Pediatric Gastrointestinal Neuroendocrine Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Gastrointestinal Neuroendocrine (Carcinoid) Tumors of the Appendix

Clinical Presentation

The most common site for neuroendocrine (carcinoid) tumors is the appendix. In a single-institution retrospective review of 45 cases of neuroendocrine (carcinoid) tumors in children and adolescents between 2003 and 2016, the appendix was the primary site in 36 patients.[1][Level of evidence C2] No recurrences were observed among the patients with appendiceal primary tumors treated with appendectomy alone, which supports resection of the appendix without hemicolectomy as the procedure of choice.

Most neuroendocrine tumors of the appendix are discovered incidentally at the time of appendectomy. Most of them are small, low-grade, localized tumors.[2,3,4]

Treatment of Gastrointestinal Neuroendocrine Tumors of the Appendix

Treatment options for neuroendocrine tumors of the appendix include the following:

1. Appendectomy.

In adults, it has been accepted practice to remove the entire right colon in patients with large neuroendocrine tumors of the appendix (>2 cm in diameter) or with tumors that have spread to the lymph nodes.[5,6,7,8]

In children and adolescents, however, study results suggest that appendectomy alone is sufficient treatment for appendiceal neuroendocrine tumors, regardless of size, position, histology, or nodal or mesenteric involvement. Right hemicolectomy is unnecessary in children. Routine follow-up imaging and biologic studies were not beneficial.[5,8,9,10]

Evidence (appendectomy alone):

1. The Italian Tumori Rari in Etá Pediatrica project performed a prospective registry study that evaluated 113 patients with appendiceal neuroendocrine tumors.[9][Level of evidence C1] Primary re-excision was not recommended for completely excised tumors smaller than 2 cm, except for microscopic/macroscopic residual tumor on the margins of the appendix. In these cases, cecum resection and pericecal node biopsy was recommended. Decisions about tumors larger than 2 cm were made at the discretion of the primary physicians. However, physicians were discouraged from performing right hemicolectomy unless margins were positive. Of the 113 study participants, 108 had tumors smaller than 2 cm. Thirty-five patients had extension of tumor beyond the appendiceal wall. Five tumors invaded the serosa, and 28 tumors invaded the periappendiceal fat. Margins were clear in 111 of 113 patients.
   • At 41 months of follow-up, all 113 patients were alive.
   • The five patients with tumors larger than 2 cm did well.
   • One patient had resection of the cecum; no residual tumor was found.
   • One patient had a right hemicolectomy (tumor was <2 cm with clear margins, but an octreotide scan was possibly positive; no tumor was found).

   The study concluded that appendectomy alone should be considered curative for most cases of appendiceal neuroendocrine tumors. The procedure of choice is a resection of the appendix without hemicolectomy.

2. A French multicenter study of children younger than 18 years with neuroendocrine tumors of the appendix was carried out by surveying pediatric surgeons from 1988 to 2012. A total of 114 patients were identified. Risk factors for secondary right hemicolectomy were extension into the mesoappendix, positive margins, size larger than 2 cm, and high proliferative index. Eighteen patients met the above criteria and were observed.[10]
   • All patients were alive and disease free at follow-up.
   • In addition, follow-up radiological studies and biological tests were not found to be helpful.

   The investigator's recommendation was that appendectomy alone is sufficient treatment for neuroendocrine tumors of the appendix.

3. A systematic review and meta-analysis of 38 studies of appendiceal neuroendocrine tumors identified 958 cases with a mean age at presentation of 11.6 years. Tumor size was 2 cm or smaller in 85% of the cases. Of the 24 papers that reported the status of the margin of resection, 97% had negative margins. Nodal involvement was reported in ten series and was present in 1.4% of cases, with higher rates seen in patients whose tumors were larger than 2 cm (35%). Vascular involvement was seen in 11% of 510 patients, and invasion of the mesoappendix or periappendiceal fat was reported in 29% of 910 patients.[8]
   • According to the European and American Neuroendocrine Tumor Societies, 189 patients met the criteria for a secondary procedure after initial appendectomy, but only 69 patients underwent a secondary procedure (n = 43, hemicolectomy; n = 2, ileocecectomy; n = 1, cecectomy; n = 2, ileocolectomy; n = 21, not specified).
   • Of the 120 patients who did not have a secondary procedure, 91 patients had tumors extending to the mesoappendix, 5 patients had vascular invasion, 4 patients had positive margins, 12 patients had tumors 2 cm or larger, 1 patient had a high proliferative index, and 7 patients had positive lymph nodes. No recurrence was reported in patients who had a secondary procedure or in those who were observed. Preoperative and postoperative imaging was not helpful in managing the patients.

