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

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5 7 D. • David Stewart, M.D. Stewart, • David 2 • Ian M. Paquette, M.D. Paquette, M. • Ian 4 It should be recognized that these guidelines should should that these guidelines be should recognized It CLASSIFICATION BY HISTOPATHOLOGY BY CLASSIFICATION STATEMENT OF THE PROBLEM THE OF STATEMENT not be deemed inclusive of methods of all proper nor not be inclusive deemed care of toward methods directed of reasonably care exclusive - judgment The regard ultimate obtainingsame results. the must be made ing the proprietyof specificprocedure any in light of presented the physician allby the circumstances the individual patient. by unclear whether this increase reflects an actual change change an actual reflects whether this increase unclear recognition greater simply or the disease occurrence in Although of tumors rare, are the appendix and reporting. should be familiar withsurgeons the implications of ap- because- almost 300,000 appendec pathology, pendiceal and States, performed in the United annually are tomies 2% of in ≈1% to is found neoplasia these specimens. - de the rarity used to terms different Given and multiple their regarding consistency scribe neoplasms, appendiceal reporting but improved for allows only not classification - ap general terms, In management. precise more also for Historically, the estimated incidence of- tu incidence estimated the appendiceal Historically, - how was 0.12 cases per 1,000,000 people permors year; the incidence database studies, large recent based on ever, be as high as 0.97 per 100,000 population. may • Daniel L. Feingold, M. Feingold, • Daniel L. 6 • Wolfgang Gaertner, M.D. Gaertner, Wolfgang • 1 • Karim Alavi, M.D. Alavi, • Karim 4 62: 12 (2019) 62: OLUME V ECTUM 62: 1425–1438 62: R

& 1 Department of Surgery, Washington University School of Medicine, St. Louis, Missouri Louis, St. of School Medicine, University Washington 1 Department of Surgery, Minnesota Minneapolis, of Minnesota, University 2 Department of Surgery, Arizona Phoenix, ofArizona, University 3 Department of Surgery, Massachusetts Worcester, of Massachusetts, University 4 Department of Surgery, Ohio Cincinnati, of Cincinnati, University 5 Department of Surgery, Ohio Cleveland, Clinic, Cleveland 6 Department of Surgery, Jersey New Brunswick, New University, Rutgers 7 Department of Surgery, Sean C. Glasgow, M.D. Glasgow, Sean C. Scott R. Steele, M.D., M.B.A. M.D., Steele, R. Scott Jennifer Davids, M.D. Davids, Jennifer OLON OLON C he American Society he of Surgeons and Rectal Colon ensuring high-quality to is dedicated patient care - and manage prevention, the science, advancing by

CLINICAL PRACTICE GUIDELINES PRACTICE CLINICAL ISEASES OF THE ment of disorders and diseases of the colon, rectum, and rectum, ofment and diseases of disorders the colon, - is com Committee Guidelines The Practice Clinical anus. posed of because society they chosen who members are expertise demonstrated in the specialty ofhave and colon - lead interna to was created This Committee surgery. rectal related conditions for tional effortsquality in defining care the by This is accompanied and anus. rectum, the colon, to ofdevelopment practice the based guidelines clinical on but inclusive These are guidelines evidence. best available information Their purpose provide is to not prescriptive. a spe support dictate - ratherto decision-making than to for intended are formThese guidelines ofcific treatment. and patients the use of workers, healthcare all practitioners, of management the informationabout - whodesire con the in these guidelines. covered the topics by ditions addressed D - John Wood Robert Rutgers M.D., Feingold, Daniel L. Correspondence: Brunswick, New St, 125 Paterson Brunswick, New School Medical son [email protected] E-mail: NJ 08901. None reported. None Disclosure: Financial None reported. None Funding/Support: T Management of Appendiceal Neoplasms of Appendiceal Management Surgeons, Clinical Practice Guidelines for the the Guidelines for Clinical Practice Surgeons, The American Society of Colon and Rectal Society American The of Colon Dis Colon Rectum 2019; Rectum Dis Colon DOI: 10.1097/DCR.0000000000001530 ASCRS 2019 © The PREPARED ON BEHALF OF THE CLINICAL PRACTICE GUIDELINES COMMITTEE OF THE AMERICAN SOCIETY OF COLON AND SOCIETYAMERICAN GUIDELINES COMMITTEE OF COLON OF THE ON BEHALF OF THE CLINICAL PRACTICE PREPARED SURGEONS. RECTAL

by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3bhnalqTQiPuOeErObcGkYc0C+sRFRc02Kq2wNkH0jKo= on 12/16/2019 from https://journals.lww.com/dcrjournal Downloaded Copyright © The American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction of this article is prohibited. American Society of Colon & Rectal Surgeons, Inc. Unauthorized reproduction The Copyright © Downloaded from https://journals.lww.com/dcrjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3bhnalqTQiPuOeErObcGkYc0C+sRFRc02Kq2wNkH0jKo= on 12/16/2019 1426 GLASGOW ET AL: ASCRS GUIDELINES FOR APPENDICEAL NEOPLASMS

