The American Society of Colon and Rectal Surgeons, Clinical Practice Guidelines for the Management of Appendiceal Neoplasms

Abstract

The American Society of Colon and Rectal Surgeons is dedicated to ensuring high-quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The Clinical Practice Guidelines Committee is composed of society members who are chosen because they have demonstrated expertise in the specialty of colon and rectal surgery. This Committee was created to lead international efforts in defining quality care for conditions related to the colon, rectum, and anus. This is accompanied by the development of clinical practice guidelines based on the best available evidence. These guidelines are inclusive but not prescriptive. Their purpose is to provide information to support decision-making rather than to dictate a specific form of treatment. These guidelines are intended for the use of all practitioners, healthcare workers, and patients who desire information about the management of the conditions addressed by the topics covered in these guidelines. It should be recognized that these guidelines should not be deemed inclusive of all proper methods of care nor exclusive of methods of care reasonably directed toward obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all the circumstances presented by the individual patient. STATEMENT OF THE PROBLEM Historically, the estimated incidence of appendiceal tumors was 0.12 cases per 1,000,000 people per year; however, based on recent large database studies, the incidence may be as high as 0.97 per 100,000 population.1–3 It is unclear whether this increase reflects an actual change in the disease occurrence or simply greater recognition and reporting. Although tumors of the appendix are rare, surgeons should be familiar with the implications of appendiceal pathology, because almost 300,000 appendectomies are performed annually in the United States, and neoplasia is found in ≈1% to 2% of these specimens.4–6 CLASSIFICATION BY HISTOPATHOLOGY Given the rarity and multiple different terms used to describe appendiceal neoplasms, consistency regarding their classification not only allows for improved reporting but also for more precise management. In general terms, appendiceal neoplasms can be broadly described as epithelial, such as adenomas or adenocarcinomas, or nonepithelial (eg, neuroendocrine or lymphoma). The epithelial group is often further subdivided based on mucin production, because mucinous tumors have distinctly different biologic behavior and oncologic outcomes from nonmucinous neoplasms.4 The World Health Organization classifies the majority of noninvasive epithelial lesions as low-grade appendiceal mucinous neoplasms (LAMNs).7 Histologically, LAMNs are characterized by well-differentiated adenomas that can proliferate outside the appendix in a malignant fashion. Acellular or cellular extra-appendiceal mucin may be associated with LAMNs, although this is not a requirement. The LAMN terminology includes lesions that were described previously as mucoceles or mucinous cystadenomas, which are terms no longer in use. Some authors have suggested an intermediate grouping between traditional LAMNs and invasive carcinoma.8 These LAMNs of uncertain malignant potential may exhibit gross perforation, mural fibrosis, mucin dissecting within the appendiceal wall, or acellular mucin in the periappendiceal soft tissues. High-grade appendiceal neoplasms (HAMNs) share some histologic features with LAMNs but exhibit more aggressive cytologic atypia. The distinct biological and clinical behaviors of HAMNs are poorly characterized.9 Appendiceal adenocarcinomas may be either mucinous or nonmucinous. Mucinous adenocarcinomas are characterized by invasive glands containing high-grade cytologic atypia and extracellular mucin in >50% of the lesion.7 Appendiceal adenocarcinomas resemble their colorectal counterparts histologically, regularly expressing p53, CD44, and CDX2. They often demonstrate signet ring cells if poorly differentiated, are prone to lymphatic spread, and are staged according to the TNM classification. Goblet cell carcinoid tumors represent a variant of adenocarcinoma that demonstrates some features similar to traditional neuroendocrine tumors (NETs; eg, positive chromogranin A staining).7 However, these mixed adenoneuroendocrine carcinomas are more aggressive than traditional NETs and should generally be treated in a similar manner to classic appendiceal adenocarcinomas.10,11 Appendiceal neoplasms may perforate and spread throughout the peritoneal cavity.12 When this spread includes abundant mucin production, the term pseudomyxoma peritonei (PMP) is used. Some authors make the distinction that PMP represents a clinical finding rather than a diagnosis and should be reserved for diffuse spread of mucin throughout the abdomen as opposed to mucin deposits that are confined adjacent to the appendix.9 Because PMP often recurs after treatment and the 10-year overall survival (OS) rate after surgery for PMP is 63%, PMP should be considered a malignant condition.13,14 Variable degrees of cellularity within PMP can lead to vastly different patient prognoses.11,13,15,16 To reduce confusion and improve consistency in the literature, a consensus reporting classification was published recently for both PMP and appendiceal neoplasia.14 The authors recommended categorizing PMP based on the degree of cellularity within the mucin as follows: acellular, low-grade histologic features, high-grade histologic features, and PMP with signet ring cells (Table 1). The low-grade group includes the commonly reported