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Neuroendocrine Tumors of the Appendix

Oncology
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Introduction

Neuroendocrine tumors (NET) are the most commonly diagnosed neoplasms of the appendix, comprising approximately 50% of all appendiceal cancers.[1] The annual incidence of appendiceal NET (aNET) is approximately 0.15-0.16 per 100,000 patients, and these tumors are most frequently diagnosed on pathology following an appendectomy.[2]
Therefore, the rate of diagnosis specifically among those undergoing appendectomy is significantly higher than the annual incidence, measuring 3-5 per 1,000 appendectomies (0.3-0.5%),[2] but with one international, multi-institutional study recording a rate as high as a 1.45% of appendectomy patients.[3]
In general, neuroendocrine neoplasms are classified into 3 distinct differentiations: neuroendocrine tumors, neuroendocrine carcinomas, and mixed neuroendocrine-non neuroendocrine carcinomas, with the latter two representing more aggressive pathology that requires alternative treatment strategies compared to NETs.[4] The focus of this review will be restricted to NETs.
Despite the appendix being the fifth most common primary site for NETs of the gastrointestinal tract, there is sparse high-quality evidence to guide diagnostic and therapeutic guidelines.[4] Therefore, much of the data and management choices are derived from retrospective institutional reviews and expert guidelines.

Symptoms

No specific symptomatology frequently afflicts patients with aNET. While right lower quadrant pain may occur, the frequency of pain is often limited because up to 70% of aNETs arise in the tip of the appendix.[2] Although there is no prototypical patient demographic, a slight female predominance exists, with diagnosis often occurring in those younger than forty years old.[5]
Even if metastatic disease is present, carcinoid syndrome (as defined by diarrhea, flushing, and/or wheezing) is a very rare occurrence in patients with NET of appendiceal origin,[2] and almost all of these tumors are thought to be non-functioning or non-hormone producing. For those eventually diagnosed with aNET, acute appendicitis can be the most common presentation, which then leads to appendectomy and subsequent pathologic diagnosis.[6]

Diagnostic Workup

For the rare patient who presents with concern of aNET prior to appendectomy, a CT or MRI can be performed to both visualize any potential mass and rule out locoregional or distant metastases.[2] Because most tumors are isolated to the tip of the appendix, there is little benefit of colonoscopy in visualizing or obtaining a biopsy of the neuroendocrine tumor. However, there is concern that those with aNET are more likely to harbor synchronous intestinal tumors, with population studies reporting synchronous lesions in up to 42% of patients with any type of appendiceal neoplasm.[7]
Thus, the value of colonoscopy to assess for synchronous lesions is debated; the European Neuroendocrine Tumor Society (ENETS) 2016 guidelines[2] note that the use of colonoscopy in aNET should follow general population indications, while the American Society of Colon and Rectal Surgeons recommends performing colonoscopies in those with aNET even in the setting of low-quality evidence.[7] Lastly, like with NETs of other origins, a baseline serum Chromogranin A or urine 5-HIAA/plasma Serotonin in the presence of metastasis can be obtained for use during follow-up, although the latter is rarely elevated in aNETs.[2]
For the majority of patients who are diagnosed with aNET after an appendectomy, further workup depends on the need for additional surgical intervention – which is determined by tumor size, location, margins, and high-risk features. In patients who, by consensus, do not require additional treatment – like those with tumors < 1 cm and negative margins – ENETS does not recommend any additional workup.[2] For those tumors > 1 cm, a CT or MRI could be utilized for lymph node evaluation, while somatostatin receptor imaging (such as a DOTATE PET scan) may be added for tumors > 2 cm or with risk factors for metastases.[2]