pendiceal neoplasms can be broadly described as epithelial, TABLE 1. Histologic classification of PMP such as adenomas or adenocarcinomas, or nonepithelial (eg, neuroendocrine or lymphoma). The epithelial group is Pathologic lesion Criteria often further subdivided based on mucin production, be- Acellular mucin • Mucin within peritoneal cavity cause mucinous tumors have distinctly different biologic without neoplastic epithelial cells behavior and oncologic outcomes from nonmucinous Low-grade mucinous • Epithelial component typically scanty 4 carcinoma peritonei • Minimal cytological atypia neoplasms. The World Health Organization classifies the (DPAM) • Strips, gland-like structures or small majority of noninvasive epithelial lesions as low-grade ap- cell clusters pendiceal mucinous neoplasms (LAMNs).7 Histologically, High-grade mucinous • Relatively more cellular LAMNs are characterized by well-differentiated adenomas carcinoma peritonei • Cribriform growth pattern that can proliferate outside the appendix in a malignant (PMCA) • High-grade cytological atypia • Numerous mitoses fashion. Acellular or cellular extra-appendiceal mucin may High-grade mucinous • Any lesion with a signet ring cell be associated with LAMNs, although this is not a require- carcinoma peritonei component, that is, round cells with ment. The LAMN terminology includes lesions that were with signet rings cells intracytoplasmic mucin pushing described previously as mucoceles or mucinous cystadeno- (PMCA-S) nucleus against cell membrane mas, which are terms no longer in use. Some authors have Adapted from Carr et al.9 suggested an intermediate grouping between traditional DPAM = disseminated peritoneal adenomucinosis; PMCA = peritoneal mucinous carcinomatosis; PMCA-S = peritoneal mucinous carcinomatosis with signet ring 8 LAMNs and invasive carcinoma. These LAMNs of un- cells; PMP = pseudomyxoma peritonei. certain malignant potential may exhibit gross perforation, mural fibrosis, mucin dissecting within the appendiceal porting classification was published recently for both PMP wall, or acellular mucin in the periappendiceal soft tissues. and appendiceal neoplasia.14 The authors recommended High-grade appendiceal neoplasms (HAMNs) share some categorizing PMP based on the degree of cellularity within histologic features with LAMNs but exhibit more aggres- the mucin as follows: acellular, low-grade histologic fea- sive cytologic atypia. The distinct biological and clinical tures, high-grade histologic features, and PMP with sig- behaviors of HAMNs are poorly characterized.9 net ring cells (Table 1). The low-grade group includes Appendiceal adenocarcinomas may be either muci- the commonly reported term of disseminated peritoneal nous or nonmucinous. Mucinous adenocarcinomas are adenomucinosis, whereas peritoneal mucinous carcino- characterized by invasive glands containing high-grade matosis is designated as high grade. Because the group- cytologic atypia and extracellular mucin in >50% of the ing is based on histology, clinical features such as omental lesion.7 Appendiceal adenocarcinomas resemble their co- caking or ovarian involvement may represent either low- lorectal counterparts histologically, regularly expressing or high-grade PMP. This classification aligns with other p53, CD44, and CDX2. They often demonstrate signet schemes and helps determine treatment and prognosis.17,18 ring cells if poorly differentiated, are prone to lymphatic Nonepithelial appendiceal neoplasms include NETs. spread, and are staged according to the TNM classifica- These lesions are histologically similar to those found else- tion. Goblet cell carcinoid tumors represent a variant of where in the GI tract.7 Appendiceal NETs are frequently adenocarcinoma that demonstrates some features similar asymptomatic and identified incidentally after routine to traditional neuroendocrine tumors (NETs; eg, positive appendectomy. Staging remains controversial and may be chromogranin A staining).7 However, these mixed adeno- based on tumor size, depth of invasion, or degree of differ- neuroendocrine carcinomas are more aggressive than tra- entiation. Other rare nonepithelial appendiceal neoplasms ditional NETs and should generally be treated in a similar include GI stromal tumors, lymphomas, and neural prolif- manner to classic appendiceal adenocarcinomas.10,11 erations, which are not considered in this guideline. Appendiceal neoplasms may perforate and spread 12 throughout the peritoneal cavity. When this spread in- METHODOLOGY cludes abundant mucin production, the term pseudomyxoma peritonei (PMP) is used. Some authors make the Selected members of the ASCRS Clinical Practice Guide- distinction that PMP represents a clinical finding rather lines committee drafted de novo position statements after than a diagnosis and should be reserved for diffuse spread performing a thorough search and review of the relevant of mucin throughout the abdomen as opposed to mucin literature. With input from the authors, a professional deposits that are confined adjacent to the appendix.9 Be- librarian conducted a systematic literature search en- cause PMP often recurs after treatment and the 10-year compassing January 1, 1997, to April 30, 2019, inclusive, overall survival (OS) rate after surgery for PMP is 63%, across the Ovid Medline, Embase, and Scopus medical PMP should be considered a malignant condition.13,14 Var- databases. Pertinent inclusion criteria were English lan- iable degrees of cellularity within PMP can lead to vastly guage article and adult human patients, and both current different patient prognoses.11,13,15,16 To reduce confusion and archaic terminology for appendiceal neoplasms were and improve consistency in the literature, a consensus re- included as follows: (appendiceal, appendix, appendicular)