term of disseminated peritoneal adenomucinosis, whereas peritoneal mucinous carcinomatosis is designated as high grade. Because the grouping is based on histology, clinical features such as omental caking or ovarian involvement may represent either low- or high-grade PMP. This classification aligns with other schemes and helps determine treatment and prognosis.17,18TABLE 1.: Histologic classification of PMPNonepithelial appendiceal neoplasms include NETs. These lesions are histologically similar to those found elsewhere in the GI tract.7 Appendiceal NETs are frequently asymptomatic and identified incidentally after routine appendectomy. Staging remains controversial and may be based on tumor size, depth of invasion, or degree of differentiation. Other rare nonepithelial appendiceal neoplasms include GI stromal tumors, lymphomas, and neural proliferations, which are not considered in this guideline. METHODOLOGY Selected members of the ASCRS Clinical Practice Guidelines committee drafted de novo position statements after performing a thorough search and review of the relevant literature. With input from the authors, a professional librarian conducted a systematic literature search encompassing January 1, 1997, to April 30, 2019, inclusive, across the Ovid Medline, Embase, and Scopus medical databases. Pertinent inclusion criteria were English language article and adult human patients, and both current and archaic terminology for appendiceal neoplasms were included as follows: (appendiceal, appendix, appendicular) AND (adenocarcinoma, carcinoma, mucinous, pseudomyxoma, signet*, cystadenoma, tumor*, tumour*, neoplasm, cancer). These groups were combined with various treatment modalities to include surgery and chemotherapy. Refer to Figure 1 for the full search algorithm. Directed searches of references in selected published articles yielded additional records. The initial search produced 2135 records after removal of duplicates. These were screened for relevance, yielding 901 abstracts for review as the basis for the recommendations. A directed search of references embedded in the candidate publications was performed. Emphasis was placed on prospective trials, meta-analyses, systematic reviews, and practice guidelines. Peer-reviewed observational studies and retrospective studies were included when higher-quality evidence was insufficient. The final source material used was evaluated for methodologic quality, the evidence base was examined, and a treatment guideline was formulated by the subcommittee. The final grade of recommendation and level of evidence for each statement were determined using the Grades of Recommendation, Assessment, Development, and Evaluation system (Table 2). When agreement was incomplete regarding the evidence base or treatment guideline, consensus from the committee chair, vice chair, and 2 assigned reviewers determined the outcome. Members of the American Society of Colon and Rectal Surgeons (ASCRS) Clinical Practice Guidelines Committee worked in joint production of these guidelines from inception to final publication. Recommendations formulated by the subcommittee were reviewed by the entire Clinical Practice Guidelines Committee. Final recommendations were approved by the ASCRS Executive Committee. In general, each ASCRS Clinical Practice Guideline is updated every 5 years.TABLE 2.: The GRADE System: grading recommendationsFIGURE 1.: Literature search flow sheet. CPG = Clinical Practice Guidelines.GENERAL CONSIDERATIONS 1. Patients with appendiceal neoplasms should undergo a complete history and physical examination. Grade: Strong recommendation based on low-quality evidence, 1C. Neoplasms of the appendix are not often suspected before surgery and may be discovered either intraoperatively or incidentally in the pathologic specimen. Vague symptoms of fatigue, weight gain, chronic abdominal pain, and early satiety may be signs of advanced disease. Tumors can also present as appendicitis, bowel obstruction, or a pelvic mass.19,20 A thorough history and physical examination are essential. History should include previous surgical history, particularly appendectomy, with review of the associated operative note and pathology report, because patients may not be aware of the presence of an incidental neoplasm or mucin. Pathology slides should typically be reviewed in cases of diagnostic uncertainty. Physical examination should include a pelvic and digital rectal examination to assess for pelvic masses and mobility of surrounding structures. Rare presentations of mucinous appendiceal neoplasms include findings of pseudomyxomatous material in ventral, incisional, and inguinal hernias.21,22 Although decision-making for performing an interval appendectomy after initial nonoperative management of presumed appendicitis is complex, the surgeon must consider that the risk for occult appendiceal neoplasm appears greater in this subgroup compared with the general population.23–28 Modern retrospective and database studies suggest an incidence of malignancy between 2.3% and 12.0%; in particular, older age and indeterminate imaging appear to be significant risk factors for appendiceal cancer.23,24,26,27 Periappendiceal abscess may be an even stronger predictor of occult neoplasm; the Finnish Peri-Appendicitis Acuta multicenter randomized controlled trial found an overall neoplasm incidence of 20% in these patients.27 At a minimum, patients should be informed of this risk. 2. Colonoscopy should be performed in patients with confirmed or suspected appendiceal neoplasms. Grade: Strong recommendation based on low-quality evidence, 1C. Patients