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INTRODUCTION — Neoplasms of the appendix are rare. They are found in approximately 1 percent of appendectomy specimens  and account for only approximately one-half of 1 percent of intestinal neoplasms . Carcinoid tumors are the most common, comprising over 50 percent of appendiceal neoplasms in most series (table 1) .
However, the distribution of appendiceal neoplasms might be changing over time. In a large series of appendiceal tumors derived from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute between 1973 to 2003, the most frequent histology was a mucinous adenocarcinoma followed by intestinal-type adenocarcinoma; carcinoid tumors comprised only 11 percent (table 2) . The difference in natural history of these different histologies is illustrated by their differing five-year disease-specific survival rates.
NEUROENDOCRINE TUMORS — The term "carcinoid" has generally applied to neuroendocrine tumors (NETs) originating in the digestive tract, lungs, or rare primary sites, such as kidneys or ovaries. Use of the term carcinoid usually implies a well-differentiated histology; in modern terminology, the rare high-grade or poorly differentiated NETs are referred to as neuroendocrine carcinomas. (See "Pathology, classification, and grading of neuroendocrine tumors arising in the digestive system", section on 'Classification and terminology'.)
As with other intestinal NETs, those arising in the appendix can secrete serotonin and other vasoactive substances (table 3). These substances are responsible for the carcinoid syndrome, which is characterized by episodic flushing, wheezing, diarrhea, and right-sided valvular heart disease. Midgut NETs (ie, appendix, small bowel) are more commonly associated with the classic carcinoid syndrome than those that arise in the foregut or hindgut (table 4). More than 90 percent of patients with carcinoid syndrome have metastatic disease, typically to the liver. (See "Clinical characteristics of carcinoid tumors" and "Clinical features of the carcinoid syndrome".)
Appendiceal NETs are detected most commonly in patients in their forties, which is much younger than the average age for other primary malignant appendiceal neoplasms [4-6]. Epidemiologic studies show a slight but consistently higher incidence in women. (See "Clinical characteristics of carcinoid tumors", section on 'Appendix'.)
Clinical presentation — The majority of NETs are located in the distal one-third of the appendix where they are unlikely to cause obstruction [1,7]. As a result, most patients are asymptomatic. Symptoms are more likely with large tumors and with metastases beyond the regional lymph nodes. Approximately 10 percent of appendiceal NETs are located at the base of the appendix, where they can cause obstruction, leading to appendicitis .
The endoscopic appearance of appendiceal NETs is pictured in the figure (picture 1).
Staging and prognosis — The 2010 American Joint Committee on Cancer (AJCC) staging manual contained a tumor, node, metastasis (TNM) staging system for well-differentiated appendiceal NETs for the first time; the most recent version (eighth edition, 2017) is outlined in the table (table 5) . Notably, goblet cell carcinoids and poorly differentiated NETs are considered more aggressive and are classified according to the criteria for appendiceal carcinomas. (See "Staging, treatment, and posttreatment surveillance of nonmetastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors" and 'Goblet cell carcinomas' below.)
Staging workup — Only rarely do appendiceal NETs metastasize to the liver. To assess possible liver involvement, consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend a helical, contrast-enhanced, triple-phase computed tomography (CT) scan or magnetic resonance imaging (MRI). Contrast-enhanced MRI is preferred by some physicians because of its greater sensitivity for liver metastases. (See "Diagnosis of the carcinoid syndrome and tumor localization", section on 'Magnetic resonance imaging'.)
Somatostatin receptor-based diagnostic imaging (with indium-111 pentetreotide single-photon emission computed tomography [SPECT] imaging [OctreoScan] or Gallium Ga-68 DOTATATE positron emission tomography [PET] scanning) offers whole-body imaging and is the most sensitive imaging modality for diagnosis and staging of metastatic disease outside of the liver. (See "Diagnosis of the carcinoid syndrome and tumor localization", section on 'Indium-111 pentetreotide (OctreoScan)' and "Diagnosis of the carcinoid syndrome and tumor localization", section on 'Functional PET imaging with 68-Ga DOTATATE' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)
However, in general, radiographic investigation with any of these modalities is unnecessary unless there is evidence of intraabdominal or mesenteric disease, tumor size larger than 2 cm, incomplete resection, or symptoms suggestive of carcinoid syndrome. (See "Diagnosis of the carcinoid syndrome and tumor localization".)
Assay of tumor markers — If there is suspicion for liver metastases or the carcinoid syndrome, measurement of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine collection is indicated. As a general rule, serum concentration of chromogranin A (CGA, a protein that is stored and released with peptides and amines in NETs) parallel 5-HIAA excretion. Although serum levels of CGA are a more sensitive marker than urinary 5-HIAA for gastroenteropancreatic NETs, including those arising in the appendix; they are less specific . Elevated CGA levels are present in a number of other conditions (table 6), and specificity depends on the cutoff value. (See "Diagnosis of the carcinoid syndrome and tumor localization", section on 'Biochemical testing for the carcinoid syndrome'.)
Prognosis — Clinical behavior and prognosis are best predicted by tumor size. Tumors less than 2 cm (found in approximately 95 percent of patients) are unlikely to have metastasized, while up to one-third of larger lesions are metastatic at diagnosis but usually to regional nodes rather than the liver [8,11-13]. In one series of 150 patients with appendiceal NETs from the Mayo Clinic, none of the 127 patients with tumors <2 cm metastasized compared with 3 of 14 with tumors 2 to 3 cm and four of nine with tumors larger than 4 cm .
Outcome is stage dependent. However, there are no data assessing prognosis using the stage groupings from either the 2010 or the 2017 AJCC staging classification. (See 'Staging and prognosis' above.)