Primary search terms: (appendiceal OR appendix OR appendicular) AND (adenocarcinoma OR carcinoma OR mucinous OR pseudomyxoma OR signet* OR cystadenoma OR tumor* OR tumour* OR neoplasm* OR cancer*) AND (therapy

n OR treatment OR chemotherapy OR HIPEC OR immunotherapy OR antineoplastic OR surgery OR oncological procedure OR diagnosis) Databases: Ovid Medline, Embase, Scopus Years covered: January 1, 1997–April 30, 2019

Identificatio Language: English

Total records (n = 3854) Total records after duplicates removed (n = 2135)

ening Records excluded (n = 1234) • Commentary/letters/errata (n = 105) Sc re Records screened • Irrelevant/unrelated (n = 131) (n = 2135) • Case reports (n = 858) • Pediatric patients (n = 81) • Duplicate publications (n = 59) y

Articles and abstracts assessed for Full-text articles excluded (n = 748)

Eligibilit eligibility (n = 901)

Studies referenced in CPG assignments Included (n = 153)

FIGURE 1. Literature search flow sheet. CPG = Clinical Practice Guidelines.

AND (adenocarcinoma, carcinoma, mucinous, pseudomyx- methodologic quality, the evidence base was examined, oma, signet*, cystadenoma, tumor*, tumour*, neoplasm, and a treatment guideline was formulated by the subcom- cancer). These groups were combined with various treat- mittee. The final grade of recommendation and level of ment modalities to include surgery and chemotherapy. evidence for each statement were determined using the Refer to Figure 1 for the full search algorithm. Directed Grades of Recommendation, Assessment, Development, searches of references in selected published articles yield- and Evaluation system (Table 2). When agreement was in- ed additional records. The initial search produced 2135 complete regarding the evidence base or treatment guide- records after removal of duplicates. These were screened line, consensus from the committee chair, vice chair, and for relevance, yielding 901 abstracts for review as the basis 2 assigned reviewers determined the outcome. Members for the recommendations. A directed search of references of the American Society of Colon and Rectal Surgeons embedded in the candidate publications was performed. (ASCRS) Clinical Practice Guidelines Committee worked Emphasis was placed on prospective trials, meta-anal- in joint production of these guidelines from inception to yses, systematic reviews, and practice guidelines. Peer- final publication. Recommendations formulated by the reviewed observational studies and retrospective studies subcommittee were reviewed by the entire Clinical Prac- were included when higher-quality evidence was insuf- tice Guidelines Committee. Final recommendations were ficient. The final source material used was evaluated for approved by the ASCRS Executive Committee. In general,

TABLE 2. The GRADE System: grading recommendations Methodologic quality Description Benefit versus risk and burdens of supporting evidence Implications 1A Strong recommendation, Benefits clearly outweigh risk RCTs without important Strong recommendation, can high-quality evidence and burdens or vice versa limitations or overwhelming apply to most patients in evidence from observational most circumstances without studies reservation 1B Strong recommendation, Benefits clearly outweigh risk RCTs with important limitations Strong recommendation, can moderate-quality evidence and burdens or vice versa (inconsistent results, apply to most patients in methodologic flaws, indirect, most circumstances without or imprecise) or exceptionally reservation strong evidence from observational studies 1C Strong recommendation, Benefits clearly outweigh risk Observational studies or case Strong recommendation but low- or very-low-quality and burdens or vice versa series may change when higher- evidence quality evidence becomes available 2A Weak recommendation, Benefits closely balanced with RCTs without important Weak recommendation, best high-quality evidence risks and burdens limitations or overwhelming action may differ depending evidence from observational on circumstances or patients’ studies or societal values 2B Weak recommendations, Benefits closely balanced with RCTs with important limitations Weak recommendation, best moderate-quality evidence risks and burdens (inconsistent results, action may differ depending methodologic flaws, indirect, on circumstances or patients’ or imprecise) or exceptionally or societal values strong evidence from observational studies 2C Weak recommendation, Uncertainty in the estimates of Observational studies or case Very weak recommendations; low- or very-low-quality benefits, risks and burden; series other alternatives may be evidence benefits, risk, and burden may equally reasonable be closely balanced Adapted from Guyatt G, Gutermen D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians Task Force. Chest. 2006;129:174-181. Used with permission. GRADE = Grades of Recommendation, Assessment, Development, and Evaluation; RCT = randomized controlled trial.

each ASCRS Clinical Practice Guideline is updated every structures. Rare presentations of mucinous appendiceal 5 years. neoplasms include findings of pseudomyxomatous material in ventral, incisional, and inguinal hernias.21,22 Although decision-making for performing an interval GENERAL CONSIDERATIONS appendectomy after initial nonoperative management of 1. Patients with appendiceal neoplasms should presumed appendicitis is complex, the surgeon must con- undergo a complete history and physical sider that the risk for occult appendiceal neoplasm appears examination. Grade: Strong recommendation greater in this subgroup compared with the general popu- based on low-quality evidence, 1C. lation.23–28 Modern retrospective and database studies sug- Neoplasms of the appendix are not often suspected before gest an incidence of malignancy between 2.3% and 12.0%; surgery and may be discovered either intraoperatively or in particular, older age and indeterminate imaging appear incidentally in the pathologic specimen. Vague symptoms to be significant risk factors for appendiceal cancer.23,24,26,27 of fatigue, weight gain, chronic abdominal pain, and early Periappendiceal abscess may be an even stronger predictor satiety may be signs of advanced disease. Tumors can also of occult neoplasm; the Finnish Peri-Appendicitis Acuta present as appendicitis, bowel obstruction, or a pelvic multicenter randomized controlled trial found an overall mass.19,20 A thorough history and physical examination are neoplasm incidence of 20% in these patients.27 At a mini- essential. History should include previous surgical history, mum, patients should be informed of this risk. particularly appendectomy, with review of the associated operative note and pathology report, because patients may 2. Colonoscopy should be performed in patients not be aware of the presence of an incidental neoplasm with confirmed or suspected appendiceal or mucin. Pathology slides should typically be reviewed neoplasms. Grade: Strong recommendation in cases of diagnostic uncertainty. Physical examination based on low-quality evidence, 1C. should include a pelvic and digital rectal examination Patients with appendiceal neoplasms are at increased risk to assess for pelvic masses and mobility of surrounding of harboring synchronous colonic lesions compared with

