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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES
FACULTY OF MEDICINE
CARCINOID TUMORS IN CHILDREN: A SYSTEMATIC REVIEW
Clinic of Pediatrics
AUTOR: Ricardo Edgar García García, MF
SUPERVISOR: Eglė Ramanauskienė, MD, PhD
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TABLE OF CONTENTS
SUMMARY……… 3
CONFLICTS OF INTEREST………..4
CLEARANCE ISSUED BY THE ETHICS COMMITTEE………...4
ABBREVIATIONS & TERMS………...4
INTRODUCTION………5
AIM & OBJECTIVES………...6
LITERATURE REVIEW……….7-25 RESEARCH METHODOLOGY & METHODS………26
RESULTS………...27-36 DISCUSSION OF THE RESULTS ……….37- 40 CONCLUSION ………..41
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SUMMARY
Ricardo Edgar García García.
Carcinoid tumors in children: a systematic review
Aim: Systematic assessment of the selected criteria, according to strictly performed selection of
literature in order to minimize selection bias. The search process will be conducted in different languages, including English, Spanish, Portuguese, Lithuanian and French.
Objectives: To report incidence, clinical features, histology, localization, stages, treatment, survival &
long-term follow up recommendations of carcinoid tumors in children; as well as to evaluate new diagnostic and treatment methods.
Methods: A primary search was conducted online for the research topic on different databases such as PUBMED, Embase and Cochrane. A secondary search reviewing the bibliographies was performed to identify additional relevant studies. Finally, 36 studies were selected for the research. Included studies focused on the appendiceal (n=687) and bronchial (n=186) carcinoid tumors in children.
Results: Appendiceal carcinoids: This review included 18 studies with a total of 687 patients aged < 18 years, 39,24% males and 60,76% females. Incidence of appendiceal carcinoids per appendectomies was 0,296%. The chief complaint was abdominal pain. 70 % of the carcinoids were located in the tip of the appendix. The disease was localized in 63% of the cases and there were 13 cases of distant disease. Median tumor size was 6,93 mm and <2cm in 95,45% of the cases. The gold standard for diagnosis was a biopsy with histopathological investigation from an incidental finding on the appendix. Appendectomy alone was the choice of treatment in 88,94% of cases. Survival rate was 100%. Follow-up ranged from one month to 456 months.
Bronchial carcinoids: 18 studies with a total of 186 patients aged < 18 years were included on this
section. 67,92% were males. Incidence of bronchial carcinoids among primary lung tumors, both benign and malignant was 17,81%. The chief complaint was pneumonia unresponsive to treatment. Typical: atypical ratio was 7:1. It was a localized disease in 78% of the cases and there were 2 cases of distant disease. Median tumor size was 22,3 mm. The gold standard for diagnosis is bronchoscopy with biopsy and pathological examination. The choice of treatment was lobectomy in 63,5% of cases and regional lymphadenectomy was an additional treatment in 63,5 % of cases as well. Survival rate was 96,67%. Follow-up ranged from one month to 384 months.
Conclusions: The studies appraised for this systematic review were mainly of low-level evidence, yet
some results are significant and others identify areas of future research. Nevertheless, this study is the largest data collection for appendiceal and bronchial carcinoid in children up to the date.
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CONFLICT OF INTEREST
There was not any conflict of interest.SOURCES OF FUNDING
NoneETHICS COMMITTEE CLEARANCE
It was not required.ABBREVIATIONS LIST (by alphabetic order):
5-HIAA, 5-hydroxyindoleacetic acid; AC, appendiceal carcinoid; CA 19-9, carbohydrate antigen 19-9; CA 50, carbohydrate antigen 50; CBD, common bile duct; CEA, carcinoembryonic antigen; ChrA, Chromogranin A; CS, carcinoid syndrome; CT, computed tomography; FAP, familial adenomatous polyposis; GI, gastrointestinal; hCG, human chorionic gonadotropin; IBS, inflammatory bowel syndrome; ICR, ileocecal resection; LUL, left upper lobe; MEN, multiple endocrine neoplasia; MIBG, iodine-123-meta-iodobenzylguanidine; NA, not available; NEN, neuroendocrine neoplasia; NES, neuron specific enolase; NET, neuroendocrine tumors; OS, Octeotride scan; PT, primary tumor; RCTs, randomized control trials; RHC, right hemicolectomy; SA, simple appendectomy; SSR, somatostatin receptor; SSRS, Somatostatin receptor scintigraphy; US, ultrasound;.
TERMS
Localized: There is no spread of the malignancy beyond the boundaries of the organ. Appendiceal:
Tumor involves the appendix, up to its serous layer. According to ENETS (European Neuroendocrine Tumour society), this would be stage 0 or I. Bronchial: Tumor has not spread outside the lungs (does not involve pleura, diaphragm, mediastinum, chest wall muscles and so on). This would be stage I according to American Cancer Society (ACS).
Regional: Regional stage refers to tumor extension beyond the limits of the organ of origin. Although
the boundary between localized and regional tumor extension is usually well-identified, the boundary between regional and distant spread is not always clear. Appendiceal: Tumor extends to the vessels (blood and lymphatics), nerves and mesoappendix. According to ENETS, this would be stage II.
Bronchial: Tumor has spread to structures adjacent to the lungs, to the lymph nodes within the lung or
to the hilar lymph nodes on the same side of the primary tumor. This stands for stage II or IIIa according to ACS.
Distant: Distant stage is also called remote, diffuse, disseminated, metastatic, or secondary disease.
Cancer cells can travel from the primary site in any of four ways: extension from primary organ beyond adjacent tissue into next organ; travel in lymph channels beyond the first drainage area; hematogenous or blood-borne metastases; and spread through fluids in a body cavity. Appendiceal: Tumor has disseminated into regional lymph nodes or has metastatized. According to ENETS, this would be stage III or IV. Bronchial: Tumor has metastatized into different organs or into distant, carinal or mediastinal lymph nodes. This would be a stage IIIb or IV according to ACS.
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INTRODUCTION
Carcinoid tumors are highly studied in adults. However their study on children is poorer and there are no clear guidelines for diagnosis, staging, management or even follow up in this age group. Therefore, we believe it is important to clearly establish these components for pediatrics, since carcinoid tumors had shown to behave differently in pediatrics than in adults.
Through this study I want to collect the data on carcinoid tumors in children from the last ten years and draw some conclusions which will guide in new diagnostic methods and management of this rather rare condition. As well, epidemiological and pathological data will be evaluated and systematically analyzed.
The main advantages that my systematic review seeks over previous published studies are the reduction of bias, combination and organization of the published information mainly in order to remove replicated information, a meta-analysis of the recent data on carcinoid tumors in children when possible, the resolution of possible controversies between conflicting findings and the presentation of some reliable basis for decision making.
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AIM AND OBJECTIVES OF THE THESIS
The aim of this systematic review is the assessment of the latest evidence investigating carcinoid tumors in children by identifying, appraising and synthesizing all latest available data found on PubMed, Cochrane library, Medline/OvidSP & further databases regarding our topic in question.
Objectives:
1. To report the incidence of carcinoid tumors in children. 2. To report the clinical features of carcinoid tumors in children. 3. To report the histology of carcinoid tumors in children. 4. To report the localization of carcinoid tumors in children. 5. To report the stages of carcinoid tumors in children. 6. To report the treatment of carcinoid tumors in children. 7. To report the survival of carcinoid tumors in children.
8. To report the long-term follow up recommendations of carcinoid tumors in children. 9. To evaluate new diagnostics and treatment methods of carcinoid tumors in children.