Prognosis was addressed in an analysis of 900 appendiceal NETs derived from the Surveillance, Epidemiology, and End Results (SEER) registry of the National Cancer Institute . Five-year, appendiceal NET-specific survival rates were as follows:
●Tumor size <3 cm without regional nodal or distant metastases — 100 percent
●Tumor size ≥2 but <3 cm with regional node metastases, or tumor size ≥3 cm with or without regional nodal or distant metastases — 78 percent
●Distant metastatic spread — 32 percent
The prognostic significance of mesoappendiceal invasion is controversial.
Treatment — Optimal surgical management for appendiceal NETs is subject to some debate. Because most are discovered incidentally in an appendectomy specimen done for other reasons, a decision must be made whether or not to return the patient to the operating room for a right colectomy. Unlike simple appendectomy, colectomy removes the draining lymph nodes of the appendix and any residual disease that might remain at the base of the appendix or in the mesoappendix.
Data from the large Mayo Clinic series cited above suggest that tumor size is an important determinant of the need for further surgery . None of the 120 patients with tumors less than 2 cm developed disease recurrence after simple appendectomy compared with 1 of 12 with a larger tumor. Furthermore, in a compilation of reports from single centers, and large population and literature surveys, the risk of nodal metastases was 0, 7.5, and 33 percent for patients with appendiceal NETs <1.0, 1 to 1.9, and >2 cm, respectively (table 7) .
These data, taken together with the fact that as many as 88 percent of those with regional nodal metastases survive for five years or longer, support the view that patients with tumors >2 cm in size should undergo right colectomy.
On the other hand, whether or not a colectomy should be performed in some patients with smaller tumors is unclear:
●Although the Mayo Clinic series suggests that appendectomy is sufficient in such cases , at least two reports demonstrate a higher potential for metastatic spread with small tumors in the setting of mesoappendiceal invasion [15,16].
●A review of the SEER database of the National Cancer institute reported much higher rates of lymph node metastases than previously appreciated for tumors <2 cm . Among patients reported to the database between 1988 and 2003, lymph node metastases were found in 15 percent of patients (4 of 27) with typical appendiceal NETs less than 1 cm and in 47 percent of patients (16 of 34) with NETs between 1.0 and 1.9 cm. The 10-year survival in these two groups was 100 and 92 percent, respectively, while it was 91 percent in patients with NETs >2 cm, despite the fact that 86 percent of them had lymph node metastases. Whether these excellent outcomes reflected favorable biology or the impact of surgical removal of nodal metastases is unclear.
●A second SEER-based series of 573 patients with well-differentiated appendiceal NETs reported to the registry between 1988 and 2013 reported a 31 percent probability of nodal metastases in tumors 1.1 to 2 cm and a 64 percent probability in tumors >2 cm . The analysis also indicated the prognostic importance of the number of nodes evaluated; among those with tumors >1 cm, five-year overall survival rates were worse when 12 or fewer lymph nodes were identified (five-year survival 88 versus 96 percent).
A nomogram has been developed to predict the risk of nodal metastases based on tumor size and depth of invasion; however, there is no agreement as to what level of risk would warrant a right hemicolectomy .
Thus, there is limited evidence on which to base clear indications for right hemicolectomy in patients with a diagnosis of appendiceal NET. Consensus-based guidelines from the North American Neuroendocrine Tumor Society (NANETS) and European Neuroendocrine Tumor Society (ENETS) suggest completion hemicolectomy for all tumors >2 cm and for smaller tumors between 1 and 2 cm in the presence of deep mesoappendiceal invasion, positive or unclear margins, higher proliferative rate (grade 2), angioinvasion, and mixed histology [goblet cell carcinoid, adenocarcinoid] [20,21]. We agree with these guidelines and pursue complete right colectomy for all tumors >2 cm and for those tumors <2 cm if there is evidence of mesoappendiceal or vascular invasion, positive or uncertain margins, and mixed histology. However, others disagree and consider appendectomy alone to be adequate for tumors <2 cm, even with mesoappendiceal invasion or other adverse histologic features.
For NETs between 1.0 and 1.9 cm in the absence of mesoappendiceal invasion and for tumors less than 1 cm in size, there is general agreement that simple appendectomy alone is adequate. Prior to the procedure, a full colonoscopy should be undertaken to rule out a synchronous colon cancer.
The surgeon should also perform a complete inspection of the bowel since up to 25 percent of midgut NETs (small bowel, proximal colon) may be multifocal and sometimes associated with malignant gastrointestinal tumors of other histologic types [22,23].
Posttreatment follow-up — There are no randomized trial data or evidence-based guidelines for follow-up after resection of a gastrointestinal NET at any site. Recommendations are generally based upon risk and anticipated patterns of recurrence based upon the primary tumor characteristics. Various organizations have put forth recommendations for follow-up surveillance after resection:
Recommendations from the NCCN are based on size of the tumor. Patients with tumors <2 cm do not require routine surveillance, and tests should only be ordered as clinically indicated. For tumors >2 cm, a history and physical is recommended between 3 and 12 months after resection, as well as consideration of tumor markers (5-HIAA, chromogranin) and abdominal imaging; after the first year, a history and physical, and consideration of tumor markers is recommended every 6 to 12 months, with imaging only as clinically indicated.
NANETS has similar recommendations as NCCN, with the exception that tumors <1 cm do not generally require further surveillance, but tumors between 1 to 2 cm with poor prognostic features (nodal metastases, lymphovascular invasion, mesoappendiceal invasion, intermediate- or high-grade or mixed histology) should trigger surveillance similar to tumors >2 cm, with history and physical, tumor markers (5-HIAA and chromogranin), and consideration of CT or MRI imaging within three to six months of surgery and subsequently every 6 to 12 months for at least seven years after surgery .
