbidities did not permit further surgical evaluation or for a completely resected Tang A tumor (table 9) staged as T1 or T2 with no radiologic suspicion of lymph node metastases.

However, the majority of patients in contemporary series have undergone hemicolectomy (particularly for T3 or T4 tumors, which have a 15 to 24 percent risk of nodal positivity), and it is impossible to know whether the good outcomes that were described in these series could be achieved without hemicolectomy. The American Society of Colon and Rectal Surgeons, the North American Neuroendocrine Tumor Society (NANETS), and the European Neuroendocrine Tumor Society (ENETS) all recommend right hemicolectomy as the standard surgical treatment for appendiceal GCAs of any stage or histology [36,96,104].

For females with appendiceal GCAs, a benefit for bilateral salpingo-oophorectomy has been suggested because of the possibility of ovarian metastases [82,87], but its advantage remains unproven.

Adjuvant therapy — The role of adjuvant therapy for patients who have early stage GCA is unknown. Although there are only a few retrospective series to support a specific benefit for adjuvant chemotherapy [81,87,99,108], some oncologists, including the authors and editors of this topic review, suggest adjuvant chemotherapy in the setting of node-positive (stage III) disease, similar to recommendations for appendiceal adenocarcinomas. (See 'Adjuvant therapies' above.)

Recurrent or metastatic disease — Treatment decisions for advanced GCA depend on which histologic component predominates in the recurrence: adenocarcinoma or NET. We treat mixed recurrences and recurrences that are exclusively adenocarcinoma the same way that we treat advanced adenocarcinomas of the appendix. For selected patients with isolated peritoneal metastases, CRS with or without HIPEC may improve symptom control and prolong survival. (See 'Stage IV (metastatic) disease' above.)

For the less common patient who recurs with the well-differentiated NET component, long-acting octreotide is a reasonable option if the tumors express somatostatin receptors. Systemic therapy options for patients with metastatic gastrointestinal NETs are discussed elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin analogs'.)

Adenocarcinoma predominant — The utility of systemic chemotherapy for metastatic GCA in which the adenocarcinoma component predominates or for mixed recurrences has not been systematically studied. As with appendiceal adenocarcinomas, treatment commonly incorporates agents and regimens that are used for advanced colorectal cancer, such as FOLFOX (oxaliplatin plus leucovorin and infusional fluorouracil [FU]), CAPOX (capecitabine plus oxaliplatin), FOLFIRI (irinotecan plus leucovorin and infusional FU), and single-agent fluoropyrimidines. The role of biologic agents such as bevacizumab and agents targeting the epidermal growth factor receptor is not defined. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)

Chemotherapy responsiveness may be higher with appendiceal GCAs than it is for other appendiceal adenocarcinomas, particularly for the FOLFOX regimen [87,109,110]. At least one case report documents a complete and persistent remission with the FOLFOX regimen (table 7) in a patient with metastatic disease at diagnosis [110]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI'.)

As noted above, intraperitoneal spread is a common occurrence, and the intraperitoneal metastatic deposits are typically adenocarcinoma rather than NET [111,112]. Such cases behave as aggressively as an appendiceal adenocarcinoma with peritoneal spread [101,109,113]. Limited data are available, but long-term survival can be achieved in selected patients with isolated peritoneal spread who are treated with CRS with or without HIPEC [88,91,101,114-117]. In one report of 27 patients with peritoneal spread who were eligible for CRS/HIPEC, the five-year survival rate was 57 percent [114]. For patients with low-grade tumors (Tang A, (see 'Histology' above)) that appear isolated to the peritoneum, and who are predicted to have a low Peritoneal Carcinomatosis Index (PCI) score by diagnostic laparoscopy or cross sectional imaging, upfront cytoreductive surgery is an option [49]. (See 'Patient selection' below.)

However, outcomes appear to be worse for patients with Tang B and C tumors [91]. We usually approach these patients the same as those with high-grade appendiceal adenocarcinomas, with three to six months of initial chemotherapy followed by re-evaluation for CRS/HIPEC. Some consensus guidelines support either chemotherapy first or CRS followed by systemic chemotherapy depending on the PCI (algorithm 1) [49]. (See 'Aggressive cytoreduction and heated intraperitoneal chemotherapy' below.)