References:

1. Degnan AJ, Tocchio S, Kurtom W, et al.: Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr Blood Cancer 64 (9): , 2017.
2. Pelizzo G, La Riccia A, Bouvier R, et al.: Carcinoid tumors of the appendix in children. Pediatr Surg Int 17 (5-6): 399-402, 2001.
3. Hatzipantelis E, Panagopoulou P, Sidi-Fragandrea V, et al.: Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece. J Pediatr Gastroenterol Nutr 51 (5): 622-5, 2010.
4. Henderson L, Fehily C, Folaranmi S, et al.: Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience. J Pediatr Surg 49 (10): 1513-7, 2014.
5. Dall'Igna P, Ferrari A, Luzzatto C, et al.: Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions. J Pediatr Gastroenterol Nutr 40 (2): 216-9, 2005.
6. Wu H, Chintagumpala M, Hicks J, et al.: Neuroendocrine Tumor of the Appendix in Children. J Pediatr Hematol Oncol 39 (2): 97-102, 2017.
7. Boxberger N, Redlich A, Böger C, et al.: Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer 60 (1): 65-70, 2013.
8. Njere I, Smith LL, Thurairasa D, et al.: Systematic review and meta-analysis of appendiceal carcinoid tumors in children. Pediatr Blood Cancer 65 (8): e27069, 2018.
9. Virgone C, Cecchetto G, Alaggio R, et al.: Appendiceal neuroendocrine tumours in childhood: Italian TREP project. J Pediatr Gastroenterol Nutr 58 (3): 333-8, 2014.
10. de Lambert G, Lardy H, Martelli H, et al.: Surgical Management of Neuroendocrine Tumors of the Appendix in Children and Adolescents: A Retrospective French Multicenter Study of 114 Cases. Pediatr Blood Cancer 63 (4): 598-603, 2016.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgeons.
• Pathologists.
• Pediatric radiation oncologists.
• Pediatric medical oncologists and hematologists.
• Ophthalmologists.
• Rehabilitation specialists.
• Pediatric oncology nurses.
• Social workers.
• Child-life professionals.
• Psychologists.
• Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3,4,5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

• A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[9]
• The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]

  Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as Gastrointestinal Neuroendocrine Tumors Treatment.

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr.
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017.
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017.
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019.
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010.

Extra-appendiceal Gastrointestinal Neuroendocrine (Carcinoid) Tumors

Clinical Presentation

Extra-appendiceal neuroendocrine (carcinoid) tumors are rare. Most are sporadic but may also be part of a hereditary syndrome. A single-institution retrospective review identified 45 cases of neuroendocrine tumors in children and adolescents between 2003 and 2016.[1][Level of evidence C2] Extra-appendiceal primary tumors (n = 9) were associated with a higher risk of metastasis and recurrence. The Tumori Rari in Etá Pediatrica (TREP) group registered 27 patients between 2000 and 2020.[2]

Extra-appendiceal neuroendocrine tumors of the abdomen occur most often in the pancreas, but can also occur in the stomach and liver.[2] In the TREP series of 27 cases, 12 occurred in the pancreas and 10 occurred in the bronchi.[2] The most common clinical presentation is an unknown primary site. Extra-appendiceal neuroendocrine tumors are more likely to be larger, and higher grade or to present with metastases.[3] Larger tumor size has been associated with a higher risk of recurrence.[1]

The carcinoid syndrome of excessive excretion of somatostatin is characterized by flushing, labile blood pressure, and metastatic spread of the tumor to the liver.[4] Symptoms may be lessened by giving somatostatin analogs, which are available in short-acting and long-acting forms.[5]

Clinical experience with extra-appendiceal neuroendocrine tumors is reported almost entirely in adults. Histopathology is graded by mitotic rate, Ki-67 labeling index, and presence of necrosis into well-differentiated (low grade, G1), moderately differentiated (intermediate grade, G2) and poorly differentiated (high grade, G3) tumors.[6] For more information, see Gastrointestinal Neuroendocrine Tumors Treatment.

Treatment and Outcome of Extra-appendiceal Gastrointestinal Neuroendocrine Tumors

Complete surgical resection and localized disease are associated with a favorable clinical outcome.[2]

Treatment options for resectable extra-appendiceal neuroendocrine tumors include the following:

1. Surgery.[7]

Treatment options for unresectable or multifocal extra-appendiceal neuroendocrine tumors include the following:

1. Embolization.[8]
2. Somatostatin receptor 2 (SSTR2) ligands.[9,10]
3. Peptide receptor radionuclide therapy.[11]
4. Mammalian target of rapamycin (mTOR) inhibitors.[12]
5. Tyrosine kinase inhibitors.[13]
6. Immunotherapies.[14]

SSTR2 ligands include octreotide, long-acting repeatable octreotide, and lanreotide. Octreotide is not practical for therapy because its short half-life necessitates frequent administration. Long-acting, repeatable octreotide and lanreotide have been evaluated in prospective, randomized, placebo-controlled trials.[9,10] Patient age was not specified in the first trial, and eligibility was restricted to age 18 years and older in the second trial. Neither agent produced significant objective responses in measurable tumors. Both agents were associated with statistically significant increases in progression-free survival and time-to-progression, and both agents are recommended for the treatment of unresectable extra-appendiceal neuroendocrine tumors in adults.