ENETS suggests consideration of periodic radiographic imaging and SRS for T2-3 tumors of the appendix and tumor markers only in the presence of a tumor visualized by imaging .
In our practice, we generally follow the NCCN guidelines:
●For appendiceal NETs ≤2 cm confined to the appendix and treated by simple appendectomy, no follow-up is required.
●For larger or node-positive tumors treated by right hemicolectomy, between 3 and 12 months postresection, we perform a history and physical examination, obtain chromogranin testing, and consider CT imaging.
●Beyond one year postresection, we perform a history and physical examination every 6 to 12 months along with chromogranin testing and radiographic imaging studies annually.
Treatment of metastatic disease — For patients who have somatostatin receptor-positive disease (as determined by somatostatin receptor-based diagnostic imaging), symptoms of carcinoid syndrome can often be well controlled with somatostatin analogs. Although few patients have an objective tumor regression, somatostatin analogs do prolong the time to disease progress and overall survival in asymptomatic patients. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Somatostatin analogs'.)
Liver resection for selected patients may be beneficial, particularly for symptom relief. If liver resection is not feasible, then embolization of the hepatic artery might be considered. Although palliation of symptoms is obtained in over 50 percent of selected patients, response duration is short. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection' and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic artery embolization'.)
The best systemic therapy option for patients with progressive metastatic gastrointestinal NETs is not established. As a result, there is no standard regimen, and the role of chemotherapy continues to be debated. The management of metastatic gastrointestinal NETs is discussed in detail elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)
Everolimus is an option for patients with progression following somatostatin analog therapy. In addition, for patients with somatostatin receptor-positive tumors (as determined by somatostatin receptor-based diagnostic imaging), treatment with peptide receptor radioligand therapy (eg, lutetium-177-DOTA-octreotate [177Lu-DOTA-TATE]) is a reasonable option, either at the time of progression on somatostatin analog or following progression on everolimus, where it is available. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)
EPITHELIAL TUMORS — The literature regarding classification of epithelial tumors of the appendix is confusing, particularly for mucinous tumors [25,26]. The 2010 World Health Organization (WHO) classification recognizes three main categories of mucinous neoplasms: mucinous adenoma, low-grade appendiceal mucinous neoplasm (LAMN, also called appendiceal neoplasms of uncertain malignant potential), and appendiceal adenocarcinoma .
Most schemes attempt to classify the tumors as either benign or malignant according to their clinical behavior, but there is some overlap. As an example, mucoceles that develop from adenomas can be completely eradicated with complete excision. But "benign" adenomas that perforate can recur as disseminated peritoneal mucinous tumors. The term pseudomyxoma peritonei (PMP) is typically applied to this clinical scenario. PMP is discussed in more detail below. (See 'Pseudomyxoma peritonei' below.)
The spectrum of epithelial neoplasms ranges from the benign mucocele to an aggressive adenocarcinoma. Survival differs according to histologic type (table 8) . The different types of epithelial tumors will be discussed according to their level of aggressiveness.
Appendiceal mucoceles — In the broadest sense, the term appendiceal mucocele refers to any lesion that is characterized by a distended, mucus-filled appendix; it may be associated with either a benign or malignant condition.
●Mucosal hyperplasia, which is histologically similar to a hyperplastic colon polyp.
●Simple or retention cysts, characterized by degenerative epithelial changes due to obstruction (eg, fecalith) and distention.
●Mucinous adenomas (previously called cystadenomas), which are histologically benign and morphologically reminiscent of adenomatous colon polyps or villous adenomas. Mucinous adenomas are confined to the mucosa.
●Mucinous appendiceal tumors of uncertain malignant potential. The mucinous appendiceal tumors (which are referred to as LAMNs by the WHO) demonstrate pushing invasion with tongues of epithelium dissecting outward into the muscularis mucosae .
●Mucinous appendiceal adenocarcinomas (previously referred to as cystadenocarcinomas), which demonstrate glandular invasion into the stroma and/or PMP.
Mucoceles that are due to hyperplasia or that arise from an accumulation of mucus distal to an obstruction in the appendiceal lumen, even if they rupture, are not associated with recurrence of the problem. In contrast, mucoceles that develop from true neoplasms (cystadenomas or cystadenocarcinomas) secrete mucin. Rupture can lead to intraperitoneal spread of neoplastic cells and the clinical picture of PMP. This syndrome is discussed in detail below. (See 'Pseudomyxoma peritonei' below.)
Surgical resection should be pursued, even for a benign-appearing appendiceal mucocele, since lesions that appear to be benign on imaging studies may harbor a cystadenocarcinoma. The clinical manifestations, diagnosis, and management of appendiceal mucoceles are discussed in detail separately. (See "Appendiceal mucoceles".)
Pseudomyxoma peritonei — PMP is a unique condition characterized by diffuse collections of gelatinous material in the abdomen and pelvis, and mucinous implants on the peritoneal surfaces. The term PMP was originally applied to intraperitoneal mucinous spread originating from a cystadenoma of the appendix. As the tumor 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" . Inevitably, this condition progresses to intestinal obstruction, which is fatal without treatment.
Over the years, the term PMP began to be used more generally by some authors and clinicians to signify not only intraperitoneal mucinous dissemination from rupture of a benign cystadenoma, but also peritoneal dissemination of mucus-producing invasive adenocarcinomas of the appendix, large and small bowel, lung, breast, pancreas, stomach, bile ducts, gallbladder, and fallopian tubes/ovary [29,30].
However, the term PMP should be limited to "a pathologically and prognostically homogeneous group of cases characterized by histologically benign peritoneal tumors that are frequently associated with an appendiceal mucinous adenoma" [28,29]. These cases are more recently categorized as disseminated peritoneal adenomucinosis (DPAM) .