Post-treatment surveillance — Because GCA is a more aggressive entity than appendiceal NET, we suggest post-treatment surveillance using a comparable strategy to colorectal cancer (table 8); this is consistent with guidelines from ENETS [96]. The optimal duration of surveillance is not established, but many institutions follow these patients for recurrence of the adenocarcinoma component for five years (as is typically recommended after resection of a colon cancer) and follow for recurrence of the NET component for up to 10 years (as is done for other gastroenteropancreatic NETs). (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Post-treatment follow-up'.)

PERITONEAL DISSEMINATION OF A RUPTURED LAMN OR BENIGN MUCOCELE (PSEUDOMYXOMA PERITONEI) — The term pseudomyxoma peritonei (PMP) refers to a clinical syndrome characterized by diffuse mucinous peritoneal involvement, often in association with a mucinous appendiceal lesion that has presumably ruptured. As noted above, we prefer to restrict this definition to a pathologically and prognostically homogeneous group of cases characterized by histologically benign peritoneal mucin that is associated with a ruptured low-grade appendiceal mucinous neoplasm (LAMN) or, less commonly, a ruptured appendiceal mucocele; these cases can be collectively designated diffuse peritoneal adenomucinosis (DPAM). The clinical presentation, evaluation, and treatment of this group of patients are discussed in this section. The management of patients with peritoneal mucinous carcinomatosis, which denotes the presence of peritoneal lesions that are composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma, is described above. (See 'Definition and evolution of terminology' above and 'Cytoreductive surgery and heated intraperitoneal chemotherapy' above.)

Clinical presentation — PMP is more common in females and is found unexpectedly in approximately 2 of every 10,000 laparotomies [10]. The most common presenting symptom in both males and females is increasing abdominal girth; in men, the second most common symptom is an inguinal hernia (accounting for some 25 percent of cases), while for women, it is an ovarian mass palpated at the time of a routine pelvic examination [9]. When mucoid fluid is encountered at the time of a hernia repair, recovery of the fluid and hernia sac for histologic study is important [118]. (See "Classification, clinical features, and diagnosis of inguinal and femoral hernias in adults".)

Radiographic studies — The radiographic appearance of PMP is characteristic. On computed tomography (CT) scan, the mucinous material is similar in density to water and appears heterogeneous. Scalloping of the liver, spleen, and mesentery is easily demonstrated, and calcifications are common (image 1). The undersurface of the diaphragm may be greatly thickened by large cystic masses of mucinous tumor (image 2). A striking early finding is the characteristic peripheral location of tumor within the abdomen and pelvis, and the relative sparing and central displacement of the small bowel and mesentery (termed the "redistribution phenomenon") [9,119].

It has been suggested that the presence of tumor implants >5 cm on the jejunum, proximal ileum, or adjacent mesentery is more consistent with peritoneal mucinous carcinomatosis than DPAM [9,119]. The presence of segmental obstruction of the small bowel also raises suspicion for mucinous peritoneal carcinomatosis, and both findings predict a less favorable outcome from aggressive cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) [119]. Whether gadolinium-enhanced magnetic resonance imaging (MRI) can better distinguish between DPAM and peritoneal mucinous carcinomatosis is under study and not yet established [120]. (See 'Definition and evolution of terminology' above.)

Treatment — The optimal treatment for PMP (defined throughout the rest of this review as the benign form, DPAM) is debated. The natural history is one of indolent but progressive growth, and if left untreated, this is a fatal condition. While some consider standard treatment to be periodic surgical debulking for symptomatic disease, this treatment is not curative but aims to relieve symptoms by resecting gross disease to limit the buildup of mucus and its pressure effect. Increasingly, an aggressive approach to these patients that includes CRS/HIPEC is advocated because of the possibility of long-term relapse-free survival (and possibly cure) in a subset of patients. However, this is controversial, and in our view, patients who are potentially eligible for this approach should be referred to a center that specializes in peritoneal surface malignancies for a discussion of the risks and benefits of this approach. For appropriately selected patients and at centers with expertise in this procedure, CRS followed by HIPEC is a preferred alternative to periodic debulking without HIPEC, particularly for those with DPAM histology. The importance of surgical technique and surgeon experience to the success and safety of this approach cannot be overemphasized.