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LITERATURE REVIEW
CARCINOID TUMORS IN CHILDREN
Carcinoid tumors are rare malignancies first described over 100 years ago. The term ―carcinoid‖ was replaced with ―well-differentiated endocrine neoplasm‖ by the World Health Organization in the year 2000; more appropriately descriptive of these typically slow-growing neuroendocrine tumors (NETs). Most of NETs occur sporadically and are nonhereditary, with the ability to secrete various vasoactive substances (these substances include serotonin & its metabolites, corticotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, catecholamines, gastrin and kallikrein). [7, 33, 53, 59]
Despite their sporadic occurrence, carcinoid tumors may be associated with hereditary syndromes like multiple endocrine neoplasia (MEN); the mutation of the MEN1 gene being the most common somatic mutation in sporadic tumors like carcinoids. For example, some of the foregut tumors may show a loss of heterozygosity at 11q13. Poorly differentiated NETS may show loss of heterozygosity for p53 or the adenomatous polyposis coli tumor suppressor gene.[54]
They are rare, low-grade, malignant NETs derived from the neoplastic proliferation of neuroendocrine cells throughout the body.[7] The term ―carcinoid‖ is considered an inadequate description of well-differentiated NETs, which consist of a heterogeneous group of cancers occurring in many different body sites with diverse clinical, histological, and genetic characteristics.[7] This tumors express multiple somatostatin receptors, somatostatin receptor type 2 (SSR2) being clearly predominant, which represent the molecular basis for the clinical use of somatostatin analogues in the treatment of endocrine tumors and their in vivo localization.[32]
The incidence of NET in children and adolescents is 2.8 cases per million individuals overall. [7, 47] The majority of carcinoid tumors are found in the gastrointestinal (GI) tract and the bronchial system. In pediatric patients, carcinoid tumors constitute the second most common neoplasm of the GI tract after lymphomas. [7, 8, 57] Approximately 85% of carcinoid tumors arise in the gastrointestinal tract and the appendix is the most common site. [15, 33]
This is in contrast to adult patients in whom carcinoid tumor is the most common malignant neoplasm of the GI tract (85%), with the small bowel being the most common location (45%) followed by the rectum (20%) and appendix (17%).[56]
In children, the majority of neuroendocrine tumors are benign or low-grade malignancies with a small percentage presenting as high-grade tumors. [58]
Because carcinoids are derived from neuroendocrine cell compartments, their frequency of occurrence correlates with the site density of neuroendocrine cells. These cells are left over from early embryonic development, and are widespread in the body, particularly in the digestive tract. [15]. That explains that nearly 60% of carcinoid tumors arise along the small intestine, which is the largest endocrine organ, followed by 25% within the bronchopulmonary system, which reflects the high density of Kulchitsky cells in the respiratory epithelium.[55] They are classified according to their embryologic origin:
-foregut carcinoids: most commonly originate in the respiratory tract, stomach, duodenum, biliary system, or pancreas; -midgut carcinoids: originate in the small intestine, appendix, cecum, and proximal colon; -hindgut carcinoids originate in the distal colon and rectum. [7] They have also been found primary carcinoids in other organs such as testis and ovaries, possibly due to migration of neuroendocrine cells to those areas during the embryologic development. [23, 13]
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Carcinoid tumors in children are usually small and have a favorable prognosis and a low probability of metastatic lesions. [33] According to one study published in 2013, the 5-year malignant carcinoid survival for pediatric patients was 94%, independently from the tumor location. [14]
Appendiceal carcinoids Background
Appendiceal carcinoids are rare in children, with an incidence of less than 0.2 cases per 100,000 individuals. [54] They represent the most common form of gastrointestinal NETs among children and young adults.[7,61] There is a slight female preponderance [3,4,6,7,11,15]. Median age at presentation is 12 years old [1, fig1]
A summary of existing series totaling more than 350,000 pediatric appendectomies noted an overall incidence between 2 and 5 per 1000 cases [11] This is consistent with the majority of papers reviewed that found the rate of carcinoid tumours in children to be approximately 0.3%–0.9% of those undergoing appendicectomies, in most cases for presumed appendicitis. [2, 16, 89]
Most of these tumors are found retrospectively after operation for suspected acute appendicitis, [62] are usually less than 1 cm in diameter, rarely metastasize, and overall, have a benign behavior in children. [7]
Development
AC is composed of neuroendocrine cells and is thought to arise from the subepithelial endocrine cells in the lamina propria and submucosa or from Kultschitsky cells at the base of Lieberkuhn‘s glands. [15, 63]
Localization
The tumor involves the midappendix and the base of the appendix, in approximately 15% and 10% of patients, respectively. The appendiceal tip is the most common site (accounts for nearly 75%). [7] On a large retrospective multicenter study with 114 patients, the tumor was at the tip of the appendix in 61 patients (53.5%), in the mid-portion in 25 patients (22%), and at the base in 12 patients (10.5%). [1,fig.2]
Presentation
The symptoms in patients with early disease are often vague, insidious at onset, [62] and indistinguishable from acute appendicitis in more than 50% of cases.[2,7]
Among children, patients commonly have acute appendicitis and had one or more of the following signs and/or symptoms, including abdominal pain, diarrhea, nausea, vomiting and fever. [15]
fig. 1
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Chronic right lower quadrant pain may occur because the tumor causes intermittent partial obstruction, even though only 25% of histopathologic specimens confirm an obstructing factor. [7]
Carcinoid syndrome has never been reported in children with appendiceal carcinoids. [1, 2, 3, 7, 33]
Diagnosis
Preoperative or even intraoperative diagnosis of appendicular NEN is challenging for surgeons unless they present with tumour specific symptoms or signs, such as carcinoid syndrome or they have a metastatic disease. [3] It is worth to mention that these last two conditions were never reported on appendiceal carcinoid in children, except for regional lymph node metastasis. Most cases are diagnosed postoperatively with a detailed histological examination. [3]
Intraoperatively the presumed diagnosis is appendicitis 75% of the time. [2]
For example, in a study with 28 pediatric patients in 2015, all cases of appendiceal carcinoid were detected incidentally at the time of either planned diagnostic laparoscopy or laparoscopic appendectomy, and approximately half had evidence of concurrent appendicitis on review of the specimen. [4]
Therefore, the goal standard for diagnosis is specimen biopsy with histological examination. [2, 3, 4, 7, 21]
A combination of hematologic and
biochemical markers, urinary
investigations, and imaging studies is used to initially evaluate the extent of disease and subsequent follow-up. [6,7, table 2a] The goals for initial evaluation include identification of the primary tumor, staging, and treatment planning. [7]
So, diagnostic workup includes analysis of urine 5-HIAA (5-hydroxyindoleacetic acid) and plasma levels of ChrA, US examination of the liver, and CT of the thorax and abdomen. [6, 7, 37]
For patients with PT greater than 1 cm, an OS has to be performed. [6] Some
authors extended the diagnostic workup by also requiring 5-HIAA and ChrA, β-HCG human chorionic gonadotropin, serotonin, and carcinoembryonic antigen. In case of a
negative OS, 136 iodine methylbenzguanidine scintigraphy, CT of the thorax, as well as abdominal US and MRI are required. In addition, they recommend testing for multiple endocrine neoplasia type 1 by molecular biologic analysis. [37]
CT scan has limited sensitivity on detecting small intestinal tumors, and they are usually identified only after metastasizing to other regions, as demonstrated by mesenteric disease, lymphadenopathy, and liver disease. [7] NETs are generally vascular tumors that enhance intensively with intravenous contrast during early arterial phases of imaging with washout during the delayed portal venous phase;
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therefore, a rapid bolus of intravenous contrast is recommended.[62] MRI can be used when patients are allergic to iodine contrast material or if they have renal insufficiency, and it is of even more interest in the pediatric population because it avoids radiation exposure. NETs can have variable appearances on non contrast MRI, and they can be hypointense or isointense on T1-weighted images. [62]
Chest X-ray and abdominal US are neither specific for carcinoid tumor nor very sensitive. [7]
Carcinoid tumors are NETs that variably express somatostatin receptors (types 2 and 5). These receptors can be radiolabeled by somatostatin analogues (111In-diethylenetriamine pentaacetic), with the ultimate goal of tumor localization. The sensitivity of SRS for localizing these NETs is up to 90%. [7] SSRS is used as a whole body scan. Its limitations include subcentimeter lesions, low somatostatin receptor density, and a 2- day imaging protocol. [7]
In addition, more recent tracers such as EDDA/HYNIC-octreotate can be used.