Although this narrow definition creates a more homogeneous entity for the purpose of evaluating treatment efficacy, it makes comparison of published results difficult as the definition has not been widely accepted. Although some consider that disseminated mucin-producing adenocarcinomas of the appendix (referred to as peritoneal mucinous carcinomatosis) fall into the category of PMP, this variant is an aggressive subset of peritoneal mucinous tumors that does not behave similarly to the more indolent DPAM [32,33]. The prognostic differences between 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 .
●In another retrospective multicenter series of 2298 patients presenting with PMP and undergoing cytoreductive surgery and intraperitoneal chemotherapy, 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 . (See 'Aggressive cytoreduction and intraperitoneal chemotherapy' below.)
Clinical presentation — PMP is more common in females and is found unexpectedly in approximately two of every 10,000 laparotomies . The most common presenting symptom in both men and women 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 . When mucoid fluid is encountered at the time of a hernia repair, recovery of the fluid and hernia sac for histologic study is important . (See "Classification, clinical features, and diagnosis of inguinal and femoral hernias in adults".)
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 relative sparing and central displacement of the small bowel and mesentery (termed the "redistribution phenomenon") [28,36].
It has been suggested that the presence of tumor implants >5 cm on the jejunum, proximal ileum, or adjacent mesentery is more consistent with mucinous adenocarcinoma with secondary peritoneal carcinomatosis than DPAM [28,36]. The presence of segmental obstruction of the small bowel also raises suspicion for peritoneal adenocarcinomatosis, and both findings predict a less favorable outcome from aggressive cytoreduction and heated intraperitoneal chemotherapy (HIPEC; see below) . Whether gadolinium-enhanced magnetic resonance imaging (MRI) can permit the preoperative distinction between DPAM and peritoneal mucinous carcinomatosis is under study and not yet established .
Treatment — Standard treatment for PMP (defined throughout the rest of this review as the benign form, DPAM) is repeated surgical debulking for symptomatic disease . This treatment is not curative but aims to resect gross disease to limit the buildup of mucus and its pressure effect. Disease recurrence requires repeated and progressively more difficult surgery due to adhesions and fibrosis.
The addition of external beam radiotherapy, intraperitoneal radioisotopes, intraperitoneal chemotherapy, and systemic chemotherapy have been attempted to improve outcomes . 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 ten years (table 9) [30,38,39].
Aggressive cytoreduction and intraperitoneal chemotherapy — A more aggressive approach that includes radical surgical removal of all intraabdominal and pelvic disease and the administration of intraperitoneal heated chemotherapy has been adopted by some clinicians aiming for cure. In view of the rarity of extraperitoneal spread in patients with PMP or DPAM, it would seem intuitive that intraperitoneal chemotherapy (which can permit a several-fold increase in drug concentration in the abdominal cavity compared to 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 [39-42].
Drug penetration may be enhanced by heating the perfusate containing chemotherapy, an approach termed HIPEC [28,42]. This approach is best suited to patients with minimal residual disease (deposits smaller than 2 to 2.5 mm) after surgical cytoreduction. It is unlikely that even a heated solution of chemotherapy could penetrate large tumor deposits.
Sugarbaker and colleagues have written the most extensively about treatment of peritoneal surface malignancy with aggressive surgical debulking and HIPEC. His group uses four clinical assessments to select patients who are most likely to benefit from combined treatment [36,42]:
●Histopathologic assessment – Noninvasive malignancies, such as PMP or peritoneal mesothelioma, are more likely to be made visibly disease-free through a peritonectomy procedure and are less likely than other invasive histologies to have spread to regional nodes, liver, or other systemic sites. (See "Malignant peritoneal mesothelioma: Treatment".)
●Preoperative contrast (oral and intravenous [IV])-enhanced 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 cytoreduction 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 'Clinical presentation' above.)
In another report, extensive disease in the right upper quadrant on preoperative CT was particularly related to a poorer survival outcome . Others use a scoring system (simplified preoperative assessment for appendix tumor [SPAAT]) to predict the likelihood of an incomplete surgical cytoreduction at the time of surgery [44,45]. 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.
●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 derived intraoperatively.
The specifics of the Sugarbaker approach to heated intraoperative (usually mitomycin) and early postoperative intraperitoneal chemotherapy (usually fluorouracil) have been described in detail [36,42].
Results from the three largest series are detailed below:
●A 2001 report from Sugarbaker's group included 108 patients with PMP treated over a 10-year period (1983 to 1993) with surgical debulking and intraoperative intraperitoneal mitomycin (with or without heating) . The chemotherapy regimen also included intraperitoneal fluorouracil (FU) during postoperative days 1 to 6 and three subsequent courses of adjuvant intravenous mitomycin and intraperitoneal FU.
The patient population was heterogeneous. 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 carcinoma (all of the appendiceal mucinous adenocarcinomas were of the signet ring cell variant, see below); 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 10).
●The influence of histology on outcomes was addressed in an earlier report from Sugarbaker's group that included 385 patients with peritoneal surface spread of appendiceal malignancy who underwent aggressive surgical debulking and heated or unheated intraperitoneal chemotherapy from 1989 to 1999 [46,47]. In multivariate analysis, prognostic factors for survival included completeness of cytoreduction, the histopathology of the appendiceal malignancy, and the extent of previous surgical interventions. Patients who underwent complete cytoreduction for adenomucinosis (DPAM) had a five-year survival rate of 86 percent; with those with "hybrid" pathology, the five–year survival rate was 50 percent. Patients who had incomplete cytoreduction (>2.5 mm residual) had markedly worse outcomes (five- and 10-year survival rates of 20 and 0 percent, respectively).