Management Decisions and Controversies

Surgical resection remains the primary treatment of aNET. Because most aNETs are diagnosed following resection during appendectomy, sufficient treatment may be completed simultaneously with diagnosis. Yet, which tumors would benefit from surgical resection beyond appendectomy, thereby requiring surgeons to perform a formal right hemicolectomy (RHC) with regional lymphadenectomy, remains the essential management decision of aNETs. A basic decision tree is depicted in Figure 1.
Because of the overall rarity and malignant nature of this disease, the level of evidence on which recommendations are based is limited, while the likelihood of obtaining randomized evidence remains slim.[8] Like other malignancies, the need for more extensive resection along with lymphadenectomy rests on the tumor’s metastatic potential, which influences survival rates. For aNET, various tumor characteristics have been shown to be predictive of the likelihood of lymph node spread, and thereby, influence the decision to perform further resection. Many of these risk factors are determined on pathology report following an appendectomy and include high tumor grade, mesoappendix invasion, serosal invasion, higher tumor T stage, lymphovascular invasion, and positive margin status.[5]
Generally, the first factor that determines whether RHC is indicated is gross tumor size, which is stratified into three cohorts: < 1 cm, 1-2 cm, and > 2 cm. For tumors > 2 cm, consensus guidelines from multiple societies, including ENETS[2] and the North American Neuroendocrine Tumor Society (NANETS),[9] recommend that RHC with lymphadenectomy should be performed. This recommendation is based on the increased likelihood of locoregional spread with increasing size or tumor T stage, which can lead to worse outcomes. For example, some studies quote a 5-year survival as low as 12% for patients with advanced, metastatic disease versus nearly 100% survival in early-stage/smaller lesions.[2] Hence, for tumors < 1 cm that are located in the tip of the appendix, with negative margins (R0), and no aforementioned risk factors on pathology, experts agree that an appendectomy alone serves as adequate surgical resection.
The importance of tumor location within the appendix is linked with margin status because those in the base of the appendix theoretically have higher likelihood of extending into the cecum. In a National Cancer Database (NCDB) study on aNET, an R0 resection was shown to be influential of outcomes, as positive margins carried a hazard ratio of 5.62 (p < .01) on overall survival.[8] Therefore, patients with any tumor in the base of the appendix or with non-R0 resection are recommended to undergo RHC.
Controversy: Pathology Risk Factors That Drive Further Surgical Resection
For tumors < 1 cm, discrepancies in surgical decision-making arise when certain pathologic factors are present given the varied reports of how these factors predict lymph node status. For example, authors of a single institutional study from Copenhagen used multivariable regression to determine that only positive margin resection and tumor mesoappendix invasion > 3 mm were associated with lymph node metastases.[10]
Meanwhile, a retrospective multi-institutional review analyzed 100 aNET patients who had lymph nodes resected to compare factors between those with positive node metastases (n = 23) versus negative nodes (n = 77). The authors reported that those with positive nodes had significantly higher rates of tumor > 2 cm, lymphovascular invasion, perineural invasion, and larger pathologic T stage, but similar margin status.[5] Although this later study did not control for other factors via multivariable analysis, this highlights that high quality evidence is lacking in terms of identifying satisfactory prognostic factors, especially with the variations and contradictions in retrospective results.
Consequently, expert societies provide different suggestions depending on the presence of some of these factors. For example, ENETS guidelines state that when mesoappendix invasion > 3 mm is present, RHC is “advisable” despite studies showing prognosis may not be affected.[2] Meanwhile, the NANETS 2010 consensus paper remarks that tumors < 1 cm at the tip of the appendix without lymphovascular or mesoappendix invasion are cured by appendectomy.[9] Without bluntly recommending RHC otherwise, the implication appears that any mesoappendix invasion, as well as lymphovascular invasion, could warrant RHC in most cases, until better evidence emerges.
Controversy: Management of 1-2 cm aNETs
While there is frequently, although not always, the consensus in the treatment strategy for tumors < 1 cm or > 2 cm under specified conditions, patients with tumors that measure 1-2 cm fit into a more nuanced treatment algorithm.
In their multi-institutional study in which 359 aNET patients were discussed at a regional committee meeting, Rault-Petit et al.[5] found that 102 patients were recommended for RHC by the committee, of which only 72 would undergo RHC based on ENETS guidelines. Of these 30 discrepancies, 25 tumors measured 1-2 cm; meaning that of the 100 patients with 1-2 cm tumors discussed by the committee, a 75% agreement rate was recorded between the committee and ENETS compared to > 98% agreement rate for those with tumors < 1 cm or > 2 cm. This discrepancy highlights the variation in approaches, which arises due to the lack of data on how size truly affects rates of lymph node spread and survival.