99mTc-EDDA/HYNIC-octreotate shows a high affinity for SSRs and rapid target localisation. This new tracer has a similar biodistribution to 111In-Octreoscan, but we found that it detected more metastases with a higher target/nontarget ratio. 99mTc-EDDA/HYNIC-octreotate SRS appears to be helpful in staging and in determining the SRS status of well-differentiated NETs (WHO groups 1 and 2), and it seems to be the method of choice in the detection of a primary focus that cannot be detected with other imaging methods. 99mTc-EDDA/HYNIC-octreotate, with high image quality, on-site availability and a 1-day imaging protocol, is an excellent alternative to 111In-labelled octreotide for imaging somatostatin receptor-positive tumours. [32]
Histology
When analyzing the histologic features of carcinoid tumors, they are frequently separated into ―typical‖ and ―atypical‖ groups. [47] Approximately 90% of carcinoid tumors are typical tumors. These are predominant in pediatric series and present favorable prognosis. Atypical carcinoid tumors are rare and much more difficult to diagnose histologically. They present worse prognosis than typical lesions, with a high metastatic potential, showing increased mitotic activity, pleomorphism with hyperchromatic nuclei, abnormal ratio of nucleus to cytoplasm, increased cellularity, disorganization and necrosis.[33] By definition, typical histologic features include neuroendocrine differentiation with a classic architecture of clusters of cells in trabecular, insular, or ribbon-like patterns. When the tumors appear more aggressive or poorly differentiated with increased mitotic activity and perhaps limited necrosis, they are considered atypical, and therefore may be more clinically aggressive. Some tumors exhibit more ―aggressive‖ features, such as invasion into the lymphatic or vascular spaces or into the fat surrounding the primary tumor. The histologic pattern of the tumor should be taken into account when making clinical decisions for patient care. [47]
The 2 major histologic patterns of typical ACs are the insular pattern (more common) and the tubular variant.[64] Insular-type carcinoids of the appendix resembles those of the terminal ileum, which is an enterochromaffin cell in origin and produces serotonin. Both lymph node and liver metastasis are extremely rare in most insular- type carcinoid tumors of the appendix. The tubular variant, otherwise known as tubular carcinoid tumor, is usually only a few millimeters in size and is confined to the appendiceal tip, sometimes next to an obliterated lumen, where it grows in short cords and glands or
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tubules. The tubules are uniform in size and cuboidal, and have centrally located nuclei that are cytologically bland. Its cell of origin is the L-cell, which produces enteroglucagons and peptide YY. [62]
By staining tumor cells for Ki-67, a high-molecular-weight nuclear protein antigen structurally associated with chromatin which is an excellent marker to measure the growth fraction, as it is strictly associated with cell proliferation and not with DNA repair, [64] the clinician can get some objective evidence as to the inherent aggressiveness of the tumor, and all carcinoid tumors should be stained for this marker. Well-differentiated tumors tend to have minimal areas of atypical cytology, low mitotic counts and <2% Ki-67–positive cells. Alternatively, poorly differentiated carcinoid tumors have more malignant potential with more necrosis, higher mitotic counts and atypia present, with closer to 15% of cells showing Ki-67 positivity. Other tumor biology markers such as CD-44 and nm-23 have also shown some association with more aggressive and more malignant carcinoid tumors. In general, these well-differentiated NETs have positive immunohistochemical staining for chromogranin A, synaptophysin, and neuron-specific enolase. However, the embryonic origin of the tumor may affect some of its staining features. For example, midgut carcinoids are likely to be argentaffin positive, whereas foregut and hindgut tumors will stain argentaffin negative. [47]
Management
The latest data reported, dated in 2015, conclude that NET of the appendix do not behave aggressively in children, and appendectomy is a sufficient treatment even in the presence of size more than 2 cm or local invasion. [1]
Nevertheless, other modalities and guidelines are worth to mention, such as ileocecal resection or RHC.
Despite being the second most common GI tract neoplasm in children there are surprisingly few well defined guidelines for the management of appendix NET in the paediatric population. It is apparent therefore that the management of appendix NET lesions in children is highly uncertain. Information from the European Neuroendocrine Tumour Society (ENETS) is available. These state that in the presence of any of the following features, RHC or ileocecal resection should be performed—notably (a) tumour size greater than 20 mm, (b) invasion of the mesoappendix greater than 3 mm or transmural infiltration, or (c) R1 ‗incomplete‘ resection.[6,9,43]
Nevertheless, small appendiceal tumors make up 18% of disease found in pediatric and adolescent patients, and these tumors are typically discovered when the appendix is being removed for some other reason. In cases where the tumor is small (<1.5 cm in size), without atypical or invasive histologic features, and without positive surgical margins, primary appendectomy is a sufficient therapy. However, if the tumor shows more aggressive features (atypical histology, size >2 cm) or has positive surgical margins, a second surgery should be performed. In pediatric patients, many surgeons will perform an ileocecal resection, whereas in adult patients most surgeons perform hemicolectomies. In both groups, it is not uncommon to recommend regional lymph node sampling. It is well established
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that patients with tumors > 2 cm in size are more likely to have regional or even metastatic spread of disease. [47]
Summarizing, in adults and children, patients with tumors <1.0 cm may be treated with appendectomy alone. The treatment of those with a 1.0 - 2.0 cm tumor is less clear in both the pediatric and adult populations, and additional resection is based on patient-specific risk factors.
