Research Article
Neuroendocrine Tumors of the Appendix in Adolescents and Young Adults
Grace Onimoe1*, Eric Kodish1 and Richard Herman2
1Division of Pediatric Hematology and Oncology, Cleveland Clinic Children’s, Cleveland Ohio, USA
2Division of Pediatric Surgery, Cleveland Clinic Children’s, Cleveland Ohio, USA
*Corresponding author: Grace Onimoe, Division of Pediatric Hematology and Oncology, Cleveland Clinic Children’s, Cleveland Ohio, USA
Published: 28 Jul, 2017
Cite this article as: Onimoe G, Kodish E, Herman R.
Neuroendocrine Tumors of the
Appendix in Adolescents and Young
Adults. Clin Oncol. 2017; 2: 1318.
Abstract
Neuroendocrine tumors involving the appendix in young people are uncommon. A retrospective review of appendiceal NET at Cleveland Clinic Children’s was completed, 14 patients were identified, 3 cases were classified as intermediate grade tumors, lymph node metastasis was present in 2 cases. The largest size tumor measured 4.5 cm, 5 patients underwent right hemicolectomy per NANETS criteria, 3 patients who met this criteria did not undergo hemicolectomy. No disease recurrence. Appendiceal NET is associated with an excellent prognosis in localized disease and has low metastatic potential. A multicenter review will be beneficial in better defining criteria for a second surgery.
Abbreviations
RHC: Right Hemicolectomy; NANETS: North American Neuroendocrine Tumor Society; NET: Neuroendocrine Tumor; PT: Patient; AYA: Adolescents and Young Adults; RX: Treatment; LN: Lymph Node; PT: Patient; NO: Number
Introduction
Neuroendocrine tumors (NET) are rare in the pediatric population and originate from the
neuroendocrine cells of the gastrointestinal tract, the appendix being the most common site.
A summary of existing series reports an incidence between 2 and 5 per 1000 cases in pediatric
appendectomies [1]. Despite their low incidence, NET represent the most frequent tumor involving
the gastrointestinal tract in children and adolescents [2-4].
Most appendiceal NET are incidental findings in a post-appendectomy specimen and therefore
have no characteristic tumor-specific symptoms. Clinical presentation of appendiceal NET is similar
to acute appendicitis, but it can be an incidental intra-operative finding during appendectomy or
other surgical procedures [5].
The metastatic potential depends on the size, depth, and site of the tumor [6].
We reviewed our institutional experienceconcerning treatment and outcomes and compared to
current NANETS guidelines.
Methods and Results
We performed a retrospective review of adolescent and young adult (age 15-23) patients
diagnosed with appendiceal NETbetween January 2010 to May 2016. Data which included
demographics, presenting symptoms, mode of imaging, pathologic review, disease workup,
treatment, post treatment surveillance were collected and analyzed, 14 patients were identified as
diagnosed with appendiceal NET (Table 1). Females were in the majority (9/14). The most common
presenting symptom was abdominal pain.
All patients underwent appendectomy, withpost-operative diagnosis from pathology
examination. Mean age at diagnosis was 17.2 years (age 15-23 years), 5 patients underwent right
hemicolectomy with indications being tumor size >2 cm, perineural invasion and lymph node
metastasis; PT 2 TS 4.5 cm, tumor invasion, LN involvement; PT8 TS 2 cm, Grade 1, No invasion
/LN involvement, PT 9 TS 1.8 cm, no invasion, positive LN, PT 11 TS 0.4 cm, Grade 1, Perineural
invasion, No LN involvement and PT 14 with tumor size of 3 cm.
PT 7 had TS >2 cm while patient 12 TS could not be determined, both did not undergo RHC;
and are alive and well at follow-up periods of 36 months and 14
months respectively.
Overall, tumor size ranged from microscopic foci to 4.5 cm, 2
patients had metastatic disease involving the regional lymph nodes
only and 1 patient had lymphovascular involvement (Table 1). The
patients with lymph node involvement had additional findings of
mesoappendix involvement (PT 2) and intermediate grade (PT 9),
3 patients had intermediate risk disease per NANETS consensus
guidelines for the diagnosis and management of NET, 1 patient
had a perforated appendix; patient did report flushing and diarrhea
occurring prior to presentation (15 year old female who presented
with 4 days of vomiting, diarrhea, occasional flushing with shivering
& intermittent fever and abdominal pain).
This patient was found to have regional lymph node involvement
and underwent right hemicolectomy.
Post-surgery surveillance included imaging utilized CT abdomen
more commonly, octreotide scan, Chromogranin A and 5 HIAA.
Follow-up duration ranged from 2 – 77 months (median = 12
months). Relapses did not occur.
Table 1
Table 2
Table 2 Surgical Approaches from NANETS consensus guidelines for the management of well differentiated NETs of the Appendix [7].
Discussion
The first case of an appendiceal NET was described by Berger in
1882, but it was not until 1907 that the term karzinoid was coined by
Sigfried Oberndorfer at the German Pathologic al society Summit in
Dresden ([7]).
Appendiceal NET represent tumors with a low metastatic
potentialand in the majority of patients, surgery is curative.Majority
in children arise in the appendix; however they can also occur in other
primary sites including the small intestine, bronchus and others [8,9].
These lesions are more likely to be found in females, as reported
in several publications [6,10].
Classic carcinoid syndrome which consists of some combination
of wheezing, flushing, diarrhea, hypotension and /or abdominal pain
is rare in young patients with NETas they rarely have metastasis to the
liver or other sites ([7]).
Incidence at our institutions concurs with the rare occurrence of
this tumor in pediatric patients.
