search for




 

Review Article
Childhood Neuroendocrine Tumors of Appendix: Suggested Approach and Management
Clin Pediatr Hematol Oncol 2023;30:53-9.
Published online October 31, 2023
© 2023 Korean Society of Pediatric Hematology-Oncology

Muhammad Matloob Alam1, Abdulrhman Alathaibi1, Mohamed Magdi Refai1, Abdulaziz Alsaedi2 and Muhammad Usman Tariq3

1Department of Pediatric Hematology/Oncology, 2Department of Pediatric/Pediatric Endocrinology and 3Department of Laboratory, Alhada Armed Forces Hospital, Taif, Saudi Arabia
Correspondence to: Muhammad Matloob Alam
Department of Hematology/Oncology, Alhada Armed Forces Hospital, Alhada, Taif, Saudi Arabia
Tel: +966-545968691
Fax: +966-0127543823
E-mail: dr.matloobalam@hotmail.com
ORCID ID: orcid.org/0000-0002-9267-0129
Received July 28, 2023; Revised September 13, 2023; Accepted September 29, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Appendiceal neuroendocrine tumors (NET) although rare, but the most common tumors of the gastrointestinal tract in children and adolescents. NET of the appendix is typically undiagnosed preoperatively, are usually not associated with specific neuroendocrine symptoms, and a high percentage are initially identified by pathologists. For well-differentiated tumors of <1 cm and complete (R0) resection, no follow-up is required. Unlikely, tumor size >2 cm or tumor with high-risk features confer a relevant risk of recurrence and further imaging and surgical procedures are warranted. No consensus, clear recommendation or management guidelines are available for the management of appendiceal NET in children. Herein, current article will provide an overview of literature and suggested guidelines for evaluation and management of childhood neuroendocrine tumors of appendix.
Keywords: Appendiceal neuroendocrine tumors, Children, Histopathology, Surgery, Management options, Guideline
Introduction

Appendiceal neuroendocrine tumors (NET) although rare, even comprise the largest subgroup of appendiceal neoplasms. Approximately 80% of all appendiceal tumors including both benign and malignant tumors belong to this group [1]. NET of the appendix are also the most common tumors of the gastrointestinal tract in children and adolescents [1]. Key features of this tumor have been summarized in the box below (Box 1). A number of retrospective studies, reviews, and case reports involving appendiceal NET in children and adults have been published in recent years [2-9], however, no consensus, clear recommendation or management guidelines are available. In this review we will try to summarizes the best available management options that can be opted while investigating a case of appendiceal NET including histopathological findings, laboratory testing, surgical options and follow up (Fig. 1).

Figure 1. (A) Low power view of tumor involving appendiceal wall. Tumor is extending into mucosa on right (smaller arrows) and mus-cularis propria on left (larger arrow) (B) medium power view of tumor involving mucosa. Tumor is attenua-ting the overlying epithelium (larger arrow). Residual intact crypts are also appreciable (smaller arrows) (C). Tumor is infiltrating into mus-cularis propria (arrow). (D) High power view of tumor having round uniform nuclei with finely stippled (salt and pepper) chromatin.
Discussion

1) Epidemiology

Incidence rate of NET of the appendix have been reported approximately 0.15/100,000/year in the SEER database [10] as well as in other population-based databases from Europe [11-14]. A higher incidence rate has been observed in the past few decades to up to 0.4-0.6/100,000/year in the UK [11]. However, it is thought that true incidence of appendiceal NET is still underestimated due to many factors including less referral to higher centers and inclusion criteria of registries.

2) Clinical features

The mean age at diagnosis has been reported between 38 and 51 years, which is considerably earlier than for other gastrointestinal tract NET [5-7,11,15]. Appendiceal NETs are rarely symptomatic and more frequently diagnosed incidentally during appendicectomy with a rate of approximately 3-5 cases per 1,000 appendicectomies. However, tumor with extensive local disease or distant metastases may appear symptomatic with abdominal pain, tumor mass effect or signs of bowel obstruction [12]. An association with the carcinoid syndrome is extremely rare (1% of all cases) [11] and indicates metastatic disease [16]. Since most appendiceal NET are incidentally diagnosed by postoperative histology, thus diagnostic procedures relate mostly to postoperative staging and follow-up.