General indications for more extensive resection are based on the risk of more invasive disease and include size >2.0 cm, involvement of the base, incomplete initial resection, lymphovascular or mesoappendiceal invasion, and the pathology findings of indeterminate or high grade, goblet cell or adenocarcinoid histology . However, these indications for additional resection in children have been questioned in the pediatric literature due to the rarity of metastatic disease. [4]
Despite the requirement for RHC if an involved lymph node close to the appendix is encountered, we did not find any evidence in the literature of a benefit of RHC over SA in the pediatric population with enterochromaffin cell AC. [37]
Staging & metastasis
Appendiceal carcinoids may metastasize to the regional lymph nodes rather than the liver. Nodal metastasis occurs in 5% of patients with appendiceal primary NETs. [55] Findings support a relation between both tumor size or mesoappendiceal infiltration and the presence of nodal metastasis. [7] Metastases are extremely unusual in typical ACs, particularly those with low-to-no mitotic activity (<1 mitosis per 50 high-power fields [hpf]). [64] Despite this finding, there are reports of lymph node metastasis in children. [37]
Interestingly, in 2014 a total of 699 paediatric patients with NET tumours of the appendix had been reported since 1975, with age at diagnosis ranging from 4 to 20 years. Only 4% of tumours were larger than 2 cm in maximal diameter, however in 30.5% invasion of the mesoappendix was documented [9]
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For patients with classic, localized, childhood ACs, no recurrences or tumor- related deaths have been observed. [37,49]
Follow-up
Long-term follow-up with stressful and expensive investigations is unnecessary. [1]
However, the North American Neuroendocrine Tumor Society, National Comprehensive Cancer Network, and European Neuroendocrine Tumor Society agree that patients with ACs smaller than1cm are at low risk and do not require follow-up. The treatment of patients with ACs 1-2cm in size remains controversial, without any clear recommendations. For patients with lesions larger than 2cm, there is consensus that follow-up is required every 3-6 months postoperatively and then every 6-12 months for 7 years (history and physical examination, CgA, 5-HIAA, and possibly CT or
MRI or even octreotide scintigraphy, depending on the clinical situation). [7, 43, 47, 62]
Bronchial carcinoids Background
Carcinoid tumors have been reported to account for 80% to 85% of primary malignant
lung tumors in childhood [19, 35]. carcinoid incidence is highest among common pulmonary tumors comprising of 50–90% of all tumors among pediatric and adolescent patients [20]. Incidence of carcinoid tumors is constant at 0.44/100,000 in the Netherlands for example [20].
However, there may be ethnicity differences because incidence of Asian pediatric and adolescent population with tracheobronchial tumors in a retrospective review of medical records from a single center in China reported that mucoepidermoid carcinoma presented with the highest incidence, accounting for 73.68% (14/19) of all tumors, while there were only two carcinoid cases, which presented a difference in occurrence when compared with the data reported previously in western studies. [20]
Some authors reported that carcinoid tumors accounted for 11% to 13% of all pediatric pulmonary tumors. A retrospective review from a single institution with 90years experience (1918-2008) presents 8 cases of bronchial carcinoid (20% of total tumors). [22]. Regarding primary tumors of epithelial, 63% have been accounted for carcinoid tumor. [5]
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Bronchial carcinoid tumor is the most common pulmonary tumor in childhood. Up to 75% of pediatric lung tumors are malignant; 50% of these are bronchial adenomas: carcinoid, mucoepidermoid carcinoma and adenoid cystic carcinoma. Carcinoid tumor accounts for 90% of total bronchial adenomas. [25]
Historically, bronchial adenomas encompassed carcinoid, mucoepidermoid, and adenoid cystic tumors. Currently this traditionally used term has been reclassified by the WHO, and these tumors are categorized now as either carcinoid or salivary gland tumors. [22]
It occurs with a nearly equal ratio of affected males and females (1.6:1) [7]
The mean age of diagnosis is from 10 to 13 years old. [51]
Development
Bronchial carcinoids are well-differentiated neuroendocrine malignant tumors derived from pulmonary neuroendocrine cells. Carcinoid tumors are neuroendocrine tumors of endodermal origin arising from Kulschitzky cells, normally found in the basal layer of bronchial epithelium. [44] These specialized cells belong to the APUD (Amine Precursor Uptake and Decarboxylation) system and are characterized by its capacity to synthetize neuroendocrine peptides (serotonin, histamine, prostaglandins, kallikrein, dopamine…) [51]
Bronchial carcinoids are found in approximately 5% of patients with MEN I, but a retrospective analysis demonstrated that the prevalence could be as high as 30%. [66]
Localization
Approximately 75% of bronchial carcinoid tumors originate from lobar bronchi, and 15% from the periphery of the lungs. [19]
Bronchial carcinoid tumors in the pediatric population usually arise in the main lobar or segmental bronchi, especially near the bronchial bifurcations. [44]
Local invasion or distant metastasis has been reported in a significant percentage of children (27%) [29] The reported rate of metastases in children with bronchial carcinoid
tumour ranges from 9% to 40% [42]
When it comes to distant metastasis, they can occur to the liver, skeleton, central nervous system, skin, and mammary glands in 3% and 21% of typical and atypical carcinoid tumors, respectively [7]
Presentation
Children usually present with recurrent pneumonia unresponsive to antibiotic treatment, wheezing unresponsive to asthma treatment and atelectasis. Fever, weight loss & chest pain also may occur. [33,42] While in adults the most common symptoms are cough and hemoptysis; these may as well happen in children. [25,68]
Bronchial obstruction is the cause of most of the signs and symptoms present, including cough, hemoptysis, obstructive pneumonitis, pleuritic pain, atelectasis and dyspnea. [33,47] The association between bronchial carcinoid tumors and carcinoid syndromes is rare. [33]
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Clinical manifestations are secondary to their intraluminal growth, release of vasoactive substances, and potential to metastasize. [44]
Carcinoid syndrome is rarely seen with bronchial carcinoid, especially in children. [44]
Diagnosis
Bronchial carcinoid tumors are likely to be discovered on computed tomography (CT) or magnetic resonance imaging (MRI) imaging. [47] Radiologic imaging features primarily depend on tumor location and cannot distinguish between typical and atypical BPCs. [7]
Chest X-ray and CT are useful methods. The commonest findings on chest x-ray and CT are atelectasis, consolidation, bronchiectasis, infiltration, visible tumour mass and pleural effusion. [42] CT can also demonstrate
the presence of any mass; the size, characteristics, and extent of the primary tumor; lymphadenopathy; or presence of distant metastasis.[7]
Whereas MRI can be used to resolve ambiguous findings on CT scans,but it is not a routine diagnostic modality for lung imaging. MRI may prove helpful in distinguishing smaller carcinoid tumors from adjacent normal vascular structures. [7]
In patients that pneumonia or other symptoms who do not improve in spite of antibiotics, diagnosis must be confirmed with computerized tomography and or fiberoptic bronchoscopy. [19]
Endoscopy plays a central role in the diagnosis and initial management of carcinoids [26]. For the confirmation of the diagnosis, anatomicopathological study of the lesion is required. [52]
Delay in diagnosis is common, having cases of delay up to 48 months. [42]
Spirometry can be useful for assessing lung functionality, often showing an obstructive pattern in cases of bronchial carcinoid in children. [44]
A unique trait of carcinoid tumors is their expression of somatostatin receptors. Radiolabeled somatostatin analogues such as 111In-octreotide are used in somatostatin receptor scintigraphy to localize these tumors in more than 80% of cases. Somatostatin receptor scintigraphy has been useful in the diagnosis, follow-up, and staging of pediatric patients. [7]
Immunostaining: CgA stains in approximately 100% of typical carcinoids, compare with 77% or more of atypical carcinoids; neuron-specific enolase is present in 92% or more of typical carcinoids as compared with 83% or more of atypical carcinoids. [7]
Histology
Bronchial carcinoids are classified into two distinct forms, typical and atypical, with different histological features, clinical courses and prognoses. [26]
Their histologic nature, characterized by cellular organization in nests or bands, and the rich fibrovascular stroma allow recognition of their neuroendocrine phenotype through routine microscopic