Initial expectant management — For asymptomatic patients with limited peritoneal disease (no or limited disease on imaging) and low-grade mucinous tumors who underwent resection of the primary tumor, expectant observation can be undertaken. A retrospective study of 30 expectant observation patients with a median follow-up time of 52 months showed 95 percent five-year overall survival and 82 percent five-year progression-free survival [121].

Periodic surgical debulking — At some institutions, a standard approach for symptomatic patients is periodic surgical debulking for symptomatic disease [10]. Periodic resection to remove gross disease limits the buildup of mucus and its pressure effect, and it can offer prolonged relief of PMP-related symptoms and extended survival [122]. However, inevitable disease recurrence requires repeated and progressively more difficult surgery due to adhesions and fibrosis.

The addition of external beam radiation therapy (RT), intraperitoneal radioisotopes, intraperitoneal chemotherapy, and systemic chemotherapy has been attempted to improve outcomes [10]. Whether any of these additional treatments prolongs survival is unclear because randomized clinical trials have not been performed, and agreement on definitions of clinical subsets is lacking. Retrospective data from small groups of patients treated at three different centers using a combination of these approaches demonstrate that a reasonable percentage of patients live five years (probably reflecting the indolent natural history of this condition), but survival is clearly diminished at 10 years (table 10) [11,122-124].

Aggressive cytoreduction and heated intraperitoneal chemotherapy — A more aggressive approach that includes radical surgical removal of all intraabdominal and pelvic disease (CRS) and the administration of HIPEC has been increasingly adopted at centers with expertise in peritoneal surface malignancies, with the goal of cure [49]. In view of the rarity of extraperitoneal spread in patients with PMP from DPAM, it would seem intuitive that intraperitoneal chemotherapy (which can permit a several-fold increase in drug concentration in the abdominal cavity compared with systemic administration) might control growth of peritoneal disease. However, despite this regional advantage, penetration into tumor tissue is limited to a maximum of 1 to 2 mm from the surface [124-127].

Drug penetration may be enhanced by heating the perfusate containing chemotherapy [9,127]. This approach (HIPEC) is best suited to patients with minimal residual disease (deposits smaller than 2 to 2.5 mm) after CRS. It is unlikely that even a heated solution of chemotherapy could penetrate large tumor deposits.

The chemoperfusion regimens used for HIPEC have been different at different centers. Most centers in the United States use mitomycin, while in Europe, there is a preference for oxaliplatin. There is only a single randomized trial comparing these approaches [74]. In this multicenter trial, 121 patients with isolated peritoneal surface malignancy from a primary appendiceal tumor were randomly assigned intraoperatively to receive mitomycin or oxaliplatin in the HIPEC perfusate after complete surgical cytoreduction. Patients predominantly had low-grade appendiceal tumors (68 percent), but the specific histologies were not reported. Preoperative chemotherapy was administered to 20 percent of patients in the oxaliplatin group compared with 10 percent of the mitomycin group. There was no difference in three-year survival between the groups (73 percent in both), and postoperative complication rates were similar. Both groups had an initial decline in physical and functional aspects of quality of life (QOL) in the early postoperative period, but at both 12 and 24 weeks postoperatively, HIPEC perfusion with oxaliplatin was associated with significantly better physical and functional QOL outcomes. Additional data from randomized trials are needed before it can be concluded that any one chemotherapy regimen is better than another.

The specifics of the Sugarbaker approach to heated intraoperative (usually mitomycin) and early postoperative intraperitoneal chemotherapy (usually fluorouracil [FU]) have been described in detail [119,127].