3) Histopathology

Neuroendocrine tumors (NETs) of the appendix originate from neuroendocrine cells present within mucosal crypts as well as subepithelial neuroendocrine cells present within the lamina propria and submucosa of the appendix wall. On gross examination, small-sized and incidentally discovered tumor are not visible, however, larger tumors have yellow cut surface. Tip of the appendix should be entirely submitted to avoid missing the smaller tumors. Histology is essential to establish the diagnosis.

Histologically, NETs are composed of large nests, trabeculae, ribbons and tubular structures formed by uniform, polygonal-shaped tumor cells. Tumor cells have granular eosinophilic cytoplasm and typical stippled (salt and pepper) chromatin. Tumor can extend towards mucosal surface to ulcerate it or extend deeper into muscularis propria, mesoappendix and adjacent structures (Fig. 1).

Histopathological confirmation of the diagnosis requires positive immunohistochemical (IHC) staining for at least one of the neuroendocrine markers including synaptophysin, Chromogranin A (CgA) and Chromogranin B (CgB) (Fig. 2). Mitotic activity and necrosis are infrequently observed in NET [17]. MIB-1 IHC is performed to determine the MIB-1/Ki-67 proliferative index of the tumor (Fig. 2C). The NETs are graded according to the current WHO classification (Table 1) which is an essential diagnostic parameter as it defines the therapeutic strategy [18,19]. Tumors are staged on the basis of size and extent of invasion according to European neuroendocrine tumor society (ENETS) and Union for international cancer control (UICC)/American joint committee on cancer (AJCC) staging systems (Table 2, 3) [19,20]. Major histopathological and immunohistochemical findings of appendiceal NET have been shown in the following figures (Fig. 1, 2).

Table 1 . Grading of appendiceal NET based on the proliferative capacity of tumors according to WHO criteria [17,18,20].

Index/grade Grade 1Grade 2Grade 3
Ki67 index≤2%3-20%>20%
Mitotic index<22-20>20

Either the Ki67 index (MIB1 antibody; % of 2,000 cells in areas of highest nuclear labelling), or the mitotic count per 10 HPF (2 mm2, at least 40 fields at ×40 magnification), evaluated in areas of highest mitotic density, should be reported..



Table 2 . Comparison of primary tumor (T) staging for endocrine tumors of the appendix according to ENETS [18] versus UICC/AJCC [20] (TNM classification).

ENETSUICC/AJCC
1Tumor ≤1 cm invading submucosa and muscularis propria1a: Tumor ≤1 cm in greatest dimension
1b: Tumor >1 cm but ≤2 cm in greatest dimension
2Tumor ≤2 cm invading submucosa, muscularis propria and/or minimally (up to 3 mm) invading subserosa/mesoappendix2: Tumor >2 cm but ≤4 cm
3Tumor >2 cm and/or extensive (>3 mm) invasion of subserosa/mesoappendix3: Tumor >4 cm or with subserosal invasion or involvement of mesoappendix
4Tumor invades peritoneum/other organs
4: Tumor perforates peritoneum or directly invades other adjacent organs or structures, e.g., abdominal wall and skeletal muscle


Table 3 . Comparison of disease staging for endocrine tumors of the appendix according to ENETS [18] versus UICC/AJCC [20] (TNM classification).

StagingENETS stageUICC/AJCC stage
Stage IT1N0M0Stage IT1N0M0
Stage IIaT2N0M0Stage IIT2-3N0M0
Stage IIbT3N0M0
Stage IIIaT4N0M0Stage IIIT4N0M0
Stage IIIbany TN1M0any TN1M0
Stage IVany Tany NM1Stage IVany Tany NM1

T, primary tumor (x: primary tumor cannot be assessed, 0: no evidence of primary tumor); N, regional lymph node metastasis (x: regional lymph nodes cannot be assessed, 0: no regional lymph node metastasis, 1: regional lymph node metastasis); M, distant metastasis (x: distant metastasis cannot be assessed, 0: no distant metastases, 1: distant metastasis)..



Figure 2. Tumor cells are showing positive expression for (A) synapto-physin and (B) Chromogranin A. (C) Tumor cells are showing low Ki-67 index. Basal cells of intact crypts are showing high Ki-67 index and serving as positive internal con-trol (arrows).