the general population, with population-based studies re- APPENDICEAL NETS porting 13% to 42% of patients with primary epithelial appendiceal lesions having concurrent colorectal neopla- 4. Preoperative assessment of patients with sia.5,6,29,30 In a population-based study from the Nether- appendiceal NETs should typically include history lands from 1995 to 2005 that included 1482 patients with and physical examination, colonoscopy, and CT or an appendiceal epithelial neoplasm, 193 (13%) had an MRI of the chest, abdomen, and pelvis. Grade: Strong recommendation based on low-quality evidence, 1C. incidental colonic adenoma (n = 37) or adenocarcinoma Preoperative evaluation of patients with appendiceal NETs (n = 156).5 In this study, the primary pathology of the ap- should involve a thorough history and physical examina- pendiceal neoplasms was reported as mucinous cystadeno- tion, with a review of systems that specifically document ma (32%), mucocele (31%), and nonmucinous adenoma the presence or absence of symptoms that could be associ- (26%), and the majority of the colonic adenocarcinomas ated with carcinoid syndrome, such as facial flushing, di- discovered were right sided. By comparison, single-insti- arrhea, and dyspnea. NETs arising from the small intestine tution studies suggest that <4% of patients with colorec- or from the colon are associated with higher rates (15%– tal cancer have synchronous appendiceal neoplasms.31,32 30%) of synchronous NETs compared with appendiceal In a single-surgeon series of 169 consecutive patients who NETs, the latter having a low incidence of synchronicity underwent prophylactic appendectomy during segmental often uncalculated in many series.41 Irrespective of the risk resection for colorectal cancer (including 63 right colec- of synchronous NETs, a preoperative colonoscopy is im- tomies), the rate of incidental appendiceal neoplasia was 32 portant because of the association of NETs with synchro- 4%. Although appendiceal neoplasms are rarely diag- nous noncarcinoid neoplasms.42 A series of 13,715 NETs nosed at the time of colonoscopy, they may present en- from various body regions, including different segments doscopically with an inverted or mass-like protrusion or 30,33 of the alimentary tract, reported a synchronous cancer mucous or polypoid tissue at the appendiceal orifice. rate of 22.4% for the entire NET cohort.43 Smaller series report similar rates of synchronous malignancies, with 3. Appendectomy should be performed if a grossly colorectal cancers representing between 25% and 50% of abnormal appendix is encountered during an these synchronous lesions.44,45 Because appendiceal NETs unrelated abdominal operation. Grade: Strong can metastasize to the liver, as well as to the lungs, and recommendation based on low-quality evidence, 1C. because the management of metastatic NET differs from During an abdominal or pelvic operation, appendectomy nonmetastatic appendiceal NET, patients should typically is warranted for incidental findings of luminal dilation, se- undergo clinical staging with an intravenous, contrast- rosal puckering or irregularity, or a mass. Care should be enhanced CT or MRI of the chest, abdomen, and pelvis. taken to avoid intraoperative perforation and spillage, and conversion to open surgery may be necessary in certain 5. NET-specific imaging is not required for all patients 34–36 situations. In a small series of 24 consecutive patients with appendiceal NETs. Grade: Weak recommendation with appendiceal mucinous neoplasms, all were managed based on moderate-quality evidence, 2B. laparoscopically without intraoperative spillage. In this Because most appendiceal NETs will express somatostatin series, the majority required partial cecectomy (15/24; receptors, somatostatin receptor scintigraphy (SRS) can 62.5%) or ileocecectomy (8/24; 33.3%), whereas 1 patient be used to identify foci of NETs.46 Furthermore, because underwent simple appendectomy.37 The extent of resection SRS can confirm that enhancing lesions express somato- is predominantly based on involvement of the base of the statin receptors, this study is useful in supporting the se- appendix. The priority is obtaining a pathologic diagnosis lection of somatostatin receptor antagonists as therapy in with a grossly negative margin. In most cases, appendec- settings of locally advanced or metastatic disease.47 With tomy or partial cecectomy is sufficient when an abnormal the fine resolution of modern CT and MRI, complemen- appendix is encountered incidentally. When performing a tary use of SRS provides the highest yield in cases of in- laparoscopic approach, surgeons should consider using a determinate findings for potentially metastatic disease specimen retrieval bag to help avoid spilling mucin. based on CT and MRI and in patients with symptoms An incidental finding of intraperitoneal mucin sug- consistent with carcinoid syndrome (eg, flushing, diar- gests the presence of a mucinous neoplasm of the GI or rhea, and bronchospasm). Although ≈80% or more of gynecologic tracts. In this setting, careful inspection of the NETs will express somatostatin receptors, suggesting that appendix (and adnexa in a female patient) is warranted. SRS is likely to reveal the presence of an NET,48 there are Data from multiple retrospective, single-institution stud- insufficient data to support the routine use of SRS for ies do not support routine appendectomy for a normal- routine surveillance. appearing appendix in the setting of an ovarian mucinous Positron emission tomography (PET)-CT scans are neoplasm, because the incidence of synchronous appendi- an additional imaging modality for evaluating metastatic ceal pathology in these cases is low.38–40 disease from appendiceal NETs. In comparison with tra-