fig. 3 A carcinoid tumor of the right upper lobe
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techniques. In addition to morphology, the possibility of demonstrating the cells‘ neurosecretory capacity contributes to a strengthening of neuroendocrine differentiation in these tumours. [30]
Histopathology (typical vs atypical) in carcinoid tumors are important as regards to metastasis [19] TC is a variant of neuroendocrine tumour with a low grade
histological malignancy profile (rare mitosis and pleomorphism, absence of necrosis), and it rarely metastasizes. Typical carcinoids have an excellent long-term prognosis with 5-year survival rates ranging from 87 % to 97 %. Patients with atypical carcinoid have a greater risk of developing metastases and show a 5-year survival rate ranging from 56 % to 77 % [26]
Based on histological evaluation—namely, the presence/absence of necrosis and normal/raised mitotic index—carcinoid tumors are
classified in to typical (10%) or atypical (90%) subgroups. An elevated mitotic index (>2 mitoses/10 HPF) associated with necrosis is consistent with an atypical carcinoid tumor and with a worse prognosis as compared to typical tumors. [44]
Microscopic features include sheets, nests, and cords of monotonous small cells with stippled nuclear chromatin and a delicate vascular network in the background [29, fig.3]
Immunohistochemically, these tumor cells usually express the following neuroendocrine markers (synaptophysin, chromogranin A, CD 56). [51]
Staging
The American Joint Committee on Cancer (AJCC) and the IASLC have recently published a TNM staging system for NETs of the lung, which is displayed in Table 4. However, because data are yet to be collected to validate the parameters used for separating different stages, it is recommended that the extent of involvement of the primary organ and adjacent tissues and structures be specifically indicated in the pathology reports. This will allow easy conversion to any newer, data-based staging systems that may emerge. Reports should provide a TNM stage based on a system that is specifically referenced. [24]
Management
The method of resection of bronchial tumors varies based on the tumor location and surgeon performing the procedure [47]
fig. 4
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The correct approach of bronchial carcinoids is surgical removal with clear margins and systematic lymph node dissection. The need for excision is justified by the risk of lymph node metastases, which have an incidence ranging from 6 % to 25 % [26, 65] Radiotherapy and/or chemotherapy are recommended as adjuvant therapies in some cases. [51]
Lung parenchyma must be preserved as much as possible while performing the resection of the tumor. [19] Where technically possible, parenchyma-saving resections should be performed and pneumonectomy and lobectomy avoided, as these guarantee similar oncologic results with a better quality of life and avoid skeletal problems [26]
In parenchyma-saving procedures such as sleeve resection is imperative that a frozen section of both bronchial margins be unequivocally free of tumor. The criteria for this procedure include a benign or low-grade malignant bronchial lesion without extrabronchial spread, small basis of implant of the lesion with normal bronchial tree at its periphery, and absence of hilar or mediastinal nodal metastasis. [7]
With the reasons that rich vascularization of carcinoid tumors and the phenomena of iceberg‖(extraluminal spread), endoscopic resection can be risky as well as failing to ensure the removal of the mass with safe surgical margins. [19, 65]
A bronchial wall infiltration is usually associated (the so-called iceberg phenomenon) and laser resection often turns out to be incomplete or in an insufficient specimen for a correct pathological evaluation for differentiation of a typical carcinoid from the atypical variant. Moreover, lymph nodes cannot be evaluated for disease extension. This generally leads to further surgical treatments and general anesthesia, with obvious discomfort and related risks for the patient. [44]
Other than symptomatic control of carcinoid syndrome, no adjuvant therapies are recommended for pediatric pulmonary carcinoid tumors. [22]
It is especially important in the pediatric population to spare lung parenchyma and to grant as much respiratory function as possible. [51]
Laser ablation and cryotherapy are being studied as new therapy methods. The criteria for laser ablation with curative intent include typical type of tumor histology, polypoid growth of the tumor, absence of obvious distal metastases, lesions proximal to subsegmental level, and absence of lymph node enlargement (carcinoid tumor <1 cm at its short axis).
Meanwhile, cryotherapy is a cytotoxic method used to treat infiltrating tumors, including in situ cancers. [7]
Survival
The overall survival in children is approximately 90% [29].
Theoretically, five-year survival rates for local, regional, and disseminated disease are 81%, 77%, and 26%, respectively. No mortality was seen in our series. However, the one patient with disseminated disease at presentation has been lost to follow-up. [22]
18
Nevertheless, many studies, some of them conducted on adults, suggest that the prognosis of patients with bronchial carcinoids depends mainly on histologic phenotype. The 10-year survival rates differ dramatically for patients with typical (85%) and atypical bronchopulmonary carcinoids (50%). [7]
Follow-up
Long-term follow up is needed. [42] Mainly because both typical and atypical carcinoid tumors are capable of metastasizing. Positivity for tumoral cells in the sampled lymph nodes (accurate sampling of regional lymph nodes is mandatory to define the exact spreading of the disease) and the tumor size larger than 2 cm are generally considered as negative risk factors which indicate the necessity of a strict follow-up [44]
An annual follow-up of patients is recommended because these NETs grow slowly. Clinical examination and chest radiography are recommended every 3 months for a year and every 6 months thereafter. Additional investigations include abdominal ultrasound to rule out hepatic metastases, chest CT scan, and urine and serum 5-HIAA analysis every 6 months. [7]
Carcinoid tumors in other locations:
It is really uncommon to find carcinoid tumors other than appendiceal or bronchial in the population in pediatrics, and the reported literature about these tumor locations is extremely limited to a few individual case reports.
Basically these other locations share many of their characteristics with the carcinoid tumors in the appendix and bronchi, which I explained deeply above. The next paragraphs mention other locations found in children and some differences and specificities over the appendiceal and bronchial carcinoid tumors.
Specific diagnostic tests for neuroendocrine neoplasias include neuroendocrine tumor markers chromogranin A (ChrA), urinary 5-hydroxyindoleacetic acid (HIAA), neuron specific enolase (NSE) and somatostatin receptor based imaging (SRI). A positive NSE result was associated with a distant tumor stage, while no such association was observed for ChrA or HIAA (chi-square test, p < 0.01). [13]
The prognosis depends on the histological grade of the tumor and tumor extension. In localized tumors complete surgical resection is essential for prognosis. Management of patients with regional and distant disease remains challenging, because treatment options are limited and a standardization of treatment approaches have not been achieved. To keep benefits for pediatric patients especially with metastatic tumors, classification and treatment in children should be constantly adjusted to recommendations for adults. [13]
Pancreatic carcinoids Background
According to the Surveillance, Epidemiology, and End Result (SEER) database in children NEN of the pancreas account for about one third of malignant pancreatic tumors arising from the islet cells. [13]
19
And pancreatic tumors are quite rare in childhood, resulting less than 0.2% of malignant deaths; they have different histological features and a better prognosis compared to those in adults [28]
Multiple endocrine neoplasia type 1 should always be sought in pancreatic carcinoid tumors, especially in infancy. [28]
Metastasis are common, seen in up to 50% of the cases. [46]
Localization
Pancreatic NEN were mainly located in the head of the pancreas (54 %). The mean tumor size was 5.7 cm (0.4–10.4 cm). [46]
Presentation
Obstructive jaundice is quite common, while fever, associated with loss of appetite and weight can also occur. [46]
Ill-defined mass at the right hypochondrium might be present. [46]
Majority of the patients with pancreatic NEN have no hormone secretion [28], however a significant case in a child has been reported with malignant hypertension. [46]
Diagnosis
Radiologically a low attenuation mass with calcification is a characteristic finding. CT examination can reveal a mass with a cystic component. [28] Abdominal ultrasound can be used as well.