4) Tumor markers

Elevated Chromogranin A (CgA) is seen and can be used as a tumor marker in appendiceal NET [21,22]. In the very rare patient with carcinoid syndrome, urinary 5-hydroxyindoleacetic acid (5-HIAA) is useful. To avoid falsely elevated 5-HIAA levels, proper proceedings with 24-hour urine collection and food and/or medical restrictions during the collecting period should be adhered to [23].

5) Radiology

For an accurate classification of tumors, an imaging along with histological evaluation is important. Cross- sectional imaging by either computed tomography (CT) applying modern protocols (3-phase, contrast enhanced, multi slice-detector CT) or magnetic resonance imaging (MRI; with contrast) are gold-standard imaging tests to assess the tumor burden of a patient with neuroendocrine tumor of abdomen and are important to rule out regional involvement and distant metastases [24-26].

Abdominal ultrasound can be used, and despite user- and patient’s profile-dependent limitations, it has the advantage of being a less invasive procedure [27]. How-ever, CT and MRI have greater sensitivity and specificity [28].

NET may be difficult to be radiologically visualized because of their size, and generally present as submucosal masses or nodular thickening of the wall [29]. Somatostatin receptor imaging (SRI) using either somatostatin receptor scintigraphy (SRS; e.g., indium-111) including SPECT or positron emission tomography (PET) scanning using gallium-68-labelled in combination with CT may be considered in cases when curative resection is not completely assured or when distant metastasis is suspected [24-28].

6) Classification

Currently there are two classifications, the one presented by European Neuroendocrine Tumor Society (ENETS) and another by American Joint Committee on Cancer (AJCC). Tumor size is the most important indicator for surgery decision-making, and the main indicator of metastatic disease [30] thus defining the criteria for the elaboration of both classifications. ENETS-TNM staging [18] differs for T stages from AJCC/UICC/WHO-TNM staging [20] for appendiceal tumors (Table 1) thus it is strongly recommended to indicate this in the pathology report (Table 2, 3).

Neuroendocrine tumors of the appendix can still be classified according to WHO histopathology. Tumors with ki67 index ≤2%, and mitotic index (mitoses/10 HPF) <2 are classified as G1 and have a low proliferation rate. Tumors with ki67 index between 3% and 20% or mitotic index (mitoses/10 HPF) between 2 and 20 are classified as G2. Finally, tumors with a Ki67 index >20% or mitotic index (mitoses/10 HPF) >20 are classified as G3 (Table 1) [3,30]. Tumors classified as G2 and G3 have a higher proliferation rate; as such, in tumors between 1 and 2 cm, this classification may serve as a support to help the decision between a simple appendectomy and a right hemicolectomy with lymphadenectomy.

7) Surgical procedures

Surgery is the only curative treatment for neuroendo-crine tumors, being incurable when there is unresectable metastatic disease. Two surgical procedures can be applied to treat appendiceal NET; simple appendicectomy and oncological right-sided hemicolectomy with lymphadenec-tomy.

It is generally felt that a well-differentiated appendiceal NET <2 cm is cured by appendicectomy indepen-dent of the location of the tumor. Thus, right hemicolectomy is justified only in those rare tumors 1-2 cm but with positive or unclear margins or with deep mesoappendiceal invasion (ENETS T2), higher proliferation rate (G2) and/or angioinvasion. Tumors with a diameter >2 cm should be treated by right hemicolectomy. Some experts suggest a local follow-up resection (ileocecal pole resection) with lymph node sampling if incomplete resection (R1) in a tumors size <15 mm and secondary right hemicolectomy for tumors size >15 mm even with complete resection (R0). A possible surgical approach [3-5,16,31] has been summarized in the following figure (Fig. 3). Adult studies showed that in patients with distant metastases, Octreotide, a somatostatin analogue may be beneficial in relieving the symptoms of carcinoid syndrome [30]. Loco regional therapies with embolization and/or radiofrequency ablation can be used [32]. Patients with progressive or non-responsive carcinoid syndrome may benefit from alpha interferon and hepatic artery occlusion with adjuvant chemotherapy [33,34].

Figure 3. Diagnostic Approach and Management of NET of Appendix in Children. Some experts suggest a local follow-up resection (ileocecal pole resection) with lymph node sampling if incomplete resection (R1) in a tumors size <15 mm and secondary right hemicolectomy for tumors size >15 mm even with complete resection (R0).