with appendiceal neoplasms are at increased risk of harboring synchronous colonic lesions compared with the general population, with population-based studies reporting 13% to 42% of patients with primary epithelial appendiceal lesions having concurrent colorectal neoplasia.5,6,29,30 In a population-based study from the Netherlands from 1995 to 2005 that included 1482 patients with an appendiceal epithelial neoplasm, 193 (13%) had an incidental colonic adenoma (n = 37) or adenocarcinoma (n = 156).5 In this study, the primary pathology of the appendiceal neoplasms was reported as mucinous cystadenoma (32%), mucocele (31%), and nonmucinous adenoma (26%), and the majority of the colonic adenocarcinomas discovered were right sided. By comparison, single-institution studies suggest that <4% of patients with colorectal cancer have synchronous appendiceal neoplasms.31,32 In a single-surgeon series of 169 consecutive patients who underwent prophylactic appendectomy during segmental resection for colorectal cancer (including 63 right colectomies), the rate of incidental appendiceal neoplasia was 4%.32 Although appendiceal neoplasms are rarely diagnosed at the time of colonoscopy, they may present endoscopically with an inverted or mass-like protrusion or mucous or polypoid tissue at the appendiceal orifice.30,33 3. Appendectomy should be performed if a grossly abnormal appendix is encountered during an unrelated abdominal operation. Grade: Strong recommendation based on low-quality evidence, 1C. During an abdominal or pelvic operation, appendectomy is warranted for incidental findings of luminal dilation, serosal puckering or irregularity, or a mass. Care should be taken to avoid intraoperative perforation and spillage, and conversion to open surgery may be necessary in certain situations.34–36 In a small series of 24 consecutive patients with appendiceal mucinous neoplasms, all were managed laparoscopically without intraoperative spillage. In this series, the majority required partial cecectomy (15/24; 62.5%) or ileocecectomy (8/24; 33.3%), whereas 1 patient underwent simple appendectomy.37 The extent of resection is predominantly based on involvement of the base of the appendix. The priority is obtaining a pathologic diagnosis with a grossly negative margin. In most cases, appendectomy or partial cecectomy is sufficient when an abnormal appendix is encountered incidentally. When performing a laparoscopic approach, surgeons should consider using a specimen retrieval bag to help avoid spilling mucin. An incidental finding of intraperitoneal mucin suggests the presence of a mucinous neoplasm of the GI or gynecologic tracts. In this setting, careful inspection of the appendix (and adnexa in a female patient) is warranted. Data from multiple retrospective, single-institution studies do not support routine appendectomy for a normal-appearing appendix in the setting of an ovarian mucinous neoplasm, because the incidence of synchronous appendiceal pathology in these cases is low.38–40 APPENDICEAL NETS 4. Preoperative assessment of patients with appendiceal NETs should typically include history and physical examination, colonoscopy, and CT or MRI of the chest, abdomen, and pelvis. Grade: Strong recommendation based on low-quality evidence, 1C. Preoperative evaluation of patients with appendiceal NETs should involve a thorough history and physical examination, with a review of systems that specifically document the presence or absence of symptoms that could be associated with carcinoid syndrome, such as facial flushing, diarrhea, and dyspnea. NETs arising from the small intestine or from the colon are associated with higher rates (15%–30%) of synchronous NETs compared with appendiceal NETs, the latter having a low incidence of synchronicity often uncalculated in many series.41 Irrespective of the risk of synchronous NETs, a preoperative colonoscopy is important because of the association of NETs with synchronous noncarcinoid neoplasms.42 A series of 13,715 NETs from various body regions, including different segments of the alimentary tract, reported a synchronous cancer rate of 22.4% for the entire NET series similar rates of synchronous with colorectal between and of these synchronous Because appendiceal NETs can to the as as to the and because the management of NET from appendiceal patients should typically undergo clinical with an CT or MRI of the chest, abdomen, and pelvis. imaging is not required for all patients with appendiceal NETs. Grade: recommendation based on evidence, Because most appendiceal NETs can be used to of because can that lesions this study is in the of as in of advanced or With the of CT and use of the in cases of indeterminate findings for disease based on CT and MRI and in patients with symptoms with carcinoid (eg, flushing, diarrhea, and Although or more of NETs that is to the presence of an are to support the routine use of for routine are an additional imaging for disease from appendiceal NETs. In with traditional is more for of well-differentiated NETs (eg, those expressing whereas more poorly to be or to for In 1 study, occult lesions in of NET patients with negative of which were not present on The use of routine imaging should be with the high of these should be performed in patients with or appendiceal NETs to for and disease Grade: recommendation based on evidence, Appendiceal NETs are not commonly is a significant of disease. The most produced by appendiceal NETs include chromogranin A and the evaluated with and the latter with a of either of these have associated with these are not for the of the presence of an NET or for