Biopsy and histological investigation is confirmatory. Immunohistochemically Chromogranin A is a very specific marker. [28]
Exploratory laparotomy is recommended by some authors. [46]
Management
Without evidence of distant metastasis, surgical excision performed by an expert is the preferred method of treatment, as pancreatic neoplasms in children have a relatively good prognosis. [28]
Surgery is the first-line treatment, and chemotherapy is used for non-resectable tumors or relapses. The chemotherapy consists of 4 cycles (M1, M2, M1, M2) with M1 including vincristin, etoposide, cisplatin and M2 including vindesine, dacarbazine, ifosfamide and doxorubicin. In addition, radiotherapy, 131I-MIBG therapy, 111In-octreotide therapy, the administration of somatostatin-analogues or interferon alpha have been suggested for second-line treatment and for treatment of symptoms related to hormone secretion. [13]
Pancreatic endocrine tumours, which are highly proliferative, are relatively chemosensitive.[46]
For pancreatic tumors the ENETS guidelines consider chemotherapy (streptozotocin/fl uorouracil for pancreatic NET) as first-line treatment, while the use of somatostatin analogs, interferon alpha, sunitinib and everolimus is discussed as second- or third-line treatment. [13]
Biotherapy, which includes somatostatin analogues and α-interferon, is also widely used. These medications facilitate both symptomatic control and stabilisation of tumour progression.The former has been shown to reduce the secretion of peptide hormones and possibly increase apoptosis. [46]
20 Survival
Relatively good prognosis [28]
Only a few reports have noted their malignant potential with metastasis to regional lymph nodes, the liver, lung and bone; however foregut carcinoids (like the pancreatic one) exhibit a more aggressive behavior, at least in adults. [28]
Follow-up
Regular postoperative follow-up with SPECT/CT and 5-HIIA is necessary. [28]
As with treatment of other tumours, the identification of biochemical markers is useful in monitoring therapeutic effect. General markers of endocrine pancreatic tumours include plasma chromogranin A, CA 19-9, CA 50, hCG, and CEA. Recently, the proliferation index, Ki67, has been used to help individualise treatment for those with a more malignant profile. [46]
Nasopharyngeal carcinoids Background
All reported cases in literature showed metastatic disease. [13]
The mean age of presentation was 2.3 years old. [13]
Presentation
Unspecific symptoms, such as fatigue, weight loss or enlarged cervical lymph nodes. [13]
Diagnosis
Biopsy with histological examination. [13]
Management
Surgical excision and chemotherapy. However these tumors has been shown to yield a bad response to chemotherapy and there are limited options for surgical resection. [13]
Survival
Bad prognosis [13]
Common bile duct carcinoids Background
Carcinoid tumors of CBD are exceedingly rare and account for 0.1% to 0.2% of all carcinoids of the gastrointestinal tract, and approximately 98% of all malignant neoplasms arising in the CBD are carcinomas, predominantly well to moderately differentiated adenocarcinomas. [38]
21
Due to the aforementioned rarity of these kind of tumors, I have only found one case report in the literature.
Development
These tumors are thought to arise from embryonal neural crest cells, or so-called argentaffin (Kulchitsky) cells, which migrate to sites within the respiratory and gastrointestinal tracts during neonatal development. [38]
Presentation
Painless jaundice is the most common clinical presentation of carcinoid tumor of the bile duct. [38]
Diagnosis
Both adenocarcinomas and carcinoids may have similar presenting clinical features, including painless jaundice with or without pruritus. When a primary bile duct neoplasm is suspected, differentiation between an unusual bile duct tumor, such as a carcinoid or a cholangiocarcinoma, is all but impossible before definitive surgery and histologic review. [38]
Histology
Histologic features of CBD carcinoids are similar to those of intestinal carcinoids. They tend to grow in cords, nests, or trabeculae, perineural, and lymphovascular invasion and usually invade the ductal wall. Most carcinoid tumors of the CBD are immunoreactive only for chromogranin. In addition, diffuse and strong positivity for chromogranin and synaptophysin in all of the tumor cells favors a diagnosis of carcinoid. [38]
Management
Surgical resection remains the primary treatment for biliary carcinoids and is the only therapy that offers a chance of cure. [38]
Survival
Localized disease is a sign of a good prognosis. [38]
All reported patients who have undergone a curative resection of their biliary carcinoids are still alive and free of disease at the time of last follow-up. [38]
Follow-up
All patients who presented with localized disease remained disease-free at follow-up [38]
22 Background
Metastatic disease is quite common, occurring in up to 30% of cases.
Localization
Usually the tumor is localized to the stomach, although the risk of metastasis is high. [13]
Presentation
Abdominal pain, hematemesis or hematochezia. A history of peptic ulcers has also been reported. [13]
Diagnosis
Endoscopic biopsy with histological examination confirms the diagnosis.
Histology Management
Surgical excision when possible.
In cases of metastatic disease, chemotherapy must be given. However there are no clear guidelines for pediatric patients for gastric carcinoids. Therefore, future guidelines for pediatric patients should consider the need to distinguish therapeutic approaches to different sites of NEN and incorporate the advances from trials in adults. [13]
Survival
Prognosis depends on the tumor differentiation grade and presence of metastasis. [13]
Testicular carcinoids Background
Carcinoid tumor occur in the testes either as: (1) primary pure testicular carcinoid; (2) primary carcinoid tumor associated with teratoma; (3) primary with epidermoid or dermoid cysts; and (4) metastatic carcinoid tumor to the testis Cope, in 1930, was the first to describe a testicular metastasis from an ileal carcinoid tumour, and the first primary testicular carcinoid was described by Simon et al. in 1954. Although > than 60 cases have been reported to date, testicular carcinoid remains a very rare diagnosis. Unlike testicular seminoma and non seminoma, carcinoid of the testicle does not seem to occur in a specific age group, regardless of it being a primary carcinoid, a metastasis, or a carcinoid-containing testicular teratoma [67]
Localization
Equally distributed over the left and right side. [67]
In a review of carcinoid tumors of the testis, they conclude that when a testicular carcinoid tumour is discovered, a metastasis or an intestinal primary tumour should be excluded, especially when the
23
testicular tumour is large. Urinary 5-HIAA measurement and SRS are useful diagnostic tools to seek other tumour locations. Other methods, e.g. CT and videocapsule endoscopy, can be used to search for primary intestinal tumours. [67]
Presentation
Painless mass or swelling. [23]
Diagnosis
Biopsy of the tumor usually confirms the diagnosis, [23,67] however, immunohistochemical studies including neuroendocrine markers will lead to the correct diagnosis when morphologic features are not classic, although, it is important to be aware that some Sertoli cell tumors may be positive for neuroendocrine markers. When carcinoid tumor is found within the testis, it also needs to be differentiated from metastatic carcinoid tumor to the testis. [67]
Histology
Organoid and trabecular pattern with tumor cells arranged in solid nest or cords.[67] Cytologically, the tumors had the usual morphology of carcinoid tumors composed of uniform polygonal cells with fine, granular chromatin, small nucleoli, and scant to moderate amount of granular cytoplasm. Histologically, the yellowish carcinoid tumour can be hard to distinguish from a Leydig-cell tumour. [67]
Management
Surgical: radical orchiectomy or focal excision. [23,67]
Surgery is the treatment of choice for carcinoid tumours in general. Because it is almost impossible to differentiate a carcinoid from a germ cell tumour before surgery, it would be an omission to choose another form of initial therapy. Other complementary treatments used for primary testicular carcinoid were adjuvant chemotherapy and radiotherapy. Unfortunately the response to these adjuvant therapies has not been described. However, chemotherapy and radiotherapy are known to have little effect on carcinoid tumours. [67]
Survival
Overall the prognosis of testicular carcinoid tumors in children is excellent.[23] However in adults metastasis are seen much more commonly leading to a worse overall prognosis [67], nevertheless the prognosis of patients with localized testicular carcinoid seems to be excellent in adults as well as in children [67]
Typical carcinoid tumor has better survival rates than atypical, because of the higher rate of metastatic disease in the latter. [23]
24
Of the 20 patients with primary testicular typical carcinoid tumors found premortem, all were alive at the last follow-up without recurrences or metastases. Of the 4 patients with a primary atypical carcinoid tumor, 1 with a dermoid cyst and scar at the time of diagnosis had retroperitoneal and lung metastases who after chemotherapy underwent resection of the retroperitoneal tumor showing metastatic yolk sac tumor and embryonal carcinoma. [23]
A close follow-up is essential, as there are isolated cases of testicular carcinoid tumors with a prolonged apparent interval free of disease that precede an aggressive metastatic course. [23]
5-HIIA and chest X-ray are valuable tools during the follow up. [67]
Intestinal (not appendiceal) carcinoids Background
Only 7% of small bowel carcinoids are seen at the jejunum. Jejunal carcinoid tumors are rare in children (mean age 45 y). [38]
Development
Small intestinal tumor cells are derived from intraepithelial endocrine cells and proliferation of Kultscitzky cells are responsible for carcinoid tumor in the appendix. [38]
Localization
At the small intestine, transverse colon, right ascending colon or rectum, being the last two the most common. [27]
Presentation
The authors report a rare case of carcinoid syndrome (CS) in a 12-year-old child that was caused by a carcinoid tumor located in the ileum that had metastasized mainly to the liver. [40]
Diagnosis
Urinary 5-HIAA and serum serotonin levels are elevated in 85% of the patients. [39] Serum chromogranin-A is useful in nonsecreting tumors with low levels of serotonin.