ditional 2-[18F] fluoro-2-deoxy-D-glucose PET-CT, SRS small- and intermediate-sized appendiceal NETs should is more sensitive for detection of well-differentiated NETs be made on a case-by-case basis, with consideration given (eg, those expressing somatostatin receptors), whereas to histologic features and patient comorbidities and pref- 60 2-[18F] fluoro-2-deoxy-D-glucose PET detects more erences. Although the majority of appendiceal NETs poorly differentiated tumors.49 More recently, (68Ga)dot- occur in the tip of the appendix, patients with tumor pre- atate PET-CT has been shown to be equivalent or supe- sent at the base of the appendix or those resected with rior to SRS for detecting gastroenteric NETs.50 In 1 study, a positive margin may need to undergo more extensive (68Ga)dotatate PET-CT detected occult lesions in 65.2% resection to obtain negative surgical margins.63 of NET patients with negative biochemical testing, 40% of which were not present on SRS.51 The use of routine 8. Surveillance after resection of appendiceal (68Ga)dotatate PET-CT imaging should be balanced with NETs with curative intent should involve physical the high cost of these studies. examination, serial biochemical testing, and imaging of the chest, abdomen, and pelvis using 6. Biochemical testing should be performed in patients either CT or MRI. Grade: Weak recommendation with localized or metastatic appendiceal NETs to based on low-quality evidence, 2C. establish baseline measures for future surveillance and For patients who have undergone surgical resection with disease monitoring. Grade: Weak recommendation curative intent, it is recommended that surveillance for di- based on moderate-quality evidence, 2B. sease recurrence be performed in patients deemed to be Appendiceal NETs are not commonly biochemically ac- candidates for further treatment should a recurrence be tive unless there is a significant burden of hepatic meta- detected. Surveillance involves clinical, biochemical, and static disease. The most common metabolites produced radiographic components. Although the interval between by appendiceal NETs include chromogranin A and surveillance evaluations and the duration of surveillance is 5-hydroxyindoleacetic acid, the former evaluated with not standardized because of the rarity and often indolent serum and the latter with a 24-hour urine collection. nature of NETs, the interval between surveillance exami- Elevated levels of either of these metabolites have been nations typically ranges from 6 to 12 months, depending associated with poor prognosis.52,53 Importantly, these on the histologic grade of NET, and it is generally recom- markers are not reliable for the purposes of diagnos- mended that the duration of surveillance extends for 10 ing the presence of an NET or for guiding therapeutic years after curative resection.66,67 Serum chromogranin decisions.54,55 A levels and urine 5-hydroxyindoleacetic acid levels can correlate both with response to therapy and recurrence, 7. Extent of surgical resection of appendiceal but because of the nonspecific nature of these biomark- 68 NETs is determined by tumor size and histologic ers, correlation with imaging studies is required. Cur- features. Grade: Strong recommendation rently, there are insufficient data to support routine use of based on low-quality evidence, 1C. SRS or other NET-specific imaging modalities for routine For nonmetastatic NETs confined to the appendix, treat- surveillance, although they may be beneficial in confirm- ment is generally based on the size of the primary tumor. ing recurrent disease discovered on CT or MRI, as well as Lesions <1 cm in diameter and without unfavorable fea- assessing somatostatin receptor expression for potential 69,70 tures are adequately treated with appendectomy taking therapeutic consideration. care to remove the entire mesoappendix. Long-term dis- 56–58 ease-free survival in these patients is 100%. Tumors APPENDICEAL MUCINOUS NEOPLASMS AND >2 cm are best treated with formal right hemicolectomy, ADENOCARCINOMA because the reported risk of nodal metastases may be as high as 40%.56,59–61 Appendiceal NETs between 1 and 2 cm 9. Tumor markers typically should be assessed on in size have an intermediate risk of nodal metastases in diagnosis of appendiceal epithelial neoplasms and most series.56,57,62 However, the largest clinical series found routinely followed after resection. Grade: Weak no nodal disease in primary tumors <2 cm, and some recommendation based on low-quality evidence, 2C. authors recommend appendectomy alone for all lesions The serum tumor markers CEA, CA19-9, and CA125 are under this threshold.63,64 In addition to size, histologic frequently obtained on diagnosis of appendiceal mucinous features influence surgical decision-making. Findings on neoplasms and routinely monitored to assess disease remis- histology that may be unfavorable include mesoappen- sion or progression.71 Although their individual predicta- diceal invasion >3 mm, advanced grade consisting of el- bility of disease recurrence has not been well characterized, evated mitotic index (>2 mitoses per high-power field) most high-volume institutions routinely combine tumor or Ki-67 index (>3%) and lymphatic or vascular inva- markers with imaging at baseline, during chemotherapy, sion.60,65 Decision-making for right hemicolectomy in and after surgery, if applicable. In the setting of muci-

