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Management and outcomes of appendicular neuroendocrine tumours: Retrospective review with 5-year follow-up
Available online at www.sciencedirect.com
ScienceDirect EJSO 41 (2015) 1243e1246
www.ejso.com
Management and outcomes of appendicular neuroendocrine tumours: Retrospective review with 5-year follow-up B. Amr, F. Froghi*, M. Edmond, K. Haq, R. Thengungal Kochupapy Surgical Department, Derriford Hospital, Plymouth Hospitals NHS Trust, United Kingdom Accepted 19 June 2015 Available online 8 July 2015
Abstract Background: Neuroendocrine (NEN) tumours are the commonest type of tumours affecting the appendix. The majority of cases are diagnosed incidentally on post-operative histopathological examination of the resected appendicectomy specimen. Preoperative diagnosis remains a challenge, unless the patient presents with obvious features of carcinoid syndrome or signs of metastatic disease. Hence, the authors present our five-year experience in diagnosing and managing NEN tumours of the appendix. Methods: Retrospective review of all patients underwent an emergency appendicectomy with intention to treat clinically suspected appendicitis at Derriford Hospital (Plymouth, Devon, UK) was undertaken. Patients with diagnoses other than NEN of the appendix were excluded. For patients with appendicular NEN, demographic data, pre-operative inflammatory markers, post-operative histology results as well as follow-up investigations were obtained using patients’ electronic records. Case notes were reviewed for clinical presentation, operative details and follow-up information. Results: 2724 patients underwent emergency appendicectomy between January 2009 and May 2014. Carcinoid tumours were identified in 17 histologically examined appendicectomy specimens. Clinically, all patients presented with acute appendicitis with raised inflammatory markers in 58.5% of patients. Median tumour size was 5 (1e20) mm. Median postoperative follow up was 2.9 (0.92e5.8) years. All patients remained tumour free with no evidence of metastasis or recurrence during the entire study period. Conclusion: Appendicular NEN are rare and usually diagnosed incidentally; hence precise examination of routine appendicectomy specimens is fundamental in the diagnosis. Simple appendicectomy is sufficient for tumours less than 1 cm for adequate clearance, whilst right hemi-colectomy is recommended for larger tumours. Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Keywords: Appendicitis; Neuroendocrine tumours; Carcinoid
Introduction First described by Oberndorfer in 1907, neuroendocrine (NEN) tumours are slow growing rare tumours arising from enterochromaffin cells found throughout the gastrointestinal tract and the broncho-pulmonary system.1 The appendix is the most common site for gastrointestinal carcinoid tumours. NEN represents 60% of all appendicular tumours, making it the most common tumour type affecting the appendix.2 However, appendicular NEN tumours are very rare with a reported annual incidence of 0.15/100,000 that * Corresponding author. Plymouth Hospitals NHS Trust, Derriford Hospital, Derriford Road, PL6 8DH, Plymouth, United Kingdom. Tel.: þ44 01752431486. E-mail address: [email protected] (F. Froghi).