CT scans are helpful in the diagnosis of locally advanced disease with mesenteric involvement, and liver metastasis.[39]
Management
Surgical resection [27]
Survival
Overall 10 year survival was 94% [27]
The tumor location with the best survival as in the right colon as opposed to tumors located in the left colon (5-y disease-free survival, 81.4% versus 41.7%, P < 0.001, respectively) [27]
25
Tumors of small bowel have a poorer prognosis with a 5-year survival rate of around 60% to 65%. [39]
Carcinoid syndrome
Carcinoid syndrome is rarely found in pediatric patients, although these phenomena have been described in cases of carcinoid tumors of the appendix in other reports.[7] The symptoms of carcinoid syndrome are caused by vasoactive substances such as 5-hydrotryptophan (5-HIAA), histamine, bradykinin and serotonin that are produced by tumor cells. Because these substances are metabolized during their first passage through the liver, gastrointestinal carcinoids do not cause carcinoid syndrome unless they are metastatic to the liver, with release of biogenic amines into the systemic circulation and ovary, with the release of biogenic amines into the systemic circulation from direct retroperitoneal involvement with venous drainage bypassing the liver. [7, 33, 39, 60] Interestingly if carcinoid syndrome occurs, in 90% of cases the primary tumor is in the small intestine and the symptoms appear only when the hormones produced by the tumor (serotonin, histamine, kinins) are no longer metabolized by the largely metastatic liver and enter the systemic circulation. [40]
Symptoms: The main symptoms of carcinoid syndrome are diarrhea, vasomotor manifestations (such as flushing and episodic hypotension), abdominal pain, bronchospasm, and right heart failure due to tricuspid and/or pulmonary valve damage. [33,40]
Management: octreotide analogues [33,67]
Carcinoid crisis: Although not reported in children, carcinoid crisis can be precipitated by anesthetic induction, intraoperative handling of tumor, and other invasive procedures, and is characterized by profound flushing, bronchospasm, tachycardia, and widely and rapidly fluctuating blood pressure. Neuroendocrine mediator release, which leads to high levels of serotonin and other vasoactive peptides, may be responsible for this crisis. [7]
26
RESEARCH METHODOLOGY AND METHODS
The systematic review involved a comprehensive onlinesearch of the PUBMED, Embase, SCIELO, Google scholar, Medline/OvidSP and Cochrane library from 2006 to January 2017, using the search terms ‗carcinoids‘, ‗children‘ and ‗pediatrics‘. The search was conducted in several languages, including English, Spanish, Portuguese, Lithuanian and French; which aims to reduce publication bias.
All titles were independently reviewed for inclusion. If the criteria were met, the full text was ordered for further review. Using this strategy, 108 articles were obtained for further review. After whole article review, only 30 articles met the inclusion criteria.
This primary search was supplemented by a manual review which consisted in a review of the reference lists of the articles meeting the inclusion criteria already obtained in order to identify further relevant citations which could be
included in the research. Here, 81 studies were evaluated and 6 were included in the study. Mostly, the excluded studies were duplicates or presenting with clear exclusion criteria, especially a publication date older than 10 years.
As a result, a total of 36 articles were selected for the final results.
I have not used a computer-based referenced management system during my search.
INCLUSION CRITERIA
Articles meeting the following criteria were eligible for this systematic review: English, Spanish, Portuguese, Lithuanian and French language; published in the last 10 years; focused on appendiceal and/or bronchial carcinoid tumors; had either quantitative or qualitative data; only in children and adolescents <18 years old.
EXCLUSION CRITERIA
I excluded those articles that were not specific for carcinoid tumors; articles whose patients are over 20 years old; published prior to 2006 and those with anecdotal, invalid or uncollectable data, as well as those whose data was not classified precisely. My search was restricted to studies on humans.
742 potentially relevant articles identified in literature search using
the search terms
634 articles excluded after title review,
duplicates and publication date criteria
78 articles excluded after article review. 108 full-text articles
obtained for further review
30 relevant articles, during my primary
search
Fig 5. Primary search process used to select research studies
27
RESULTS
As stated in the literature review, there are many sites where carcinoid tumors can develop in children. However, for a further discussion I have selected appendiceal and bronchial carcinoid tumors for two reasons: (1) They are the most common locations of carcinoid tumors in children, and (2) the other locations have an outstanding lack of evidence, in any type of medical literature.
The studies selected for my systematic review were heterogeneous, therefore a meta-analysis of the results could hardly ever be performed and subgroup analyses together with a narrative synthesis were the methods of choice to show the results.
Appendiceal carcinoids
Incidence:
Study Year Type Cases
Lambert et al. [1] 2015 Retrospective multicenter study 114
Vandevelde & Gera [2] 2015 Retrospective single center study 22
Fallon et al. [4] 2015 Retrospective single center study 28
Anastasiadis et al. [6] 2014 Retrospective single center study 4
S. Fernández at al. [8] 2015 Retrospective single center study 28
Henderson et al. [9] 2014 Retrospective multicenter study 27
Alemayehu et al. [10] 2014 Retrospective single center study 9
Kim et al. [11] 2014 Retrospective single center study 13
Ketan et al [15] 2013 Retrospective single center study 7
Hatzipantelis et al. [21] 2010 Retrospective single center study 19
Encinas et al. [31] 2006 Retrospective single center study 8
Neves et al. [33] 2006 Retrospective single center study 8
Christianakis et al. [36] 2010 A case report 1
Cernaianu et al. [37] 2010 A case report 1
Mathur et al. [61] 2012 A case report 1
Boxberger et al. [68] 2013 Prospective multicenter study 237
Scott et al. [69] 2011 Retrospective single center study 47
Virgone et al. [70] 2014 Retrospective multicenter study 113
Total 687
Study Incidence Age (years): mean Gender
Among
malignancies Per appendectomies Males Females NA
Lambert et al. [1] 12 43 71
Vandevelde & Gera [2] 0,350% 12,5 22
Fallon et al. [4] 0,200% 13,8 13 15
Anastasiadis et al. [6] 0,490% 10,75 1 3
S. Fernández at al. [8] 0,480% 13 15 13
Henderson et al. [9] 12,5 27
28 Alemayehu et al. [10] 0,250% 10,9 7 2 Kim et al. [11] 0,420% 13,7 1 12 Ketan et al [15] 15 3 4 Hatzipantelis et al. [21] 2,300% 10,5 9 10 Encinas et al. [31] 13 3 5 Neves et al. [33] 0,190% 12,2 2 6 Christianakis et al. [36] 0,065% 13 1 Cernaianu et al. [37] 0,080% 14 1 Mathur et al. [61] 16 1 Boxberger et al. [68] 13 99 138 Scott et al. [69] 12,3 12 34 1 Virgone et al. [70] 12 41 72 12,54 (mean age) 250,00 (total males) 387,00 (total females) 50,00 (total NA) % 1,067% 0,296% 36,39% 56,33% 7,28%
In order to calculate the overall incidence as well as the incidence per appendectomies and the average age at diagnosis, the weighted average using the number of cases as the weight of the elements (incidences) was employed.