nous adenocarcinoma of the appendix, a normal baseline dergo appendectomy alone rarely develop PMP; therefore, CA-125 has been shown to correlate with the likelihood frequent postoperative imaging for extended intervals is of achieving complete cytoreduction.72 Elevated baseline typically of minimal benefit.6,85,86 Postoperative surveillance CA19-9 has also been described as an independent pre- must be individualized in these situations according to tu- dictor of worse progression-free survival (PFS) and can be mor and patient characteristics. One approach for localized useful to diagnose disease recurrence after cytoreductive and completely resected LAMN is to obtain MRI with tu- surgery (CRS) and hyperthermic intraperitoneal chemo- mor markers every 6 months for 2 years because most early therapy (HIPEC).72,73 CEA has been reported to normalize recurrences occur within that timeframe.85 Patients with after complete cytoreduction, as compared with CA 19-9 high-grade tumors or who undergo right hemicolectomy and CA-125, which may remain elevated.74 Taflampas et because of a locally advanced or perforated tumor, ques- al75 showed a significantly longer disease-specific survival in tionable surgical margins, or who had lymphatic or peri- treated patients with normal preoperative markers, and they toneal disease should typically undergo CT or MRI every suggested that tumor marker elevation may help tailor the 4 to 6 months for the first 2 years and yearly thereafter for need for perioperative systemic chemotherapy. However, ≥5 years. In patients with acellular or low-grade peritoneal surveillance imaging seems more sensitive for detecting disease who have undergone CRS and HIPEC, CT or MRI peritoneal disease recurrence than tumor markers alone.76 of the abdomen and pelvis is recommended at 2 months With regard to the use of other markers to distin- postoperatively (baseline), then annually for ≥5 years.86,87 guish low-grade versus HAMNs, many have proposed In patients with high-grade peritoneal disease, additional molecular profiling, including cyclooxygenase 2 expres- imaging of the chest and more frequent surveillance every 6 sion and KRAS, TP53, and SMAD4 gene mutations, with- months for the first 6 years postoperatively may help detect out conclusive evidence on their impact on diagnosis or recurrent disease earlier.88 Although peritoneal recurrences management.77–81 Although some generalizations may be beyond 10 years may occur and some institution-specific extrapolated from colorectal cancer, the rarity of appen- surveillance protocols may extend to 15 years, there is no diceal adenocarcinoma limits the ability to make conclu- clear evidence supporting prolonged surveillance.89 sions regarding specific genetic defects. 11. Peritoneal cytology has minimal impact on the 10. Cross-sectional imaging with CT or MRI management of patients with appendiceal tumors and should be performed on diagnosis of appendiceal is not recommended as routine practice. Grade: Weak epithelial neoplasms and routinely followed recommendation based on low-quality evidence, 2C. after resection. Grade: Strong recommendation Although positive peritoneal cytology is useful to various based on low-quality evidence, 1C. degrees in patients with pancreatic, gastric, or ovarian ma- CT of the chest, abdomen, and pelvis is the most com- lignancy, the use of cytology in patients with appendiceal mon imaging modality used to evaluate the primary tu- neoplasms remains unknown.90–92 Some insight may be mor and assess for metastatic disease. The addition of a gained from extrapolation of studies on colorectal cancer PET scan has not been shown to improve staging or sig- with peritoneal spread. Positive peritoneal cytology occurs nificantly change management.82 MRI can detect extralu- in 23.5% of treated patients and correlates with OS (19 vs minal mucin and has also been shown to be superior to 44 mo for negative peritoneal cytology; p = 0.01).93 Yone- CT in the detection of peritoneal disease using a combina- mura et al94 also showed that positive cytology was inde- tion of diffusion-weighted imaging and delayed postgado- pendently associated with worse PFS in 205 patients with linium sequences.83 In small noncomparison studies, MRI colorectal cancer undergoing complete CRS and HIPEC. has proven useful to predict the peritoneal cancer index Neither of these studies performed subgroup analysis for (PCI) before surgery, and it is often used in postoperative patients with appendiceal malignancies or evaluated its surveillance after CRS and HIPEC.76,83 Unfortunately, ac- role in the decision to perform HIPEC. In patients with curate preoperative diagnosis can be challenging because appendiceal neoplasms, there is no evidence to support of a wide range of clinical presentations and overlapping the routine evaluation of peritoneal cytology, because its imaging appearances of appendiceal neoplasms. Although impact on management and prognosis remains unclear. some have proposed using the 2010 World Health Organi- zation pathologic classification as a framework to report 12. Patients with LAMNs with negative margins and imaging findings in patients with appendiceal neoplasms, no evidence of perforation or peritoneal involvement no structured imaging reporting systems are routinely are safely treated with appendectomy alone. Grade used in this patient population.84 of recommendation: Strong recommendation Although there are no formal surveillance guidelines based on moderate-quality evidence, 1B. for appendiceal neoplasms after appendectomy, patients In modern observational studies, oncologic outcomes af- with low-grade localized tumors of the appendix who un- ter appendectomy, including the entire mesoappendix for