Patient selection — We use a combined clinicopathologic approach to selecting patients with a peritoneal surface malignancy who are most likely to benefit from CRS/HIPEC (similar to that used by the Sugarbaker group [119,127]) that includes histopathologic assessment and an evaluation of overall disease burden, using both preoperative radiographic assessment and intraoperative evaluation:

●Histopathologic assessment – Noninvasive malignancies, such as DPAM, are more likely to be made visibly disease free through a peritonectomy procedure and are less likely than invasive adenocarcinomas to have spread to regional nodes, the liver, or other systemic sites. With these low-grade tumors, CRS/HIPEC is possible even in the setting of a high burden of disease. On the other hand, for individuals with high-grade disease (especially signet ring cell cancers), a high disease burden is likely to preclude successful complete cytoreduction. (See 'Cytoreductive surgery and heated intraperitoneal chemotherapy' above.)

●Preoperative contrast-enhanced (oral and intravenous) CT of the chest, abdomen, and pelvis – In addition to excluding liver or other systemic metastases, the two radiologic criteria that are most useful to predict a poor outcome from aggressive CRS and HIPEC are segmental obstruction of the small bowel, and the presence of tumor nodules >5 cm in diameter on small bowel surfaces or directly adjacent to the small bowel mesentery in the jejunum or upper ileum. (See 'Radiographic studies' above.)

In another report, extensive disease in the right upper quadrant on preoperative CT was particularly related to a poorer survival outcome [128]. Others use a scoring system (simplified preoperative assessment for appendix tumor [SPAAT]) to predict the likelihood of incomplete cytoreduction at the time of surgery [129,130]. This scoring system takes into account scalloping of the liver, spleen, pancreas, and portal vein, as well as foreshortening of the mesentery; scores ≥3 were associated with a high likelihood of incomplete cytoreduction.

●The peritoneal cancer index and the completeness of cytoreduction score – Two other clinical indices, the peritoneal cancer index (PCI; a quantitative indicator of prognosis derived from the size and distribution of nodules on the peritoneal surface) and the completeness of cytoreduction score (the size of persisting tumor nodules after maximal cytoreduction), are usually derived intraoperatively [17,131,132]. The PCI score predicts the likelihood of complete cytoreduction and correlates with survival.

Preoperative imaging can also be used to predict surgical PCI with a sensitivity ranging from 44 percent with CT to 81 percent with CT plus MRI [133]. The clinical applicability of a radiologic prediction of PCI score still remains limited.

Laparoscopy is utilized more widely than preoperative radiographic studies to determine the PCI and the likelihood of complete cytoreduction, especially in patients with high-grade disease. Laparoscopy has been shown to be safe, with a positive predictive value for complete cytoreduction of 82.8 percent in one combined series of 141 patients with peritoneal surface malignancies and low-, intermediate-, or high-grade histology [67].

A prognostic model for predicting overall survival in patients with a peritoneal surface malignancy of appendiceal origin was developed by the Sugarbaker group using these variables as well as the presence/absence of distant metastases and sex (table 11) [134]. The median survival for the four identified risk groups differed significantly (240, 235, 78, and 19 months for the cohorts with good-, low-, moderate-, or high-risk disease, respectively). Others have developed a nomogram to predict the probability of disease progression and survival that is based on completeness of cytoreduction, and also age, histologic grade, and the presence or absence of involved lymph nodes [135].

Others, using data collected by the US HIPEC Collaborative, have developed a preoperative risk score for predicting incomplete cytoreduction that uses sex, the presence of ascites, and levels of tumor markers (carbohydrate antigen [CA] 19-9, carcinoembryonic antigen [CEA]) to derive an incomplete cytoreduction risk score (ICRS) [136]. The likelihood of incomplete cytoreduction was 1.6, 13, and 39 percent in those with scores of 0, 1 to 2, or 3 to 4, respectively, and increasing score group was also associated with lower five-year overall survival after CRS/HIPEC (87, 59, and 58 percent, for scores of 0, 1 to 2, and 3 to 4, respectively). The authors emphasized that this score should not be used in isolation to exclude patients from surgery.