has increased to 0.4e0.6/100,000 with a slight female predominance.3 The preoperative diagnosis of dormant appendicular NEN is challenging unless patients present with symptoms and signs of carcinoid syndrome or features of metastatic disease.5 The majority of cases are diagnosed incidentally in 3e5/1000 performed appendicectomy operations.4 Currently, a simple appendicectomy is advocated for tumours less than 2 cm and a formal right hemicolectomy for tumours greater than 2 cm due to the higher risk of mesenteric lymph node metastasis.4 Patients with appendicular NEN diagnosis have had good outcomes with a fiveyear survival rate of 85e100%.3,6,7 Given their rare nature and difficulty in preoperative diagnosis of appendicular NEN, there is a scarcity of large
http://dx.doi.org/10.1016/j.ejso.2015.06.010 0748-7983/Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
1244
B. Amr et al. / EJSO 41 (2015) 1243e1246
case series or studies in the literature. The authors therefore present a single-center case series of appendicular NEN identified from a retrospective analysis of all the appendicectomy specimens in the last five years to explore our experience in the diagnosis and management of patients with these rare tumours as well as identifying metastatic behaviour and tendency to recur. Methods A retrospective review of all patients who underwent emergency appendicectomy with the intention to treat clinically suspected appendicitis between January 2009 and May 2014 at a teaching hospital (Derriford Hospital, Plymouth, Devon, UK) was undertaken. Patients with histological findings other than NEN of the appendix and those who underwent surgery for reasons other than suspected appendicitis were excluded. Demographic data, preoperative diagnoses, investigations and operative findings for patients with the diagnosis of NEN tumours of the appendix were reviewed. Pathological reports were reviewed for tumour type, tumour size, and depth of invasion, the degree of differentiation, resection margin and lymph node involvement. Follow-up records and survival data were also examined from the hospital case notes. The study protocol has been reviewed and approved by Plymouth Hospitals NHS Trust audit department. Results Between January 2009 and May 2014, 2724 patients (47.2% M) with a median age of 24 years underwent emergency appendicectomy with the intention to treat clinically suspected appendicitis at our institution. The diagnosis of appendicular NEN tumours was histologically confirmed in 17 appendicectomy specimens. For this cohort of patients, there were 11 females (64.7%) with a median age of 20 years (range: 8e69) and 6 males (35.3%) with median age of 29.5 years (range: 16e73). During the study period we diagnosed eighteen cases with appendicular NEN, however, one case did not meet the inclusion criteria as the patient underwent a right hemicolectomy for a caecal volvulus. All patients presented with clinically suspected acute appendicitis. Laboratory investigations revealed raised white cell count (WCC) in 10 patients (58.8%). Emergency laparoscopic appendicectomy was successfully performed in 7 patients (41.2%) while 10 patients (58.3%) had their appendix surgically removed via the traditional open approach. The incidence of appendicular NEN in our series was 0.62% with a median tumour size of 5 mm (range: 1e20). 64.7% of the tumours measured less than 1 cm. Median tumour size was larger among female patients with no statistical significance ( p ¼ 0.071). The histopathological characteristics of the resected tumours are shown in
(Table 1). The tip of the appendix was the most common tumour site being identified in 64.7% of the cases. Complete resection was successfully achieved in 16 patients, whereas one patient had a perforated appendix at the time of surgery and hence the exact identification of the resection margin was not possible. Two patients with 18 mm and 12 mm tumours at the appendicular base subsequently underwent a right hemicolectomy at 80 days and 72 days respectively following the initial appendicectomy operation. For these two patients, the final histological examination did not reveal evidence of disease remnants or other lesions within the resected specimen. Serosal invasion was reported in six patients while five patients had invasion of the mesoappendix. Only one patient had a single positive lymph node deposit for a welldifferentiated, completely resected, 2 mm tumour at the centre of the appendix. Large cell type was identified in 8 cases while goblet cell was found in only two cases. None of our patients were found to have features of carcinoid syndrome and the median hospital stay was 2 days (range: 1e16). Based on the TNM classification of appendicular carcinoid (Table 2),16 11 patients (64.7%) were staged T1a and Table 1 Histopathological characteristics for the resected 17 appendicular NEN specimens. N Tumour size (%)
Tumour site (%)
Depth of invasion (%)
R0 (%) Node positive (%) Large cell NET (%) Goblet cells (%) Carcinoid features (%) Well diff (%) Low grade (%) T4 (%)
17 1 cm >1 < 2 cm ¼ 2 cm Missing (perforation) Tip Base Middle Whole appendix Mucosa Serosa Mesoappendix