8) Prognosis and follow up

In general, appendiceal NET has excellent prognosis, at least in children [16]. Survival is extremely good for limited stage disease; 5 years survival rate for local disease is 95-100% and for regional disease is 85-100%. However, few cases with distant metastasis present with relatively poor survival, where 5 years survival rate is as low as 25% [8,9,13,14,16,35,36].

There are no specific recommendations based on ran-domized trial data on follow-up after resection and no adjuvant therapy is recommended after complete resec-tion of a well-differentiated NET. Several international guidelines include strategies for follow-up based on tumor size and the surgery performed [27,37,38]. A post- surgical approach and follow-up strategies has been summarized in the following figure (Fig. 1). In the case of candidates for surveillance, follow-up should consist of a medical history and physical examination. In addition, tumor markers (including 5-HIAA and CgA) and abdominal imaging by means of an ultrasound or CT/MRI scan should be considered [2,27,37,38].

Conclusion

Appendiceal neuroendocrine tumors are although rare, but the most common tumors of the gastrointestinal tract in children and adolescents. No consensus, clear recommendation or management guidelines for children is available about this topic. Therefore, further studies are necessary to assess the risk underlying these tumors more accurately and to define the uniform guidelines about diagnosis, classification and treatment to ensure a correct approach to these patients. Herein, we present a brief review of possible best available management options that can be opted while investigating a case of appendiceal NET in children including histopathological findings, radiological diagnosis, laboratory testing, surgical options and follow up.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