Outcomes — There are no randomized trials of CRS/HIPEC in patients with DPAM, although one has been conducted in patients with peritoneal mucinous carcinomatosis. (See 'Cytoreductive surgery and heated intraperitoneal chemotherapy' above.)

Results from several single-institution series, most of which include a heterogeneous patient population, are summarized below:

●Histology is an important determinant of outcome. A 2001 report from the Sugarbaker group included 108 patients with PMP treated over a 10-year period (1983 to 1993) with CRS and intraoperative intraperitoneal mitomycin (with or without heating) [16]. The chemotherapy regimen also included intraperitoneal FU during postoperative days 1 to 6 and three subsequent courses of adjuvant intravenous mitomycin and intraperitoneal FU. One group (n = 65) had DPAM, characterized by a histologically bland or low-grade adenomatous mucinous epithelium with abundant extracellular mucin associated with fibrosis. A second group (n = 29) had peritoneal mucinous carcinomatosis (all of the appendiceal mucinous adenocarcinomas were of the signet ring cell variant). A third group (n = 14) had intermediate features. Histology was closely related to survival, with patients in the DPAM group doing significantly better than those in the other groups combined (table 12). However, five-year survival in the group with mucinous peritoneal carcinomatosis was 26 percent, and 9 percent were still alive at 10 years.

A systematic review [137] included 382 patients with the histology of DPAM only from five case series, three from the Sugarbaker group [11,16,137-139]. Five-year survival rates ranged from 70 to 86 percent, while at 10 years, 60 and 68 percent of patients in two different series were still alive (table 13).

●Patients generally do worse if optimal cytoreduction cannot be achieved [140-142].

●Several centers have reported their results using CRS/HIPEC in series that generally consist of a heterogeneous group of patients with both classically defined PMP (DPAM) and peritoneal mucinous carcinomatosis. A compilation of results (as well as reported perioperative morbidity and mortality rates) from several such series is presented in the table (table 14) [17,140,143-151].

The largest report, a multi-institutional registry-based series of 2298 patients undergoing CRS and HIPEC for peritoneal surface malignancy, included 1419 with DPAM, 700 with peritoneal mucinous adenocarcinoma, and 140 with hybrid histology [18]. Five- and 10-year survival rates for those with DPAM histology were 81 and 70 percent; for those with peritoneal mucinous carcinomatosis, they were 59 and 49 percent; and for hybrid histology, they were 78 and 63 percent, respectively.

These are impressive survival statistics, particularly for patients with DPAM. What is not clear is whether the results can be attributed to the aggressive treatment, patient selection, or both. There is insufficient evidence to conclude whether the prolonged survival is due to treatment or to biologic features that allow these patients to undergo complete CRS.

Furthermore, the quality of the CRS is dependent on the skills and level of experience of the surgeon [152]. The favorable results (particularly with regard to treatment-related toxicity) achieved by international experts in the field may not be replicated in routine clinical practice. An international list of centers with expertise in treatment of peritoneal surface malignancies exists through a patient-oriented website [153].

Randomized trials are the only way to determine the true benefit of HIPEC and aggressive debulking in the treatment of PMP. However, such a trial is unlikely to be performed, at least in the United States. In our view, at centers with expertise in this procedure, CRS followed by HIPEC is a preferred alternative to periodic debulking without HIPEC for suitable patients with symptomatic disease, particularly those with DPAM histology.

Complications — Treatment-related morbidity may be substantial, particularly if more extensive surgery is required to achieve complete cytoreduction [32,154-156]. This was illustrated in a Dutch series of 102 patients undergoing CRS/HIPEC [154]. According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) [157], grade 3 (not immediately life threatening, but hospitalization or prolongation of hospitalization required), grade 4 (life-threatening consequences, urgent intervention indicated), or grade 5 (fatal) toxicity was observed in 66 patients (65 percent); eight died of treatment-related causes. Surgical complications (defined as a postoperative event requiring reintervention) occurred in 36 patients; fistulas were frequently encountered (18 patients). The risk of a complicated recovery was significantly higher in patients undergoing the procedure for recurrent colorectal cancer, those needing three or more anastomoses, those having more than five regions affected, and those with an incomplete initial cytoreduction.