11 (64.7) 4 (23.5) 1 (5.9) 1 (5.9) 11 (64.7) 2 (11.8) 2 (11.8) 2 (11.8) 6 (35.3) 6 (35.3) 5 (29.4) 16 (94.1) 1 (5.9) 8 (47) 2 (11.8) 0 13 (76.5) 2 (1.8) 1 (5.9)
Table 2 Summary of TNM classification-7th edition of appendicular NEN (well differentiated neuroendocrine tumour). T1a T1b T2 T3 T4 N1
1 cm >1e2 cm >2e4 cm OR with extension to the caecum >4 cm OR with extension to the ileum Perforates peritoneum OR other organs or structures Regional
B. Amr et al. / EJSO 41 (2015) 1243e1246
five patients (29.4%) were staged T1b. All patients were successfully treated with a simple appendicectomy that was subsequently followed by a right hemicolectomy in two patients. None of the patients developed evidence of metastases or recurrence with a median follow-up of 2.9 years (range: 0.92e5.8). Follow-up measures included laboratory testing of Chromogranin A and B in three patients. An elevated level of Chromogranin A (96 pmol/L) with a normal Chromogranin B (59 pmol/L) was noticed in one patient six months following surgery in clinic. This was not followed-up with further tests or imaging. Three patients were followed up by laboratory measuring 24-H urinary 5-hydroxyindoleacetic acid (5-HIAA). These levels were elevated in two patients on their follow-up appointments more than 6 weeks post-operatively but returned to normal on future follow-up analysis. All patients were symptom free on follow-up. Follow-up imaging included normal Magnetic Resonance Imaging (MRI) in two patients, normal Computed Tomography (CT) scan in two patients and normal Octreotide scan in two patients. One patient aged 8 years was referred to a paediatric oncologist. All patients were followed up and remained tumour free with no evidence of recurrence or metastatic disease within the period of the study. The median follow-up was 2.9 years (range: 0.92e5.8). Only one patient who was 75 years old with metastatic prostate cancer died at 21.6 months following his surgery. Discussion The rare incidence of appendicular NEN was mirrored in this series, which was found to be as low as 0.6%. Tumour size was less than 1 cm in diameter in 64% of the cases consistent with previous studies.8e12 These tumours are indolent and have no tumour specific characteristics at presentation making preoperative diagnosis of appendicular NEN challenging unless they present with features of carcinoid syndrome. In our series, all patients presented with clinically suspected appendicitis and none were suspected to have appendicular NEN preoperatively or intraoperatively. The preoperative work-up for these patients included standard laboratory tests for acute appendicitis which could not predict the disease in this series. None of the patients had a computed tomography (CT) scan prior to surgery, however, in a series reported by Coursey et al. none of the tumours could be prospectively identified on the preoperative CT scan.5 The presence of the tumours at the tip of the appendix in the majority of our cases (64.7%) raises suspicions regarding the pathogenesis of the appendicitis through liminal obstruction in this group of patients. Histological examination confirmed features of acute inflammation in only 9 patients (52.9%). Of these, only one specimen showed acute inflammation of appendix with luminal
1245
obstruction secondary to the tumour and one case had acute inflammation around the tumour at the tip. It is therefore unlikely for these tumours to have initiated the process of appendicitis through luminal obstruction.13,14 Serosal invasion was histologically reported in six patients (35.3%) and this does not appear to affect the overall outcome.6 Mesoappendiceal invasion was identified in five cases (29.4%); however, this has no role in the prognosis of the tumours.15 Overall, the diagnosis of appendicular NEN carries a favourable outcome with excellent prognosis compared to NEN tumours of other sites.2,4,11 Only two patients in this series had a right hemicolectomy for tumours less than 2 cm at the base of the appendix due to the risk of mesenteric lymph node metastasis. Simple appendicectomy was curative in the remainder of patients. The National Comprehensive Cancer Network (NCCN) has published clinical practice guidelines for neuroendocrine tumours including appendicular carcinoids in 2013.17 It is recommended that simple appendicectomy is curative for tumours less than 2 cm confined to the appendix with follow-up as clinically indicated. For tumours larger than 2 cm, positive resection margin, or with metastatic nodal deposits, CT or MRI of the chest, abdomen and pelvis is recommended for patient evaluation. These patients would benefit from subsequent right hemicolectomy and follow-up should take place every 3e12 months by means of history and physical examination, 24-H urine 5-HIAA, chromogranin A, CT or MRI. Subsequent follow-up is then scheduled every 6e12 month up to 10 years post resection.17 The consensus guidelines of the European Endocrine Tumour Society (ENETS) published in 2012 also recommend simple appendicectomy for tumours less than 2 cm, which appears to be curative independent of the tumour site and a right hemicolectomy is within 3 months following