References
  1. Parkes SE, Muir KR, al Sheyyab M, et al. Carcinoid tumours of the appendix in children 1957-1986: incidence, treatment and outcome. Br J Surg 1993;80:502-4.
    Pubmed CrossRef
  2. Abreu RPNSA. Appendiceal neuroendocrine tumors: approach and treatment. J Coloproctol 2018;38:337-42.
    CrossRef
  3. Pape UF, Perren A, Niederle B, et al. ENETS consensus guidelines for the management of patients with neuroendo-crine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012;95:135-56.
    Pubmed CrossRef
  4. Muñoz de Nova JL, Hernando J, Sampedro Núñez M, et al. Management of incidentally discovered appendiceal neuroendocrine tumors after an appendicectomy. World J Gas-troenterol 2022;28:1304-14.
    Pubmed KoreaMed CrossRef
  5. Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroentero-pancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendo-crine Tumour Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer 2010;17:909-18.
    Pubmed CrossRef
  6. Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010;21:1794-803.
    Pubmed CrossRef
  7. Lepage C, Bouvier AM, Manfredi S, Dancourt V, Faivre J. Incidence and management of primary malignant small bowel cancers: a well-defined French population study. Am J Gastroenterol 2006;101:2826-32.
    Pubmed CrossRef
  8. Landerholm K, Falkmer S, Järhult J. Epidemiology of small bowel carcinoids in a defined population. World J Surg 2010;34:1500-5.
    Pubmed CrossRef
  9. Pape UF, Berndt U, Müller-Nordhorn J, et al. Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 2008;15:1083-97.
    Pubmed CrossRef
  10. Yao JC, Hassan M, Phan A, et al. One hundred years after 'carcinoid': epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-72.
    Pubmed CrossRef
  11. Ellis L, Shale MJ, Coleman MP. Carcinoid tumors of the gastrointestinal tract: trends in incidence in England since 1971. Am J Gastroenterol 2010;105:2563-9.
    Pubmed CrossRef
  12. Hauso O, Gustafsson BI, Kidd M, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 2008;113:2655-64.
    Pubmed CrossRef
  13. Quaedvlieg PF, Visser O, Lamers CB, Janssen-Heijen ML, Taal BG. Epidemiology and survival in patients with carcinoid disease in the Netherlands. An epidemiological study with 2391 patients. Ann Oncol 2001;12:1295-300.
    Pubmed CrossRef
  14. In't Hof KH, van der Wal HC, Kazemier G, Lange JF. Carci-noid tumour of the appendix: an analysis of 1,485 consecutive emergency appendectomies. J Gastrointest Surg 2008;12:1436-8.
    Pubmed KoreaMed CrossRef
  15. Ploeckinger U, Kloeppel G, Wiedenmann B, Lohmann R; representatives of 21 German NET Centers. The German NET- registry: an audit on the diagnosis and therapy of neuroendocrine tumors. Neuroendocrinology 2009;90:349-63.
    Pubmed CrossRef
  16. Boxberger N, Redlich A, Böger C, et al. Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer 2013;60:65-70.
    Pubmed CrossRef
  17. Couvelard A, Perren A, Sipos B. Appendiceal neuroendocrine neoplasms. In: WHO classification of tumours editorial board, ed. World Health Organisation classification of digestive tract tumours. 5th ed. Lyon: IARC Press, 2019. p. 152-5.
    CrossRef
  18. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO classification of tumours of the digestive system. Lyon: IARC Press, 2010.
    CrossRef
  19. Rindi G, Klöppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757-62.
    Pubmed CrossRef
  20. Sobin LH, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. Chichester: Wiley & Blackwell, 2009.
    CrossRef
  21. Prommegger R, Ensinger C, Adlassnig C, et al. Catestatin - a novel neuropeptide in carcinoid tumors of the appendix. Anticancer Res 2004;24:311-6.
  22. Modlin IM, Kidd M, Latich I, et al. Genetic differentiation of appendiceal tumor malignancy: a guide for the perplexed. Ann Surg 2006;244:52-60.
    Pubmed KoreaMed CrossRef
  23. O'Toole D, Grossman A, Gross D, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: biochemical markers. Neuroendocrinology 2009;90:194-202.
    Pubmed CrossRef
  24. Ricke J, Klose KJ, Mignon M, Oberg K, Wiedenmann B. Standardisation of imaging in neuroendocrine tumours: results of a European delphi process. Eur J Radiol 2001;37:8-17.
    Pubmed CrossRef
  25. Kaltsas G, Rockall A, Papadogias D, Reznek R, Grossman AB. Recent advances in radiological and radionuclide imaging and therapy of neuroendocrine tumours. Eur J Endocrinol 2004;151:15-27.
    Pubmed CrossRef
  26. Bader TR, Semelka RC, Chiu VC, Armao DM, Woosley JT. MRI of carcinoid tumors: spectrum of appearances in the gastrointestinal tract and liver. J Magn Reson Imaging 2001;14:261-9.
    Pubmed CrossRef
  27. Pape UF, Niederle B, Costa F, et al. ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology 2016;103:144-52.
    Pubmed CrossRef
  28. Arnold R, Chen YJ, Costa F, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumors: follow-up and documentation. Neuroendocrinology 2009;90:227-33.
    Pubmed CrossRef
  29. Leonards LM, Pahwa A, Patel MK, Petersen J, Nguyen MJ, Jude CM. Neoplasms of the appendix: pictorial review with clinical and pathologic correlation. Radiographics 2017;37:1059-83.
    Pubmed CrossRef
  30. Grozinsky-Glasberg S, Alexandraki KI, Barak D, et al. Current size criteria for the management of neuroendocrine tumors of the appendix: are they valid? Clinical experience and review. Neuroendocrinology 2013;98:31-7.
    Pubmed CrossRef
  31. Arnold R, Chen YJ, Costa F, et al. ENETS consensus guidelines for the standards of care in neuroendocrine tumours: follow-up and documentation. Neuroendocrinology 2009;90:227-33.
    Pubmed CrossRef
  32. O'Donnell ME, Carson J, Garstin WI. Surgical treatment of malignant carcinoid tumours of the appendix. Int J Clin Pract 2007;61:431-7.
    Pubmed CrossRef
  33. Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW. Cancers of the appendix: review of the literatures. ISRN Oncol 2011;2011:728579.
    Pubmed KoreaMed CrossRef
  34. Whitfield CG, Amin SN, Garner JP. Surgical management of primary appendiceal malignancy. Colorectal Dis 2012;14:1507-11.
    Pubmed CrossRef
  35. McGory ML, Maggard MA, Kang H, O'Connell JB, Ko CY. Malignancies of the appendix: beyond case series reports. Dis Colon Rectum 2005;48:2264-71.
    Pubmed CrossRef
  36. Landry CS, Woodall C, Scoggins CR, McMasters KM, Martin RC 2nd. Analysis of 900 appendiceal carcinoid tumors for a proposed predictive staging system. Arch Surg 2008;143:664-70. discussion 670.
    Pubmed CrossRef
  37. 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;39:753-66.
    Pubmed CrossRef
  38. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. NCCN: Plymouth Meeting, 2023.


October 2023, 30 (2)
Full Text PDF
Citation
Twitter
Facebook

Cited By Articles
  • CrossRef (0)

Author ORCID Information
  • Muhammad Matloob Alam