The poor prognosis of this group was confirmed in later report of 174 patients undergoing incomplete cytoreduction (out of a total of 645 patients with epithelial peritoneal surface malignancy of appendiceal origin undergoing surgical debulking and HIPEC) . Survival rates at one, three, and five years were 71, 34, and 15 percent, respectively.
Other groups have reported their results using radical surgery followed by HIPEC in series that generally consist of a heterogeneous group of patients with both classically defined PMP (DPAM) and peritoneal mucinous carcinomatosis [33,49]. A compilation of results (as well as reported perioperative morbidity and mortality rates) from a reported series is presented in the table (table 11) [33,46,50-56]. Results in populations with peritoneal mucinous carcinomatosis are addressed below. (See 'Heated intraperitoneal chemotherapy' below.)
Results seem to be most favorable in patients with the DPAM histology, as evidenced by the following reports (see 'Pseudomyxoma peritonei' above):
●A systematic review  included 382 patients with the histology of DPAM only, whose results with radical surgery and HIPEC were reported in five case series, three from the Sugarbaker group [30,32,49,57,58]. 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 12).
●A multi-institutional registry-based series of 2298 patients undergoing CRC and HIPEC for PMP included 1419 with DPAM, 700 with peritoneal mucinous adenocarcinoma, and 140 with hybrid histology . 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 prolonged survival is due to treatment or to biologic features that allow these patients to undergo complete cytoreductive surgery.
Furthermore, the quality of the cytoreductive surgery is dependent upon the skills and level of experience of the surgeon . 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 is available on Dr. Sugarbaker's website . Additional information on US centers is available through a patient-oriented website .
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. At centers with expertise in this procedure, cytoreductive surgery followed by HIPEC is an alternative to periodic debulking without HIPEC for suitable patients with symptomatic disease.
Goblet cell carcinomas — Histologically, goblet cell carcinomas (adenocarcinoids) have features of both adenocarcinomas and carcinoids. They are more aggressive than carcinoids and are classified and staged as appendiceal carcinomas (table 13) [62,63]. Prognosis is worse than with malignant carcinoid but better than appendiceal adenocarcinoma (table 2) [3,64].
Affected patients most often present with acute or chronic abdominal pain; very few are incidentally found at appendectomy . The average age at presentation is 52 to 58, closer to the age of presentation of adenocarcinomas (approximately 60) than carcinoids (approximately 38) [4,65,66].
The five-year survival rate for all stages combined is approximately 78 percent (table 8). Five-year survival rates according to disease stage at presentation in a series of 57 patients treated at the Mayo Clinic were as follows :
●Stage I – 100 percent
●Stage II – 76 percent
●Stage III – 22 percent
●Stage IV – 14 percent
The characteristic pattern is that of submucosal growth without a discernible tumor mass. Of all the tumor types listed in Table 6, adenocarcinoids have the lowest frequency of regional nodal metastases (17 percent in one series ), but they have the potential to spread intraperitoneally [4,67]. In the McCusker series, which included 227 adenocarcinoids, 51 percent had either spread through the serosa or had mesoappendiceal invasion, while 14 percent extended to other organs or the peritoneum . In women, adenocarcinoids may also present with ovarian metastases (a Krukenberg tumor [65,68]).
Treatment — The optimal treatment for an adenocarcinoid tumor is unclear. Some suggest simple appendectomy for localized low-grade tumors , while others advocate right colectomy for all goblet cell carcinoids [20,21,70,71]. Still others suggest right colectomy only if the tumor is >2 cm in size, involves the base of the appendix, is associated with nodal metastases, or has atypical histologic features [67,72-75]. In our own practice, we generally recommend most patients with adenocarcinoid tumors to have complete right hemicolectomy within three months of initially appendectomy if the patient is fit for additional surgery.
As noted above, intraperitoneal spread is a common occurrence, and the intraperitoneal metastatic deposits are typically adenocarcinoma rather than carcinoid [76,77]. Such cases behave as aggressively as an appendiceal adenocarcinoma with peritoneal spread (see 'Heated intraperitoneal chemotherapy' below) [67,78,79]. Aggressive debulking of intraabdominal metastases may improve symptom control and prolong survival [67,68].
Chemotherapy responsiveness may be higher with appendiceal adenocarcinoids than it is for other appendiceal adenocarcinomas [79,80]. At least one case report documents a complete and persistent remission with the FOLFOX regimen (fluorouracil, leucovorin, and oxaliplatin, (table 14)) in a patient with metastatic disease at diagnosis . (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'First-line oxaliplatin plus FU/LV'.)
The role of adjuvant therapy for patients who have early stage goblet cell carcinomas is unknown. Although there are no data to support this practice, some oncologists would consider adjuvant chemotherapy therapy in the setting of node-positive disease, similar to appendiceal adenocarcinoma. (See 'Adenocarcinoma' below.)
Adenocarcinoma — In contrast to other appendiceal neoplasms, the majority of patients with adenocarcinomas present with a picture of acute appendicitis . 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 .
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 2) .
The contrast between intestinal-type and mucinous appendiceal adenocarcinomas has been given much consideration. Intestinal-type tumors typically manifest as a focal mass without mucocele formation. Although they have a poorer prognosis in many series [83-85], others suggest that this is the case only if the disease is locoregionally advanced at presentation .
The mucinous type seems to spread more often throughout the peritoneal cavity, while differences in the frequency of nodal metastases between the two types are not as clear. Some series report that intestinal-type tumors have a higher frequency of nodal metastases , but other reports are conflicting [4,81]. In the McCusker series, the incidence of nodal metastases was not significantly different between mucinous and colonic type adenocarcinomas (26 and 31 percent, respectively) (table 15) . On the other hand, in a series of 36 patients with appendiceal adenocarcinoma from our institution, 17 of whom had full histologic information, nodal metastases were present in one of 10 colonic adenocarcinomas compared with two of seven mucinous adenocarcinomas (10 versus 28 percent) .