On the other hand, the importance of technique and surgeon experience to the success and safety of HIPEC cannot be overemphasized [150]. As with the treatment of PMP, the surgeon with the most published experience (and the lowest reported complication rates) with this approach for mucinous peritoneal carcinomatosis is Paul Sugarbaker [32,140,158,159], although other groups have reported favorable results as well [150,151]:

●One review from the Sugarbaker group included 46 patients undergoing surgical palliation with total abdominal colectomy, pelvic peritonectomy, and end ileostomy followed by HIPEC for extensive mucinous peritoneal carcinomatosis (a group that might be expected to have the highest rates of surgical morbidity and mortality) [158]. Although there were four postoperative deaths (mortality rate 8.6 percent), the incidence of postoperative grade 3 or 4 toxicity was significantly lower than that seen in the Dutch study (19.5 percent), and there was only one reported rectourethral fistula.

●A second report from this group included 356 procedures (CRS plus perioperative intraperitoneal chemotherapy) to treat either DPAM or peritoneal mucinous adenocarcinoma [159]. The total 30-day or in-hospital mortality rate was 2 percent, and 19 percent of the procedures were complicated by at least one grade 4 event (most commonly hematologic [28 percent] or gastrointestinal [26 percent]). Eleven percent of patients had to be returned to the operating room.

Post-treatment surveillance — There are no widely accepted guidelines for post-treatment surveillance following CRS/HIPEC, and practice is variable. At least one study from the US HIPEC collaborative suggests that low-frequency surveillance after CRS/HIPEC for appendiceal or colorectal cancer (every 6 to 12 months) does not result in inferior survival as compared with high-frequency surveillance (imaging every two to four months) [160]. Most recurrences were detected within three years, and no recurrence was detected after five years.

We tend to reimage patients with low-grade disease every 6 to 12 months and reimage those with high-grade disease every three to six months. We perform post-treatment surveillance for up to five years.

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: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Histologic spectrum – Neoplastic epithelial lesions can be subcategorized by histologic subtypes (serrated polyps, low-grade appendiceal mucinous neoplasms [LAMNs], high-grade appendiceal mucinous neoplasms [HAMNs], invasive adenocarcinomas [which may be mucinous or non-mucinous], and goblet cell adenocarcinomas [GCAs; previously called goblet cell carcinoids or adenocarcinoids]). (See 'Histologic spectrum of epithelial lesions' above and "Appendiceal mucinous lesions", section on 'Pathology'.)

●Adenocarcinomas

•The majority of appendiceal adenocarcinomas are diagnosed in appendectomy specimens. For most patients, we suggest right hemicolectomy rather than simple appendectomy alone (Grade 2C). Others disagree, advocating simple appendectomy alone for all unruptured, completely resected mucinous adenocarcinomas that are well differentiated. (See "Appendiceal mucinous lesions", section on 'Completely resected adenocarcinoma'.)

•We suggest not pursuing prophylactic oophorectomy in females with apparently local or locoregional tumors if the ovaries are grossly normal (Grade 2C). (See 'Ruptured tumors and the role of routine oophorectomy' above.)

•At nonspecialized centers, the initial surgery for an apparently ruptured appendiceal mucinous lesion should be limited to appendectomy or right hemicolectomy (if the rupture is contained by the right colon and mesentery), peritoneal washing with fluid cytology, and biopsy of any suspicious peritoneal lesions. More extensive surgery aimed at clearing peritoneal mucinous disease (ie, formal cytoreductive surgery [CRS]) should only be conducted by surgeons with extensive experience with peritoneal malignancies after the return of final pathology. (See 'Cytoreductive surgery and heated intraperitoneal chemotherapy' above and 'Peritoneal dissemination of a ruptured LAMN or benign mucocele (pseudomyxoma peritonei)' above.)

•We suggest a three- to six-month course of adjuvant oxaliplatin-containing chemotherapy for those with node-positive disease, extrapolating from data supporting benefit for this approach in node-positive colon cancer (Grade 2B). (See 'Adjuvant therapies' above.)