Essentially, society guidelines argue that the presence of any one of the aforementioned pathology risk factors (mesoappendix invasion, lymphovascular invasion, etc.) should push surgeons to perform RHC for a 1-2 cm tumor. In the ENETS guidelines, RHC is recommended for tumors < 1 cm in the presence of any three factors (tumor at the base, positive margins, and mesoappendix invasion), while RHC is encouraged for 1-2 cm tumors with any of these same factors or those that show grade 2 histology or lymphovascular invasion.[2]
Yet, Rault-Petit et al.[5] noted in their multi-institutional review that for those with 1-2 cm tumors specifically, no individual factor was significantly predictive of the presence of lymph node metastases. Additionally, these same authors calculated that 1.95 cm was the best tumor size cutoff to predict lymph node positivity (sensitivity .71, specificity .68),[5] while Holmager et al.[10] calculated 1.3 cm as the ideal size cutoff based on their institution’s data in which LNs were positive in 27% of aNET patients with > 2 cm tumors, 9% of those with 1-2 cm, and 0% of those with < 1 cm.
Overall, the lack of high-quality data on how size and specific pathology factors impact lymph node spread often prompts surgeons to perform RHC if any of these theoretical risk factors are discovered. 
Controversy: Does Right Hemicolectomy Change Outcomes?
Regardless of the criteria used to indicate the need for a right hemicolectomy, questions about the clinically significant impact of RHC persist. In institutional and national database studies alike, the rate of positive lymph nodes following formal lymphadenectomy during RHC or lymph node sampling during appendectomy ranged from 17%-27%.[3,5,8,10] As such, Holmager et al.[10] remarked that using their indications for RHC, 83% of the 63 patients who had completion RHC underwent an “unnecessary” operation because only 17% had positive nodes.
Given the concern of performing a more extensive operation in patients who may not benefit, survival outcomes for aNET patients have been retrospectively analyzed at both the institutional and national level. In their multi-institutional review, Pawa et al.[3] followed patients for a median of 38.5 months and discovered no instances of recurrence in aNET patients who underwent appendectomy nor RHC. Both 5 and 10-year survival rates for the 211 patients who had aNET as their only malignancy reached 99.05%, with 100% recurrence-free survival.
Although the authors do not directly compare survival rates between appendectomy and RHC, only 25% of patients in the study underwent completion RHC, implying appendectomy alone still yielded acceptable survival in many cases. Furthermore, the authors concluded that using current indications and guidelines to perform a completion RHC, 15 additional patients that only underwent index appendectomy should have undergone RHC. Of these 15 patients, none developed regional/distant recurrence nor died during the median follow-up period.
To directly compare survival between RHC and a more limited surgical approach, Nussbaum et al.[8] used the NCDB to compare patients with 1-2 cm aNET who underwent either RHC (531, 58%) or a “segmental bowel resection” (385, 42%), which was categorized as the appendectomy group given the NCDB’s recording limitations. Although some of the segmental resection/appendectomy group had lymph nodes retrieved, the authors verified this was likely unbiased sampling (not based on suspicion of extensive disease) as the rate of positive lymph nodes in both treatment groups was similar. Thus, the segmental resection group was considered an adequate representation of appendectomy without formal lymphadenectomy.
Using a Cox proportional hazards model, the authors concluded that there was no significant difference in overall survival between patients that underwent RHC versus appendectomy, and the survival rates remained statistically similar when comparing amongst three separate cohorts: RHC, appendectomy without lymph nodes samples, and appendectomy with lymph nodes sampled. The variables that did significantly impact survival, however, were the presence of lymph node metastases (hazard ratio 4.63, p < .01), positive tumor margins (hazard ratio 5.62, p < .01) and age.
Nonetheless, other sources such as the 2010 NANETS guidelines documented stark contrasts in 5-year mortality rates between tumors > 2 cm (29.5%) versus those measuring 1 cm (5%).[9] Without level one evidence to help differentiate between tumor factors that justify performing a right hemicolectomy and formal lymphadenectomy to improve mortality, physicians must utilize the guidelines available to hold discussions with patients regarding the benefits, risks, and unknowns of performing completion RHC following index appendectomy.
Controversy: Postoperative Surveillance
No protocolized surveillance exists following aNET resection, but general trends have emerged. For those who appendectomy alone was sufficient or RHC was performed for a tumor < 2 cm without residual disease or positive lymph nodes on pathology, no follow up is recommended given extremely low recurrence rates.[2,3] When regional lymph nodes or distant metastases are involved, ENETS guidelines advise long term follow-up but acknowledge no specific method has been studied.[2]
For these surveilled patients, Pawa et al.,[3] in their muti-institutional study, described monthly follow ups for 6-12 months with subsequent annual CT or MRI and tumor biomarkers. If either imaging or labs were concerning for recurrence, somatostatin receptor imaging was performed. This same protocol was also used for those who were recommended for RHC but never underwent the procedure. Additionally, while no standardized timeline exists, Ciarrocchi et al.[11] recommend extending surveillance 10 years postoperatively for those patients in which follow up is warranted. 