the initial appendicectomy operation in patients with tumours more than 2 cm.4 For tumours between 1 and 2 cm, a subsequent right hemicolectomy is recommended if there is a positive or unclear margin, deep mesoappendiceal invasion, higher proliferation rate and/or vascular invasion. No follow-up is required for tumours < 1 cm with R0 resection. For well-differentiated tumours of 1e2 cm and R0 resection, the data is insufficient for a clear-cut decision. However, in cases with deep infiltration of the mesoappendix or vascular invasion, imaging may be performed to rule out any residual disease. Patients with larger tumours (>2 cm), metastases or R1 resection, should be followed initially after 6 and 12 months postoperatively and then annually; although this approach has not been validated. The main drawback of our series lies in its retrospective nature. However, the lack of tumour specific symptoms and signs for the non-metastatic, non-carcinoid syndrome tumours, make the prospective studies more difficult to conduct. The small number of cases in our series is due to the low incidence of the disease in general as reported in the literature.3,6 It is difficult to gather information
1246
B. Amr et al. / EJSO 41 (2015) 1243e1246
regarding the macroscopic appearances of the appendixes removed in this series due to poor descriptive documentation in the operative notes. Through examination of the macroscopic appearances in the histology reports, there were no specific features which would suggest a NEN tumour was present. Hence, the authors would recommend the removal of intraoperatively normal looking appendix in the absence of other features to explain the symptoms (such as an ovarian cyst rupture or a Meckel’s diverticulum) to avoid missing an appendicular NEN tumour and the metastatic sequela that would ensue. This study certainly confirms what is already known about appendicular NEN tumours; that they are rare and simple appendicectomy appears to be curative in most cases. Summary Preoperative diagnosis of appendicular NEN is challenging for surgeons with a lack of tumour specific symptoms or signs. Most cases are diagnosed postoperatively with a detailed histological examination. Surgical management with simple appendicectomy seems to be curative for the majority of cases especially with tumours less than 1 cm. Right hemicolectomy is recommended for tumours larger than 2 cm especially those near the base or with nodal metastasis. Conflicts of interest The authors have no conflicts of interest to declare.
References 1. Oberndorfer S. Karzinoide Tumoren des D€unndarms. Frankf Z Pathol 1907;1:426–9. 2. Murray SE, Lloyd RV, Sippel RS, Chen H, Oltmann SC. Post-operative surveillance of small appendiceal carcinoid tumors. Am J Surg 2014;207(3):342–5.
3. Ellis L, Shale MJ, Coleman MP. Carcinoid tumors of the gastrointestinal tract: trends in incidence in England since 1971. Am J Gastroenterol 2010;105(12):2563–9. 4. Pape UF, Perren A, Niederle B, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology 2012;95(2):135–56. 5. Coursey CA, Nelson RC, Moreno RD, Dodd LG, Patel MB, Vaslef S. Carcinoid tumors of the appendix: are these tumors identifiable prospectively on preoperative CT? Am Surg 2010;76(3):273–5. 6. Moertel CG, Dockerty MB, Judd ES. Carcinoid tumors of the vermiform appendix. Cancer 1968;21(2):270–8. 7. Sandor A, Modlin IM. A retrospective analysis of 1,570 appendiceal carcinoids. Am J Gastroenterol 1998;93(3):422–8. 8. in’t Hof KH, van der Wal HC, Kazemier G, Lange JF. Carcinoid tumour of the appendix: an analysis of 1,485 consecutive emergency appendectomies. J Gastrointest Surg: Off J Soc Surg Alimentary Tract 2008;12:1436–8. 9. Emre A, Akbulut S, Bozdag Z, et al. Routine histopathologic examination of appendectomy specimens: retrospective analysis of 1,255 patients. Int Surg 2013;98(4):354–62. 10. Monajemzadeh M, Hagghi-Ashtiani MT, Montaser-Kouhsari L, Ahmadi H, Zargoosh H, Kalantari M. Pathologic evaluation of appendectomy specimens in children: is routine histopatholgic examination indicated? Iran J Pediatr 2011;21(4):485–90. 11. Henderson L, Fehily C, Folaranmi S, et al. Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience. J Pediatr Surg 2014;49(10):1513–7. 12. Shapiro R, Eldar S, Sadot E, Papa MZ, Zippel DB. Appendiceal carcinoid at a large tertiary center: pathologic findings and long-term follow-up evaluation. Am J Surg 2011;201(6):805–8. 13. Deans GT, Spence RA. Neoplastic lesions of the appendix. Br J Surg 1995;82(3):299–306. 14. Stinner B, Rothmund M. Neuroendocrine tumours (carcinoids) of the appendix. Best Pract Res Clin Gastroenterol 2005;19(5):729–38. 15. Rossi G, Valli R, Bertolini F, et al. Does mesoappendix infiltration predict a worse prognosis in incidental neuroendocrine tumors of the appendix? A clinicopathologic and immunohistochemical study of 15 cases. Am J Clin Pathol 2003;120(5):706–11. 16. Sobin Leslie H, MKGE, Wittekind Christian, editors. TNM classification of malignant tumours. 7th ed. Wiley-Blackwell; November 2009; p. 336. 17. NCCN clinical practice guidelines in Oncology 2014. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines_nojava. asp-site.