Clinical features:
The chief complaint in all the articles was abdominal pain.
Study
Other complaints
Carcinoid syndrome
Lambert et al. [1] Fever, N&V, chronic abdominal pain 0
Vandevelde & Gera
[2] NA 0
Fallon et al. [4] Fever, N&V 0
Anastasiadis et al. [6] Chronic abdominal pain 0
S. Fernández at al. [8] Bowel obstruction, fever, N&V, anorexia, abdominal distension and hematochezia 0 Henderson et al. [9] Fever, N&V, chronic abdominal pain 0 Alemayehu et al. [10] Asymptomatic, anorexia, vomiting, diarrea 0
Kim et al. [11] NA 0
Ketan et al [15] Familial adenomatous polyposis 0
Hatzipantelis et al.
[21] Fever, vomiting, chronic abdominal pain 1
Encinas et al. [31] Chronic abdominal pain 0
Neves et al. [33] Fever, chronic abdominal pain 0
Christianakis et al.
[36] Fever, nausea, anorexia, chronic abdominal pain 0
29
Histology, localization and staging:
Study Histology Localization Invasion/metástasis Tumor size
Base Midportion Tip NA Localized Regional Distant Unknown <2cm >2cm NA Median, mm
Lambert et al. [1] NA 12 25 61 16 92 22 104 10 8
Vandevelde & Gera [2] NA 22 14 7 1 22 6,5
Fallon et al. [4] NA 28 18 8 2 28 7
Anastasiadis et al. [6] NA 4 4 4
S. Fernández at al. [8] NA 28 23 5 27 1
Henderson et al. [9] typical, low-grade 2 5 20 11 14 2 27
Alemayehu et al. [10] NA 1 3 5 9 9
Kim et al. [11] NA 13 6 6 1 12 1 10
Ketan et al [15] typical, low grade 7 6 1 7
Hatzipantelis et al. [21] typical, low grade 19 18 1 19
Encinas et al. [31] NA 1 7 7 1 7 1
Neves et al. [33] NA 8 7 1 8 8
Christianakis et al. [36] typical, low grade 1 1 1 10
Cernaianu et al. [37] NA 1 1 1 7
Mathur et al. [61] NA 1 1 1
Boxberger et al. [68] typical, low grade 15 47 151 24 113 115 9 217 10 10
Scott et al. [69] NA 9 11 16 11 30 8 9 35 2 10 8
Virgone et al. [70] typical, low grade 2 11 62 38 83 27 1 2 108 5 5
Total 42 102 347 196 433 217 13 23 630 30 27
% 6,11% 14,85% 50,51% 28,53% 63,11% 31,63% 1,89% 3,35% 91,70% 4,37% 3,93%
Mean 6,93
% without NA results 8,55% 20,77% 70,67% 65,30% 32,73% 1,96%% 95,45% 4,54%
Median average size of the tumor was calculated using the weighted average.
Diagnosis:
The gold standard for diagnosis was a biopsy with histopathological investigation from an incidental finding on the appendix.
Cernaianu et al. [37] Chronic abdominal pain 0
Mathur et al. [61] Chronic abdominal pain 0
Boxberger et al. [68] Chronic abdominal pain, flushing 0
Scott et al. [69] NA 0
Virgone et al. [70] Chronic abdominal pain, fever, vomiting, diarrhea and flushing 0
Total 1
% 0,14 %
Study
Intraoperative findings Additional diagnostic methods
Lambert et al. [1] Appendicitis Abdominal US, Abdominal CT, Octeotride scintigraphy, NSE,
serum ChrA and serotonin, 5-HIAA levels
Table 8
30
Treatment and survival:
In Vigorne et al. [70], 3 patients developed a second neoplasm: one Hodgkin lymphoma, one ovarian mature teratoma, and one fibroadenoma of the breast.
Vandevelde &
Gera [2] Appendicitis, tumor mass Abdominal US, Abdominal CT, Octeotride scintigraphy, NSE,
serum ChrA and serotonin, 5-HIAA levels
Fallon et al. [4] NA
abdominal US,, abdominal CT (inflamed lymph nodes), urine 5-HIAA and Octeotride scintigraphy
Anastasiadis et al.
[6] Appendicitis, tumor mass Serum serotonin, Chr.A, urinary 5-HIAA, abdominal US.
S. Fernández at al. [8]
Appendicitis, tumor mass, ruptured appendix, multiple
strictures, Meckel diverticulitis, colitis, perforated 5-HIAA
appendix, small bowel obstruction.
Henderson et al.
[9] Appendicitis, peritonitis, appendiceal mass Chest X-ray, abdominal US, urine 5-HIAA levels, serum Chr.A
Alemayehu et al.
[10] Appendicitis NA
Kim et al. [11] Appendicitis, appendiceal phlegmon NA
Ketan et al [15] Appendicitis, FAP, IBS Chr. A and NSE. Positive synatophysin and argyrophil stain
Hatzipantelis et al. [21]
Appendicitis, peritonitis, periappendiceal abscess,
appendiceal mass
Abdominal US, chest and abdominal CT, 99Tc bone scan, urinary 5-HIAA levels, and OS
Encinas et al. [31] NA NA
Neves et al. [33] NA NSE, Chr.A
Christianakis et al.
[36] Appendicitis, appendiceal mass 5-HIAA
Cernaianu et al.
[37] Appendicitis Abdominal US, OS, chest and abdominal CT.
Mathur et al. [61] NA NA
Boxberger et al.
[68] Appendicitis, ruptured ovarian cyst, tumor mass OS, 5-HIAA, abdominal MRI, Chr. A
Scott et al. [69] NA NA
Virgone et al. [70] Appendicitis
Specific markers such as serum serotonine, urinary 5-HIAA, and neuroendocrine markers
such as Chr. A and NSE. Abdominal CT, MRI and US. Chest X-ray
Study Treatment Survival
Appendectomy
alone RHC/ICR Additional NA Alive
Free of disease
Lambert et al. [1] 104 10 114 114
Vandevelde & Gera
[2] 22 22 22 Fallon et al. [4] 23 5 28 28 Anastasiadis et al. [6] 4 4 4 S. Fernández at al. [8] 23 5 28 28 Henderson et al. [9] 27 27 27 Alemayehu et al. [10] 9 9 9 Kim et al. [11] 10 3 13 13 Ketan et al [15] 6 Total abdominal colectomy (n=1) 7 7 Hatzipantelis et al. [21] 19 19 19 Table 10