Staging and prognosis — The natural history and prognosis of appendiceal adenocarcinomas differ from that of adenocarcinomas arising in other large bowel sites (table 16) . 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 LAMN that invade or push into the muscularis propria) and to the N stage definitions (which now harmonize with categories for colorectal cancer) compared with the earlier 2010 version, adopts a three-tiered grading system for mucinous grading, as well as revises stage IVa disease to include intraperitoneal acellular mucin as M1a disease and intraperitoneal grade 1 tumors as M1b disease (table 13) . (See "Pathology and prognostic determinants of colorectal cancer", section on 'Appendix cancer'.)
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) . However, prognosis varies according to histologic type (table 2) , a distinction that is not evident in most series that stratify according to disease stage.
Treatment — In general, the optimal treatment for most appendiceal adenocarcinomas is a right colectomy, although this is debated. Several retrospective series that are uncontrolled for stage suggest that survival is better with colectomy as compared to simple appendectomy [2,81-84,89].
Nonetheless, given the low likelihood of nodal metastases, some authors advocate a simple appendectomy for adenocarcinomas that are confined to the mucosa or well-differentiated lesions that invade no deeper than the submucosa , and hemicolectomy for more deeply invasive tumors. Although this distinction can be difficult to make intraoperatively, a more common scenario is the unexpected finding of an adenocarcinoma when the surgical report of an appendectomy specimen is finalized. In such cases, a right colectomy need not be pursued for appendiceal adenocarcinomas that are confined to the mucosa or well-differentiated lesions that invade no deeper than the submucosa. Whether there is a survival benefit for right colectomy (versus simple appendectomy) in the setting of regionally advanced (ie, metastatic to nodes or locally to peritoneum) adenocarcinoma, particularly for mucinous adenocarcinomas, is unclear [86,91]. Practice is variable.
Routine oophorectomy has been proposed at the time of colectomy because the ovaries are a common organ for metastases [83,84,89]. Resection of ovaries that are involved with metastatic spread is clearly beneficial. As an example, in the Mayo series described above, women who underwent resection of ovarian metastases had a 31 percent five-year survival rate . However, no series has shown an improvement in survival with prophylactic oophorectomy, and this approach is not recommended.
The role of adjuvant chemotherapy for adenocarcinoma of the appendix is unknown. 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. Despite the lack of available data, many medical oncologists extrapolate from data showing the efficacy of adjuvant FU-based chemotherapy for node-positive colon cancer, particularly for patients with intestinal type adenocarcinoma (see "Adjuvant therapy for resected stage III (node-positive) colon cancer"). However, specific benefit from this approach is unproven, and there are no published recommendations from expert groups.
The benefit of adjuvant radiation therapy is also uncertain; as with chemotherapy, randomized trials have not been conducted. One small retrospective study suggested that postoperative external beam radiotherapy improves local control and survival for patients with locally advanced but nonmetastatic disease (14 of 15 had clinical bowel perforation and seven [47 percent] had microscopic residual disease after surgery) . Five of 10 patients failed locally after surgery alone; in contrast, only one of five failed locally after postoperative radiotherapy.
Heated intraperitoneal chemotherapy — Given that adenocarcinoma of the appendix often fails with intraperitoneal spread , it would seem intuitive that an aggressive approach that includes surgical removal of all intraabdominal and pelvic disease and the administration of HIPEC might control growth of peritoneal disease. This rationale is the same as applied to the treatment of pseudomyxoma peritonei (PMP). (See 'Pseudomyxoma peritonei' above.)
However, in contrast to PMP, aggressive cytoreductive surgery and HIPEC are less likely to produce lasting benefit for mucinous peritoneal carcinomatosis, and patient selection is critical. Rapid recurrence of the peritoneal surface disease, combined with progression of nodal or extraperitoneal systemic disease, interferes with long-term benefit. This approach is best suited to asymptomatic patients with small volume peritoneal carcinomatosis who are likely to be successfully cytoreduced (leaving behind deposits <2.5 mm) with surgical debulking .
As noted above, Sugarbaker's group uses four clinicopathologic assessments to select patients with peritoneal surface malignancy who are most likely to benefit from combined treatment . In general, noninvasive malignancies such as PMP or cystic mesothelioma are much more likely to undergo successful debulking and less likely than invasive adenocarcinomas to have spread to regional nodes, liver or other systemic sites.
Although CT scans can sometimes not distinguish diffuse peritoneal adenomucinosis (DPAM) from mucinous peritoneal carcinomatosis, the presence of tumor implants >5 cm on the jejunum, proximal ileum, or adjacent mesentery is more consistent with mucinous adenocarcinoma with secondary peritoneal carcinomatosis than DPAM [28,36]. In addition, the presence of segmental obstruction of the small bowel also raises suspicion for peritoneal adenocarcinomatosis, and both findings predict a less favorable outcome from aggressive cytoreduction and heated intraperitoneal heated chemotherapy (HIPEC, see below) . (See 'Pseudomyxoma peritonei' above.).
Aggressive cytoreduction and HIPEC has been tried for secondary peritoneal carcinomatosis in several centers throughout the world, although 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 surgical debulking (aiming to achieve deposits ≤2.5 mm) with HIPEC versus systemic chemotherapy without debulking . Only palliative surgery was permitted in the control patients, and they received FU and leucovorin given weekly until progression. In the experimental group, after debulking, the abdominal cavity was perfused for 90 minutes with isotonic dialysis fluid containing mitomycin and heated to 41 degrees C. After HIPEC, anastomoses were completed and the abdomen closed. Systemic chemotherapy similar to the control arm was started six weeks after cytoreduction and 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). 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 surgical debulking, and the HIPEC made little difference.