LAMN without perforation or peritoneal involvement, Turaga et al102 examined population-based data using Sur- have shown very low recurrence rates, consistent with veillance, Epidemiology, and End Results and found that the indolent behavior of these neoplasms.95–97 Appropri- right colectomy did not improve survival after adjusting ate initial surgical management is critical because iatro- for age, sex, T stage, metastatic disease, and grade. Inter- genic rupture of the appendix can convert the situation estingly, no benefit to colectomy was seen in node-positive from localized to disseminated; therefore, if an unrup- patients without peritoneal metastases either, suggesting tured LAMN cannot be safely resected laparoscopically, that nodal positivity reflects a more aggressive biology that conversion to an open operation is recommended. Lim- is not impacted by surgical resection. Despite these reser- ited published data suggest that a microscopically positive vations, it should be noted that right colectomy is some- resection margin after appendectomy for nonperforated times necessary to achieve a complete cytoreduction of LAMN does not predict disease recurrence and therefore peritoneal disease originating from the appendix. does not warrant formal right colectomy.98 Guaglio et al85 prospectively examined 41 patients with LAMN treated by 14. CRS is indicated in selected patients with appendectomy (n = 31) or right colectomy (n = 5) with appendiceal neoplasms and evidence of peritoneal close radiographic and biochemical surveillance. Appendi- involvement. Grade: Strong recommendation ceal rupture was present in 21 patients (51%). At a median based on moderate-quality evidence, 1B. follow-up of 58 months, 5-year recurrence-free survival Surgical resection remains the benchmark therapy for was 95%, with only 2 patients experiencing peritoneal re- patients with appendiceal neoplasms with peritoneal me- currences at 18 and 22 months postappendectomy. tastases. The goal of CRS is eradication of gross disease; Rarely, a primary appendiceal mucinous neoplasm when this goal is achieved, CRS is often combined with will harbor high-grade cytology yet lack infiltrative inva- intraperitoneal chemotherapy, such as HIPEC (see sub- sion associated with adenocarcinoma. These lesions are sequent recommendation). Typically, CRS entails selec- best classified as HAMNs.14 Although appendectomy alone tive peritonectomies, especially over the diaphragms and is typically sufficient for treating HAMNs, care should be within the pelvis, excision or destruction of tumor im- taken to exclude the presence of associated invasive adeno- plants on the surfaces of the small intestine and colon, su- carcinoma, including comprehensive histologic evaluation pracolic omentectomy, and other resections as indicated of the entire surgical specimen. by involvement (eg, splenectomy).110–112 Individualized decisions regarding CRS with or without HIPEC should 13. Patients with nonmetastatic adenocarcinoma of be undertaken by a multidisciplinary team, preferably at the appendix should undergo right hemicolectomy. experienced centers.109,113 Proper patient selection is cru- However, in the setting of peritoneal spread, colectomy cial in treating patients with peritoneal involvement from may not confer a survival benefit. Grade: Strong appendiceal neoplasms.114 Findings on cross-sectional im- recommendation based on low-quality evidence, 1C. aging may help determine resectability and guide selection In patients with appendiceal adenocarcinoma, the rate of of suitable candidates for cytoreduction.115,116 Diagnostic metastatic disease to regional lymph nodes ranges from laparoscopy may also be used to estimate the likelihood of 20% to 67%, with positive nodes more likely in the non- complete cytoreduction or to obtain tissue if other tech- mucinous (intestinal) subtype.99–103 Because of this sub- niques such as CT-guided biopsy are not feasible. Perito- stantial risk, adenocarcinoma confined to the appendix neal involvement may be quantified using Sugarbaker’s should be treated with right hemicolectomy, because for- Peritoneal Carcinomatosis Index (PCI) or the Peritoneal mal resection of the nodal basin allows for more com- Surface Disease Severity Score.117–119 PCI is an intraopera- plete staging and may have a therapeutic benefit.102 The tive determination based on the size of tumor deposits in recommendation for formal colectomy also includes ap- 13 regions within the abdomen and ranges from 0 to 39. pendiceal goblet cell carcinoids, tumors characterized by The Peritoneal Surface Disease Severity Score incorporates a mixture of histologic features of both neuroendocrine clinical symptoms, PCI, and tumor histology to produce and epithelial adenocarcinoma.104 The natural history of a maximum score of 22; stage IV is considered >10. Al- patients with goblet cell carcinoid of the appendix closely though useful for objectively measuring disease, such resembles high-grade appendiceal tumors, and it should scoring systems may not correlate with survival in appen- be treated in a similar manner.103,105–107 diceal neoplasms treated with complete cytoreduction.110 In the setting of peritoneal metastases, routine right However, successful cytoreduction is less likely in patients hemicolectomy to remove clinically normal lymph nodes with biliary or ureteral obstruction, multifocal bowel ob- is not recommended. Several single-institution and retro- struction, or extensive small bowel involvement. In almost spective observational studies have failed to demonstrate a every analysis of clinical and pathologic factors, complete- survival benefit to right colectomy versus appendectomy ness of cytoreduction is consistently an independent pre- alone in patients undergoing CRS and HIPEC.100,102,108,109 dictor of outcome.13,15,110,114,120–126