ScienceDirect EJSO 41 (2015) 1243e1246
www.ejso.com
Management and outcomes of appendicular neuroendocrine tumours: Retrospective review with 5-year follow-up B. Amr, F. Froghi*, M. Edmond, K. Haq, R. Thengungal Kochupapy Surgical Department, Derriford Hospital, Plymouth Hospitals NHS Trust, United Kingdom Accepted 19 June 2015 Available online 8 July 2015
Abstract Background: Neuroendocrine (NEN) tumours are the commonest type of tumours affecting the appendix. The majority of cases are diagnosed incidentally on post-operative histopathological examination of the resected appendicectomy specimen. Preoperative diagnosis remains a challenge, unless the patient presents with obvious features of carcinoid syndrome or signs of metastatic disease. Hence, the authors present our five-year experience in diagnosing and managing NEN tumours of the appendix. Methods: Retrospective review of all patients underwent an emergency appendicectomy with intention to treat clinically suspected appendicitis at Derriford Hospital (Plymouth, Devon, UK) was undertaken. Patients with diagnoses other than NEN of the appendix were excluded. For patients with appendicular NEN, demographic data, pre-operative inflammatory markers, post-operative histology results as well as follow-up investigations were obtained using patients’ electronic records. Case notes were reviewed for clinical presentation, operative details and follow-up information. Results: 2724 patients underwent emergency appendicectomy between January 2009 and May 2014. Carcinoid tumours were identified in 17 histologically examined appendicectomy specimens. Clinically, all patients presented with acute appendicitis with raised inflammatory markers in 58.5% of patients. Median tumour size was 5 (1e20) mm. Median postoperative follow up was 2.9 (0.92e5.8) years. All patients remained tumour free with no evidence of metastasis or recurrence during the entire study period. Conclusion: Appendicular NEN are rare and usually diagnosed incidentally; hence precise examination of routine appendicectomy specimens is fundamental in the diagnosis. Simple appendicectomy is sufficient for tumours less than 1 cm for adequate clearance, whilst right hemi-colectomy is recommended for larger tumours. Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
Keywords: Appendicitis; Neuroendocrine tumours; Carcinoid
Introduction First described by Oberndorfer in 1907, neuroendocrine (NEN) tumours are slow growing rare tumours arising from enterochromaffin cells found throughout the gastrointestinal tract and the broncho-pulmonary system.1 The appendix is the most common site for gastrointestinal carcinoid tumours. NEN represents 60% of all appendicular tumours, making it the most common tumour type affecting the appendix.2 However, appendicular NEN tumours are very rare with a reported annual incidence of 0.15/100,000 that * Corresponding author. Plymouth Hospitals NHS Trust, Derriford Hospital, Derriford Road, PL6 8DH, Plymouth, United Kingdom. Tel.: þ44 01752431486. E-mail address: [email protected] (F. Froghi).
has increased to 0.4e0.6/100,000 with a slight female predominance.3 The preoperative diagnosis of dormant appendicular NEN is challenging unless patients present with symptoms and signs of carcinoid syndrome or features of metastatic disease.5 The majority of cases are diagnosed incidentally in 3e5/1000 performed appendicectomy operations.4 Currently, a simple appendicectomy is advocated for tumours less than 2 cm and a formal right hemicolectomy for tumours greater than 2 cm due to the higher risk of mesenteric lymph node metastasis.4 Patients with appendicular NEN diagnosis have had good outcomes with a fiveyear survival rate of 85e100%.3,6,7 Given their rare nature and difficulty in preoperative diagnosis of appendicular NEN, there is a scarcity of large
http://dx.doi.org/10.1016/j.ejso.2015.06.010 0748-7983/Crown Copyright Ó 2015 Published by Elsevier Ltd. All rights reserved.