A phase III trial included 231 patients with advanced or metastatic extra-appendiceal neuroendocrine tumors. Patients were randomly assigned to treatment with lutetium Lu 177 (177Lu)-DOTATATE plus long-acting octreotide or high-dose long-acting octreotide (control group). While the median overall survival (OS) did not reach statistical significance, there was an 11.7-month difference, with 48.0 months (95% confidence interval [CI], 37.4–55.2) in the 177Lu-DOTATATE group and 36.3 months (95% CI, 25.9–51.7) in the control group.[15] The U.S. Food and Drug Administration approved the use of 177Lu-DOTATATE for children aged 12 years and older with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors.

Conventional cytotoxic chemotherapy appears to be inactive.[3]

In one retrospective single-institution study, the 5-year relapse-free survival rate was 41% for patients with extra-appendiceal neuroendocrine tumors. The OS rate was 66%.[3]

References:

1. Degnan AJ, Tocchio S, Kurtom W, et al.: Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr Blood Cancer 64 (9): , 2017.
2. Virgone C, Ferrari A, Chiaravalli S, et al.: Extra-appendicular neuroendocrine tumors: A report from the TREP project (2000-2020). Pediatr Blood Cancer 68 (4): e28880, 2021.
3. Boston CH, Phan A, Munsell MF, et al.: A Comparison Between Appendiceal and Nonappendiceal Neuroendocrine Tumors in Children and Young Adults: A Single-institution Experience. J Pediatr Hematol Oncol 37 (6): 438-42, 2015.
4. Tormey WP, FitzGerald RJ: The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid. Postgrad Med J 71 (839): 542-5, 1995.
5. Delaunoit T, Rubin J, Neczyporenko F, et al.: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors. Mayo Clin Proc 80 (4): 502-6, 2005.
6. Enzler T, Fojo T: Long-acting somatostatin analogues in the treatment of unresectable/metastatic neuroendocrine tumors. Semin Oncol 44 (2): 141-156, 2017.
7. Ambe CM, Nguyen P, Centeno BA, et al.: Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience. Cancer Control 24 (5): 1073274817729076, 2017 Oct-Dec.
8. Elf AK, Andersson M, Henrikson O, et al.: Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial. World J Surg 42 (2): 506-513, 2018.
9. Rinke A, Wittenberg M, Schade-Brittinger C, et al.: Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology 104 (1): 26-32, 2017.
10. Caplin ME, Pavel M, Ćwikła JB, et al.: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371 (3): 224-33, 2014.
11. Brabander T, Teunissen JJ, Van Eijck CH, et al.: Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 30 (1): 103-14, 2016.
12. Gajate P, Martínez-Sáez O, Alonso-Gordoa T, et al.: Emerging use of everolimus in the treatment of neuroendocrine tumors. Cancer Manag Res 9: 215-224, 2017.
13. Liu IH, Kunz PL: Biologics in gastrointestinal and pancreatic neuroendocrine tumors. J Gastrointest Oncol 8 (3): 457-465, 2017.
14. Vellani SD, Nigro A, Varatharajan S, et al.: Emerging Immunotherapeutic and Diagnostic Modalities in Carcinoid Tumors. Molecules 28 (5): , 2023.
15. Strosberg JR, Caplin ME, Kunz PL, et al.: 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol 22 (12): 1752-1763, 2021.

Metastatic Gastrointestinal Neuroendocrine Tumors

Treatment of metastatic neuroendocrine tumors of the large bowel, pancreas, or stomach becomes more complicated and requires treatment similar to that given for adult high-grade neuroendocrine tumors. For more information about treatment options for patients with malignant carcinoid tumors, see Gastrointestinal Neuroendocrine Tumors Treatment.

Treatment Options Under Clinical Evaluation for Pediatric Gastrointestinal Neuroendocrine Tumors

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

Latest Updates to This Summary (09 / 13 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric gastrointestinal neuroendocrine tumors. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Pediatric Gastrointestinal Neuroendocrine Tumors Treatment are:

• Denise Adams, MD (Children's Hospital Boston)
• Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
• William H. Meyer, MD
• Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
• Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
• Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ® Pediatric Treatment Editorial Board. PDQ Pediatric Gastrointestinal Neuroendocrine Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/gi-neuroendocrine-tumors/hp/pediatric-gi-neuroendocrine-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 31661208]

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Last Revised: 2024-09-13