of surgical resection of appendiceal NETs is determined by tumor and histologic Grade: Strong recommendation based on low-quality evidence, 1C. NETs confined to the appendix, treatment is generally based on the of the primary in and without features are treated with appendectomy care to the entire survival in these patients is Tumors are best treated with right because the reported risk of may be as high as Appendiceal NETs between 1 and 2 in have an intermediate risk of in most However, the clinical series found no disease in primary tumors and some authors appendectomy for all lesions this In to size, histologic features surgical on that may be include advanced grade of per or and lymphatic or for right in and appendiceal NETs should be made on a with to histologic features and patient and Although the majority of appendiceal NETs in the of the appendix, patients with tumor present at the base of the appendix or those with a positive may to undergo more resection to negative surgical after resection of appendiceal NETs with should involve physical examination, and imaging of the chest, abdomen, and using either CT or Grade: recommendation based on low-quality evidence, patients who have surgical resection with is recommended that for disease be performed in patients deemed to be for further treatment should a be and Although the interval between and the of is not because of the rarity and often of NETs, the interval between typically from to on the histologic grade of and is generally recommended that the of for after chromogranin A and can both with to and but because of the of these with imaging studies is are to support routine use of or other imaging modalities for routine although they may be in disease discovered on CT or as as for potential APPENDICEAL AND typically should be on diagnosis of appendiceal epithelial neoplasms and after Grade: recommendation based on low-quality evidence, The tumor and are frequently on diagnosis of appendiceal mucinous neoplasms and to assess disease or Although their individual of disease not most tumor with imaging at during and after if In the setting of mucinous adenocarcinoma of the appendix, a to with the of complete also described as an predictor of survival and can be to disease after surgery and intraperitoneal reported to after complete as compared with and which may a longer survival in treated patients with preoperative and they suggested that tumor may help the for chemotherapy. However, imaging more for peritoneal disease than tumor With to the use of other to low-grade many have including 2 and and without evidence on their on diagnosis or Although some may be from colorectal the rarity of appendiceal adenocarcinoma the to make regarding specific imaging with CT or MRI should be performed on diagnosis of appendiceal epithelial neoplasms and after Grade: Strong recommendation based on low-quality evidence, 1C. CT of the chest, abdomen, and is the most imaging used to the primary tumor and assess for disease. The of a not to improve or change MRI can mucin and also to be to CT in the of peritoneal disease using a of imaging and In small studies, MRI to the peritoneal cancer before and is often used in after and preoperative diagnosis can be because of a of clinical presentations and imaging of appendiceal neoplasms. Although some have using the World Health Organization pathologic classification as a to imaging findings in patients with appendiceal neoplasms, no imaging reporting systems are used in this patient Although are no guidelines for appendiceal neoplasms after appendectomy, patients with low-grade tumors of the appendix who undergo appendectomy rarely imaging for is typically of must be in these according to tumor and patient for and LAMN is to MRI with tumor every for 2 because most early within that Patients with high-grade tumors or who undergo right because of a advanced or surgical or who had lymphatic or peritoneal disease should typically undergo CT or MRI every to for the 2 and for In patients with acellular or low-grade peritoneal disease who have and CT or MRI of the abdomen and is recommended at 2 annually for In patients with high-grade peritoneal additional imaging of the and more every for the may help disease Although peritoneal may and some may to is no evidence on the management of patients with appendiceal tumors and is not recommended as routine Grade: recommendation based on low-quality evidence, Although positive peritoneal is to various degrees in patients with or ovarian the use of in patients with appendiceal neoplasms remains Some may be from of studies on colorectal cancer with peritoneal peritoneal in of treated patients and with for negative peritoneal = also that positive was associated with in patients with colorectal cancer complete and of these studies performed subgroup for patients with appendiceal or evaluated in the to In patients with appendiceal neoplasms, is no evidence to support the routine evaluation of peritoneal because on management and remains Patients with LAMNs with negative and no evidence of perforation or peritoneal involvement are treated with appendectomy of Strong recommendation based on evidence, In observational studies, oncologic outcomes after appendectomy, including the entire for LAMN without perforation or peritoneal have low with the behavior of these initial surgical management is because of the appendix can the from to if an LAMN be conversion to an open is published suggest that a positive resection after appendectomy for LAMN not disease and not right patients with LAMN treated by appendectomy (n = or right (n = with