Women with peritoneal spread often experience ovar- reported superior PFS associated with HIPEC after CRS ian involvement. Metastatic ovarian tumors may grow rap- (HR = 0.65; p = 0.03) for metastatic appendiceal muci- idly and typically are resistant to systemic chemotherapy. nous neoplasm, but there was no OS difference in their Mehta et al127 retrospectively evaluated 258 female patients multivariate analysis.142 Median OS was 16.3 years, and with ≥1 remaining ovary who underwent CRS and HIPEC median PFS was 8.2 years. Mitomycin or platinum-based for colorectal and appendiceal tumors. Overall, 141 of 258 chemotherapeutics are the most common drugs used patients (55%) had ovarian tumor involvement. Of 40 pa- during HIPEC. tients with 1 macroscopic ovarian metastasis, microscopic Aside from HIPEC, other methods for delivering involvement of the contralateral ovary was found in 18 intraperitoneal chemotherapy include the early postop- (45%) of 40. Of 141 patients in whom both ovaries were erative intraperitoneal chemotherapy (EPIC) or delayed macroscopically normal, 24 (17%) of 141 had microscopic postoperative approaches.16,126,143–149 Generally, similar re- ovarian involvement. Given the risk of occult ovarian me- sults are obtained among the various approaches, and few tastases in this patient population, bilateral salpingo-oo- head-to-head comparisons exist; a retrospective study in phorectomy should be strongly considered, and patients Norway of 93 patients compared EPIC and HIPEC after should be appropriately counseled preoperatively.128 complete cytoreduction and showed no difference in 10- The management of patients with limited peritoneal year OS and DFS.16 An ongoing randomized, controlled involvement of acellular mucin in the setting of LAMN trial of HIPEC versus EPIC may provide additional an- remains controversial, particularly when it is isolated to swers about which treatment is superior.142 the right lower quadrant.6,86,129 Appendectomy with cytoreduction of the periappendiceal peritoneum in these 16. Systemic chemotherapy may improve survival cases has been associated with reasonably low peritoneal in patients with metastatic HAMNs. Benefit from recurrence rates between 3% and 7%. Conversely, LAMNs systemic chemotherapy for low-grade lesions with associated with cellular mucin deposits are associated with peritoneal spread is questionable. Grade: Strong a higher risk of subsequent peritoneal involvement (33%– recommendation based on low-quality evidence, 1C. 78%); these patients should be considered for HIPEC.130,131 The role of systemic chemotherapy and the optimal che- motherapeutic drug regimen for treatment of metastatic 15. In selected patients with appendiceal epithelial appendiceal malignancies continues to be investigated. neoplasms, intraperitoneal chemotherapy Although lacking level I evidence, 5-fluorouracil–based may offer additional benefit for reducing systemic chemotherapy (similar to that used for colorectal peritoneal disease recurrence compared with adenocarcinoma) is typically recommended for patients CRS alone. Grade: Strong recommendation with high-grade peritoneal disease or nodal metastases. based on moderate-quality evidence, 1B. Blackham et al150 reported improved PFS with periopera- After complete resection of all gross peritoneal disease, tive systemic chemotherapy in patients with high-grade patients with appendiceal neoplasms may be treated with PMP undergoing CRS plus HIPEC, especially in patients intraperitoneal chemotherapy. Most commonly, this is who underwent suboptimal cytoreduction and those with performed concurrently with CRS through the delivery signet ring cell histology. Systemic chemotherapy showed of HIPEC. Interest in CRS and HIPEC for appendiceal no benefit in patients with low-grade disease. Bijelic et neoplasms increased after a large randomized, controlled al151 reported a 30% partial or complete tumor response trial for carcinomatosis from colorectal and appendiceal in patients with high-grade PMP who received preoper- cancers demonstrated a doubling of survival for CRS/ ative systemic chemotherapy and then underwent CRS HIPEC compared with systemic chemotherapy alone plus HIPEC. This subgroup of patients demonstrated sig- (22.3- vs 12.6-mo median OS).120 Additional long-term nificantly longer OS when compared with patients with follow-up demonstrated a median OS of 48 months and no tumor response (median not reached versus 29.5 mo a 5-year survival of 45% for those patients for whom a in those without response; p = 0.03). Targeted therapy complete cytoreduction could be achieved.132 Multiple and preoperative noncytotoxic agents based on immu- large retrospective and prospective phase II studies in- nohistochemistry for cyclooxygenase 2 expression and cluding patients with both low-grade and high-grade KRAS mutational status have shown no significant im- peritoneal disease have demonstrated improved long- pact on survival.78 Conversely, systemic chemotherapy term patient survival, decreased tumor recurrence, longer combined with bevacizumab has shown improved OS time to disease progression, and less frequent repeat op- and PFS for unresectable high-grade appendiceal adeno- erative interventions in patients who undergo CRS plus carcinoma, and currently there is a prospective phase II HIPEC compared with debulking procedures alone or trial evaluating the impact of adjuvant 5-fluorouracil– palliative systemic chemotherapy.13,15,124,133–141 A 2012 ob- based chemotherapy with bevacizumab (clinicaltrials.gov servational study by Chua et al13 including 2298 patients NCT02420509).152 Although the timing of perioperative

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