Carcinoid syndrome occurrence was rare (1/14); abdominal pain
in contrast was 100% (14/14).
Majority of patient (10/14) had low grade tumors with tumor size
being less than 2 cm.
Pediatric management of NET is derived from an adult medicine
based guideline- The NANETS guidelines [11] which is elaborated
in Table 2: small (<1cm) well differentiated carcinoids confined to
the tip of the appendix that are excised are considered cured if there
is no evidence of lymphovascular invasion or invasion into the
mesoappendix, and do not require any follow-up; <2 cm tumors
(without regional involvement) also do not require any follow up.
Right hemicolectomy is being recommended for appendiceal NET
with evidence of tumor invasion at the base of the appendix, in
patients with tumors greater than 2 cm, in those with tumor where size
cannot be determined, incompletely resected tumors, intermediate to
high grade tumors, evidence of lymphovascular invasion, invasion of
the mesoappendix, and mixed histology, 5 patients underwent right
hemicolectomy; PT 2 TS 4.5 cm, tumor invasion, LN involvement;
Patient 8 TS 2 cm, Grade 1, No invasion/LN involvement, PT 9 TS 1.8
cm, intermediate grade, PT11 TS 0.4 cm, Grade 1, lymphovascular
invasion and PT 14 with tumor size of 3 cm.
Interestingly PT 7 had TS >2cm while PT 12 TS could not be
determined, both did not undergo RHC; and are alive and well, 6
patients did not meet criteria for RHC and appropriately did not
undergo surgery. Of the five that underwent RHC two patients had
positive regional lymph nodes.
Three patients who meet NANETs criteria for RHC did not
undergo further surgery (Patient 7, 10, 12); and remain alive/disease
free with a total combined follow-up duration of 41.5 months. Our
report is limited by number of patients and duration of follow up.
A multicenter review will be beneficial in better defining criteria
for a second surgery in AYA.
Disease workup after diagnosis and surveillance in our institution
consisted of computed tomography abdominal & lung scans,
Octreotide scans, Chromogranin levels and 5-HIAA levels.
Follow up schema has been difficult to standardize, generallywe
have recommended proposed NANETS guidelines of reassessment
between 3 and 6 months after complete resection; and every 6 to 12
months for at least 7 years.
Our report adds to existing literature to pediatric patients with
appendiceal NET and regional lymph node metastases [12-15].
In conclusion,a larger patient series is needed to better define
which patients with appendiceal NETs will benefit most from
undergoing a right hemicolectomy.
Acknowledgement
Dr Peter Anderson of the department of Pediatric Hematology and Oncology, Cleveland Clinic Children’s for reviewing manuscript.
References
- Doede T, Foss HD, Waldschmidt J. Carcinoid tumors of the appendix in children--epidemiology, clinical aspects and procedure. Eur J Pediatr Surg. 2000; 10(6): 372-377.
- Hatzipantelis E, Panagopoulou P, Sidi-Fragandrea V, Fragandrea I, Koliouskas DE. Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece. J Pediatr Gastroenterol Nutr. 2010; 51(5): 622-625.
- Corpron CA, Black CT, Herzog CE, Sellin RV, Lally KP, Andrassy RJ. A half century of experience with carcinoid tumors in children. Am J Surg. 1995; 170(6): 606-608.
- Parkes SE, Muir KR, al Sheyyab M, Cameron AH, Pincott JR, Raafat F, et al. Carcinoid tumors of the appendix in children 1957-1986: incidence , treatemnet and outcome. Br J Surg. 1993; 80: 502-504.
- Vani BR, Thejaswini MU, Kumar BD, Murthy VS, Geethamala K. Carcinoids of the appendix in children: a r eminder. Case Rep Clin Pract Rev. 2003; 4(2): 69-72.
- Neves GR, Chapchap P, Sredni ST, Viana CR, Mendes WL. Childhood carcinoid tumors: description of a case series in a Brazilian cancer center. Sao Paulo Med J. 2006; 124(1): 21-25.
- Dall'Igna P, Ferrari A, Luzzatto C, Bisogno G, Casanova M, Alaggio R, et al. Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions. J Pediatr Gastroenterol Nutr. 2005; 40(2): 216-219.
- Howell DL, O'Dorisio MS. Management of neuroendocrine tumors in children, adolescents, and young adults. J Pediatr Hematol Oncol. 2012; 34 Suppl 2: S64-S68.
- Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003; 97(4): 934-959.
- Spunt SL, Pratt CB, Rao BN, Pritchard M, Jenkins JJ, Hill DA, et al. Childhood carcinoid tumors: the St Jude Children's Research Hospital experience. J Pediatr Surg. 2000; 35(9): 1282-1286.
- Boudreaux JP, Klimstra DS, Hassan MM, Woltering EA, Jensen RT, Goldsmith SJ, 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.
- Kim SS, Kays DW, Larson SD, Islam S. Appendiceal carcinoids in children--management and outcomes. J Surg Res. 2014; 192(2): 250-253.
- Cernaianu G, Tannapfel A, Nounla J, Gonzalez-Vasquez R, Wiesel T, Tröbs RB. Appendiceal carcinoid tumor with lymph node metastasis in a child: case report and review of the literature. J Pediatr Surg. 2010. 45(11): e1-e5.
- Volpe A, Willert J, Ihnken K, Treynor E, Moss RL. Metastatic appendiceal carcinoid tumor in a child. Med Pediatr Oncol. 2000; 34(3): 218-220.
- Pelizzo G, La Riccia A, Bouvier R, Chappuis JP, Franchella A. Carcinoid tumors of the appendix in children. A report of 25 cases. Acta Chir Scand. 1977; 143(3): 173-175.