•For patients with stage II disease (table 2), considerations for offering adjuvant therapy are similar to those in stage II colon cancer: higher risk features (T4, perforation, inadequate nodal sampling, or poorly differentiated histology) would lead us to favor adjuvant therapy, although there is a lack of definitive data for the benefit of adjuvant therapy. (See 'Adjuvant therapies' above.)

•Treatment for metastatic appendiceal adenocarcinoma commonly incorporates agents and regimens that are used for advanced colorectal cancer. (See 'Systemic chemotherapy' above.)

•There is no consensus on which patients with peritoneal dissemination (ie, peritoneal mucinous carcinomatosis) are appropriate candidates for CRS with heated intraperitoneal chemotherapy (HIPEC). In our view, this approach is best suited to asymptomatic patients with a good performance status who have no or limited (ie, easily resectable) extraperitoneal disease after an initial period of systemic chemotherapy and who have small-volume peritoneal disease that is likely to be successfully cytoreduced (leaving behind deposits <2.5 mm) with surgical debulking. Signet ring cell histology is not an absolute contraindication. (See 'Cytoreductive surgery and heated intraperitoneal chemotherapy' above.)

●Goblet cell adenocarcinoma

•GCAs have features of both adenocarcinomas and NETs. They are more aggressive than NETs and are classified and staged as appendiceal adenocarcinomas. (See 'Histology' above.)

•We suggest that most patients, even those with T1 or T2 favorable-histology tumors, undergo complete right hemicolectomy within three months of initial appendectomy if the patient is fit for additional surgery (Grade 2C). We suggest not pursuing prophylactic oophorectomy in females with apparently local or locoregional tumors if the ovaries are grossly normal (Grade 2C). (See 'Localized disease' above.)

•We suggest adjuvant chemotherapy in the setting of node-positive disease, similar to appendiceal adenocarcinoma (Grade 2C). (See 'Adjuvant therapy' above.)

•Treatment decisions for advanced GCA depend on which component predominates in the recurrence (adenocarcinoma or NET) and the clinical pattern of metastatic disease (see 'Recurrent or metastatic disease' above):

-We treat mixed recurrences and recurrences that are exclusively adenocarcinoma the same way that we treat advanced adenocarcinomas of the appendix, with systemic chemotherapy. (See 'Recurrent or metastatic disease' above.)

-For the less common patient who recurs with the well-differentiated NET component, long-acting octreotide is a reasonable option if the tumors express somatostatin receptors. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin analogs'.)

●Pseudomyxoma peritonei

•The term pseudomyxoma peritonei (PMP) refers to a clinical syndrome of rupture of an appendiceal lesion with diffuse mucinous peritoneal involvement. We restrict use of the term PMP to those cases with disseminated peritoneal adenomucinosis (DPAM), defined by the presence of abundant peritoneal extracellular mucin containing scant mucinous epithelium with little cytologic atypia or mitotic activity, and not peritoneal mucinous carcinomatosis. (See 'Peritoneal disease spread and pseudomyxoma peritonei' above.)

•The optimal treatment for PMP is debated:

-For asymptomatic patients with limited peritoneal disease (no or limited disease on imaging) and low-grade mucinous tumors who underwent resection of the primary tumor, we advocate expectant observation. (See 'Initial expectant management' above.)

-Periodic surgical debulking may improve symptoms but is not curative. For appropriately selected patients and at centers with expertise in this procedure, CRS followed by HIPEC is a preferred alternative to periodic debulking alone, particularly for those with DPAM histology, because of the possibility of long-term disease control and possible cure. (See 'Aggressive cytoreduction and heated intraperitoneal chemotherapy' above.)

We use a combined clinicopathologic approach in selecting patients who are most likely to benefit from CRS/HIPEC that includes histopathologic assessment and an evaluation of overall disease burden, both preoperatively and intraoperatively. (See 'Patient selection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Swanson, MD, who contributed to an earlier version of this topic review.