Summary

  • Appendiceal neuroendocrine tumors are the most common neoplasm of the appendix and commonly are diagnosed following appendectomy.
  • Workup following postoperative diagnosis depends on the need for further treatment.
  • As surgical resection remains the mainstay of management, surgeons must determine whether simple appendectomy versus right hemicolectomy with formal lymphadenectomy is indicated.
  • Because there is a sparsity of level one evidence to predict the likelihood of lymphatic metastatic disease, the decision to proceed with right hemicolectomy is guided by the presence of high-risk tumor characteristics.
  • Characteristics like tumor size > 2 cm, location at the base of the appendix, and positive tumor margins are thought to be indications for right hemicolectomy, while others such as mesoappendix and lymphovascular invasion vary amongst guidelines.
  • Data on long-term outcomes and potential mortality benefits of performing right hemicolectomy versus appendectomy remain restricted to retrospective reviews and can vary accordingly.
  • Ultimately, physicians should utilize the available guidelines to discuss and determine management options with patients diagnosed with an appendiceal neuroendocrine tumor.

References

  1. Memorial Sloan Kettering Cancer Center. Types of Appendiceal Cancer. https://www.mskcc.org/cancer-care/types/appendiceal/diagnosis/types. Accessed November 12, 2022.
  2. Pape UF, Niederle B, Costa F, et al. ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology. 2016;103(2):144-152.
  3. Pawa N, Clift AK, Osmani H, et al. Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More. Neuroendocrinology. 2018;106(3):242-251.
  4. Volante M, Grillo F, Massa F, et al. Neuroendocrine neoplasms of the appendix, colon and rectum. Pathologica. 2021;113(1):19-27.
  5. Rault-Petit B, Do Cao C, Guyétant S, et al. Current Management and Predictive Factors of Lymph Node Metastasis of Appendix Neuroendocrine Tumors: A National Study from the French Group of Endocrine Tumors (GTE). Ann Surg. 2019;270(1):165-171.
  6. Abdelaal A, El Ansari W, Al-Bozom I, et al. Frequency, characteristics and outcomes of appendicular neuroendocrine tumors: A cross-sectional study from an academic tertiary care hospital. Ann Med Surg. 2017;21:20-24.
  7. Glasgow SC, Gaertner W, Stewart D, et al. The American Society of Colon and Rectal Surgeons, Clinical Practice Guidelines for the Management of Appendiceal Neoplasms. Dis Colon Rectum. 2019;62(12):1425-1438.
  8. Nussbaum DP, Speicher PJ, Gulack BC, et al. Management of 1- to 2-cm carcinoid tumors of the appendix: Using the national cancer data base to address controversies in general surgery. J Am Coll Surg. 2015;220(5):894-903.
  9. Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: Well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas. 2010;39(6):753-766.
  10. Holmager P, Willemoe GL, Nielsen K, et al. Neuroendocrine neoplasms of the appendix: Characterization of 335 patients referred to the Copenhagen NET Center of Excellence. Eur J Surg Oncol. 2021;47(6):1357-1363.
  11. Ciarrocchi A, Rindi G, Pietroletti R. Diagnosis and Treatment of Primary Tumors of the Appendix: a Critical Review. J Gastrointest Cancer. 2021;52(2):471-475.