and Appendiceal was present in patients At a of survival was with only 2 patients peritoneal at and a primary appendiceal mucinous neoplasm high-grade associated with These lesions are best as Although appendectomy is typically sufficient for care should be taken to the presence of associated invasive including histologic evaluation of the entire surgical specimen. Patients with adenocarcinoma of the appendix should undergo right However, in the setting of peritoneal spread, may not a survival Grade: Strong recommendation based on low-quality evidence, 1C. In patients with appendiceal the rate of disease to from 20% to with positive more in the nonmucinous Because of this adenocarcinoma confined to the appendix should be treated with right because resection of the allows for more complete and may have a The recommendation for also includes appendiceal cell tumors characterized by a of histologic features of both neuroendocrine and epithelial The history of patients with cell carcinoid of the appendix high-grade appendiceal tumors, and should be treated in a similar In the setting of peritoneal routine right to is not single-institution and retrospective observational studies have to demonstrate a survival to right appendectomy in patients and population-based using and and found that right not improve survival after for and grade. no to was in patients without peritoneal that reflects a more aggressive that is not by surgical these should be that right is necessary to a complete of peritoneal disease from the appendix. is in selected patients with appendiceal neoplasms and evidence of peritoneal Grade: Strong recommendation based on evidence, resection remains the for patients with appendiceal neoplasms with peritoneal The of is of gross when this is is often combined with intraperitoneal such as the and within the or of tumor on the of the small intestine and colon, and other as by involvement (eg, regarding with or without should be by a at patient is in patients with peritoneal involvement from appendiceal on imaging may help determine and of for may also be used to the of complete or to tissue if other such as are not involvement may be using or the is an intraoperative based on the of tumor deposits in within the abdomen and from to The clinical and tumor to a of is considered Although for such systems may not with survival in appendiceal neoplasms treated with complete However, is in patients with or obstruction, bowel obstruction, or small bowel In almost every of clinical and pathologic of is an predictor of with peritoneal spread often ovarian ovarian tumors may and typically are to chemotherapy. evaluated female patients with who underwent and for colorectal and appendiceal of patients had ovarian tumor patients with 1 ovarian involvement of the was found in of patients in both were 24 of had ovarian Given the risk of occult ovarian in this patient population, should be and patients should be The management of patients with peritoneal involvement of acellular mucin in the setting of LAMN remains particularly when is to the right Appendectomy with of the periappendiceal in these cases associated with reasonably low peritoneal rates between and LAMNs associated with cellular mucin deposits are associated with a higher risk of peritoneal involvement these patients should be considered for In selected patients with appendiceal epithelial neoplasms, intraperitoneal may additional for peritoneal disease compared with Grade: Strong recommendation based on evidence, complete resection of all gross peritoneal patients with appendiceal neoplasms may be treated with intraperitoneal chemotherapy. this is performed with the of in and for appendiceal neoplasms increased after a large controlled trial for carcinomatosis from colorectal and appendiceal demonstrated a of survival for compared with demonstrated a of and a survival of for those patients for a complete could be large retrospective and prospective studies including patients with both low-grade and high-grade peritoneal disease have demonstrated improved patient tumor longer time to disease and operative in patients who undergo compared with or A observational study by including patients reported associated with after = = for appendiceal mucinous neoplasm, but was no in their was and was or are the most used during from other methods for intraperitoneal include the early intraperitoneal or similar are the various and a retrospective study in of patients compared and after complete and no in 10-year and An controlled trial of may provide additional about which treatment is may improve survival in patients with from for low-grade lesions with peritoneal spread is Grade: Strong recommendation based on low-quality evidence, 1C. The of and the for treatment of appendiceal to be Although level evidence, to that used for colorectal is typically recommended for patients with high-grade peritoneal disease or reported improved with in patients with high-grade PMP in patients who underwent and those with signet ring cell no in patients with low-grade disease. reported a partial or complete tumor in patients with high-grade PMP who preoperative and underwent This subgroup of patients demonstrated longer when compared with patients with no tumor not in those without = and preoperative based on for 2 and have no significant on combined with improved and for high-grade appendiceal and is a prospective trial the of with Although the of as with other are potential of preoperative including the to assess disease and patient that be in the majority of patients, and for disease to appear on imaging and of