Several institutions have published their experience with this approach for peritoneal mucinous carcinomatosis from an appendiceal adenocarcinoma:
●In a report from Australia, 46 patients with peritoneal metastases from mucinous or nonmucinous appendiceal adenocarcinoma underwent surgical debulking and HIPEC with mitomycin C and/or early postoperative chemotherapy with intraperitoneal fluorouracil . The 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 surgical debulking and HIPEC over a 17-year period . 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 overall 5- and 10-year survival rates were 72 and 54 percent, respectively.
●Another retrospective analysis included 282 patients with peritoneal mucinous carcinomatosis of appendiceal origin treated with CRS; most had HIPEC . Before undergoing the procedure, 39 percent received systemic chemotherapy. Intraoperatively, a complete surgical cytoreduction was achieved in 82 percent, despite a high peritoneal cancer index (PCI) of 14, as assessed by the Dutch simplified PCI . Most received HIPEC using mitomycin. Major postoperative morbidity occurred in 25 percent of patients and the 60-dady mortality rate was 1.1 percent.
At a median follow-up of 1.98 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 those with visible residual tumor, even as small as 2.5 mm. The authors concluded that meaningful long-term survival can be achieved using an aggressive approach to therapy, even in patients with extensive peritoneal disease.
Although it is difficult to know whether debulking and/or addition of HIPEC impacted survival, these long-term outcomes are far superior to any reported for similar group of patients with peritoneal spread from appendiceal adenocarcinoma treated without debulking 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 the HIPEC.
Complications — Treatment-related morbidity may be substantial particularly if more extensive surgery is required to achieve complete cytoreduction [86,97-99]. This was illustrated in a Dutch series of 102 patients undergoing surgical cytoreduction followed by HIPEC . According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) , grade 3 (not immediately life-threatening but hospitalization or prolongation of hospitalization required), 4 (life-threatening consequences, urgent intervention indicated) or 5 (fatal) toxicity was observed in 66 (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 significant higher in patients undergoing the procedure for recurrent colorectal cancer, those needing three or more anastomoses, having more than five regions affected, and 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 . 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 Sugarbaker [46,86,102,103], although other groups have reported favorable results as well [101,104]:
●One review from Sugarbaker's 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 who might be expected to have the highest rates of surgical morbidity and mortality) . Although there were four postoperative deaths (mortality rate 8.6 percent), the incidence of postoperative grade 3 or 4 toxicity was significantly lower than 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 (cytoreductive surgery plus perioperative intraperitoneal chemotherapy) to treat either DPAM or peritoneal mucinous adenocarcinoma . 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 operative room.
Systemic chemotherapy — The utility of systemic chemotherapy for metastatic appendiceal adenocarcinoma and PMP has not been systematically studied. As a result, much is unknown.
Historically these tumors (particularly mucinous adenocarcinomas) have been considered refractory to intravenous fluorouracil (FU)-based chemotherapy, although the following data suggest this is not the case:
●A report from M. D. Anderson included 54 patients with a mucinous adenocarcinoma, signet ring cell adenocarcinoma, or PMP, each originating from the appendix, who received at least two courses of chemotherapy . 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). The 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 . The overall response rate was approximately 45 percent, and median progression-free and overall survival was 6.9 and 20.4 months, respectively.
●The only published phase II trial in advanced unresectable PMP suggested activity for capecitabine combined with mitomycin C . Eligible patients had unresectable DPAM (n = 27) or peritoneal mucinous carcinomatosis without (n = 3) or with (n = 10) intermediate or discordant features; those with bowel obstruction or any condition that might affect the oral absorption of capecitabine were excluded. At the time of enrollment, 23 patients (58 percent) had progressing disease while 17 (42 percent) had a stable pattern of tumor growth. Treatment consisted of capecitabine (1250 mg/m2 twice daily on days 1 to 14 every 21 days) and mitomycin (7 mg/m2 on day 1 every six weeks).
After six months, three 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. Of the 17 patients with stable disease prior to trial entry, three had a reduction in the volume of mucus which was maintained at three and six months; nine others had persisting stable disease, and five progressed. Two patients with initially unresectable disease were able to undergo potentially curative surgical cytoreduction after chemotherapy. Thus, of 39 assessable patients, 15 (38 percent) appeared to benefit from treatment.
Overall, therapy was reasonable 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.
●As previously noted, a durable response has been reported using an oxaliplatin-based regimen in a patient with advanced goblet cell carcinoma (adenocarcinoid). (See 'Goblet cell carcinomas' above.)
One problem is accurate response assessment, as illustrated by a prospective study of 34 consecutive patients with mucinous peritoneal carcinomatosis who received neoadjuvant treatment with oxaliplatin plus short-term infusional FU and leucovorin (FOLFOX, (table 14)) or capecitabine plus oxaliplatin . By radiographic (CT) assessment, 22 patients (65 percent) were thought to have stable disease, seven (20 percent) to have progression, and five (15 percent), a partial response. However, intraoperative findings were consistent with progressive disease in 50 percent of cases, and 29 percent of patients had histologic evidence to support some response to therapy.
There is no clear evidence supporting the superiority of any particular chemotherapy regimen in patients with appendiceal adenocarcinoma or PMP. Given the greater antitumor efficacy of oxaliplatin and irinotecan-based regimens compared to FU alone (with or without leucovorin) in patients with metastatic colorectal adenocarcinoma, trials utilizing these regimens for appendiceal adenocarcinoma are urgently needed. The role of molecularly targeted therapies such as bevacizumab, cetuximab, and panitumumab (all approved for treatment of metastatic colorectal cancer) in addition to chemotherapy is unknown in this disease.
Despite the paucity of data on efficacy, medical oncologists typically utilize combinations of these agents in a manner that is similar to that used in the treatment of metastatic colorectal cancer. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials" and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations".)
Utility of tumor markers — A variety of serum markers have been associated with gastrointestinal tract tumors, particularly carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9, and CA-125. For example, in the case of colorectal cancer, CEA is useful for prognostication at the time of initial diagnosis, and for posttreatment 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 "Surveillance after colorectal cancer resection", section on 'Carcinoembryonic antigen' and "Systemic chemotherapy for metastatic colorectal cancer: General principles", section on 'Assessment during therapy' and "Chemotherapy for advanced exocrine pancreatic cancer", section on 'Treatment endpoints' and "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Tumor markers'.)
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 [109-113].
If initially elevated, tumor markers such as CEA, CA 19-9, or CA-125 may be useful in the posttreatment 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 and HIPEC .
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 to apply in this setting. (See "Surveillance after colorectal cancer resection", section on 'Carcinoembryonic antigen'.)
SUMMARY AND RECOMMENDATIONS
●Appendix cancer is rare and most commonly found incidentally in an appendectomy specimen that was obtained for an unrelated condition. The main histologic types are carcinoids, adenocarcinomas, adenocarcinoids, cystadenomas, and cystadenocarcinomas. (See 'Introduction' above.)
●For appendiceal well-differentiated neuroendocrine tumors (NETs), there is limited evidence on which to base clear indications for right hemicolectomy. However, we suggest reoperation and right colectomy for tumors larger than 2 cm and for tumors 1 to 1.9 cm with mesoappendiceal or vascular invasion, positive or uncertain margins, or mixed histology (eg, adenocarcinoid) (Grade 2C). Most patients have localized disease, and the prognosis is excellent.
Simple appendectomy alone is sufficient for tumors <1.0 cm in the absence of mesoappendiceal invasion and for tumors 1 to 1.9 cm that lack mesoappendiceal invasion and other adverse histologic features. (See 'Neuroendocrine tumors' above.)
Following treatment, we follow the National Comprehensive Cancer Network (NCCN) guidelines for posttreatment surveillance (see 'Posttreatment follow-up' above):
•For appendiceal NETs ≤2 cm confined to the appendix and treated by simple appendectomy, no follow-up is required.
•For larger or node-positive tumors treated by right hemicolectomy, between 3 and 12 months postresection, we perform a history and physical examination, obtain chromogranin testing, and consider computed tomography (CT) imaging.
•Beyond one year postresection, we perform a history and physical examination every 6 to 12 months along with chromogranin testing and consideration of radiographic imaging studies annually.
●The spectrum of epithelial tumors of the appendix ranges from the benign mucocele to an aggressive adenocarcinoma. Simple appendectomy, taking care not to rupture the tumor intraoperatively, is sufficient therapy for benign appendiceal mucoceles, cystadenomas, and some cystadenocarcinomas. A right colectomy is indicated for cystadenocarcinomas with mesenteric or adjacent organ involvement, complicated mucoceles with involvement of the terminal ileum or cecum, cystadenocarcinomas, and for goblet cell carcinoids. (See 'Appendiceal mucoceles' above and "Appendiceal mucoceles", section on 'Management' and 'Treatment' above.)
●Pseudomyxoma peritonei (PMP) is a unique condition characterized by diffuse collections of gelatinous material in the abdomen and pelvis, and associated with mucinous implants on the peritoneal surfaces. In our view, this term should be reserved for the clinical situation in which a ruptured cystadenoma seeds the peritoneal cavity with mucus-producing epithelial cells, termed diffuse peritoneal adenomucinosis (DPAM). The natural history is one of indolent but progressive growth, and if left untreated, this is a fatal condition.
A standard treatment for PMP is repeated surgical debulking for symptomatic disease. This treatment is not curative but aims to limit the buildup of mucus and its pressure effect. A more aggressive approach using radical surgical cytoreduction of all intraabdominal and pelvic disease, and heated intraperitoneal chemotherapy (HIPEC) has been adopted by some clinicians aiming for cure. At centers with expertise in this procedure, cytoreductive surgery followed by HIPEC is an alternative to periodic debulking without HIPEC for suitable patients with symptomatic disease. The importance of surgical technique and surgeon experience to the success and safety of this approach cannot be overemphasized. (See 'Pseudomyxoma peritonei' above.)
●In contrast to other appendiceal tumors, adenocarcinomas more often present with a clinical picture of acute appendicitis. We consider that standard treatment is a right colectomy unless the tumor is confined to the mucosa or a well-differentiated lesion that invades no deeper than the submucosa.
The role of adjuvant chemotherapy for adenocarcinoma of the appendix is unknown. Despite the lack of available data, we suggest adjuvant FU-based chemotherapy for patients with node-positive intestinal type adenocarcinoma, extrapolating from data on adjuvant chemotherapy for node-positive colon cancer (Grade 2B). (See 'Adenocarcinoma' above.)
●Optimal treatment of patients with intraperitoneal dissemination of appendiceal adenocarcinoma (mucinous peritoneal carcinomatosis as distinguished from DPAM) is unclear. Selected patients treated with aggressive surgical cytoreduction and HIPEC may do well long-term, but patient selection and the experience of the treating team are critical. In uncontrolled series from experienced institutions, long-term survival rates in highly selected patients range from 28 to 72 percent at 3 to 10 years. (See 'Heated intraperitoneal chemotherapy' above.)
●The benefit of systemic chemotherapy for advanced disease is unknown. Although mucinous appendiceal adenocarcinomas have been thought to be relatively chemotherapy-refractory, case reports suggest some level of benefit for therapy in individual patients. (See 'Systemic chemotherapy' above.)
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