1244
B. Amr et al. / EJSO 41 (2015) 1243e1246
case series or studies in the literature. The authors therefore present a single-center case series of appendicular NEN identified from a retrospective analysis of all the appendicectomy specimens in the last five years to explore our experience in the diagnosis and management of patients with these rare tumours as well as identifying metastatic behaviour and tendency to recur. Methods A retrospective review of all patients who underwent emergency appendicectomy with the intention to treat clinically suspected appendicitis between January 2009 and May 2014 at a teaching hospital (Derriford Hospital, Plymouth, Devon, UK) was undertaken. Patients with histological findings other than NEN of the appendix and those who underwent surgery for reasons other than suspected appendicitis were excluded. Demographic data, preoperative diagnoses, investigations and operative findings for patients with the diagnosis of NEN tumours of the appendix were reviewed. Pathological reports were reviewed for tumour type, tumour size, and depth of invasion, the degree of differentiation, resection margin and lymph node involvement. Follow-up records and survival data were also examined from the hospital case notes. The study protocol has been reviewed and approved by Plymouth Hospitals NHS Trust audit department. Results Between January 2009 and May 2014, 2724 patients (47.2% M) with a median age of 24 years underwent emergency appendicectomy with the intention to treat clinically suspected appendicitis at our institution. The diagnosis of appendicular NEN tumours was histologically confirmed in 17 appendicectomy specimens. For this cohort of patients, there were 11 females (64.7%) with a median age of 20 years (range: 8e69) and 6 males (35.3%) with median age of 29.5 years (range: 16e73). During the study period we diagnosed eighteen cases with appendicular NEN, however, one case did not meet the inclusion criteria as the patient underwent a right hemicolectomy for a caecal volvulus. All patients presented with clinically suspected acute appendicitis. Laboratory investigations revealed raised white cell count (WCC) in 10 patients (58.8%). Emergency laparoscopic appendicectomy was successfully performed in 7 patients (41.2%) while 10 patients (58.3%) had their appendix surgically removed via the traditional open approach. The incidence of appendicular NEN in our series was 0.62% with a median tumour size of 5 mm (range: 1e20). 64.7% of the tumours measured less than 1 cm. Median tumour size was larger among female patients with no statistical significance ( p ¼ 0.071). The histopathological characteristics of the resected tumours are shown in
(Table 1). The tip of the appendix was the most common tumour site being identified in 64.7% of the cases. Complete resection was successfully achieved in 16 patients, whereas one patient had a perforated appendix at the time of surgery and hence the exact identification of the resection margin was not possible. Two patients with 18 mm and 12 mm tumours at the appendicular base subsequently underwent a right hemicolectomy at 80 days and 72 days respectively following the initial appendicectomy operation. For these two patients, the final histological examination did not reveal evidence of disease remnants or other lesions within the resected specimen. Serosal invasion was reported in six patients while five patients had invasion of the mesoappendix. Only one patient had a single positive lymph node deposit for a welldifferentiated, completely resected, 2 mm tumour at the centre of the appendix. Large cell type was identified in 8 cases while goblet cell was found in only two cases. None of our patients were found to have features of carcinoid syndrome and the median hospital stay was 2 days (range: 1e16). Based on the TNM classification of appendicular carcinoid (Table 2),16 11 patients (64.7%) were staged T1a and Table 1 Histopathological characteristics for the resected 17 appendicular NEN specimens. N Tumour size (%)
Tumour site (%)
Depth of invasion (%)
R0 (%) Node positive (%) Large cell NET (%) Goblet cells (%) Carcinoid features (%) Well diff (%) Low grade (%) T4 (%)
17 1 cm >1 < 2 cm ¼ 2 cm Missing (perforation) Tip Base Middle Whole appendix Mucosa Serosa Mesoappendix
11 (64.7) 4 (23.5) 1 (5.9) 1 (5.9) 11 (64.7) 2 (11.8) 2 (11.8) 2 (11.8) 6 (35.3) 6 (35.3) 5 (29.4) 16 (94.1) 1 (5.9) 8 (47) 2 (11.8) 0 13 (76.5) 2 (1.8) 1 (5.9)
Table 2 Summary of TNM classification-7th edition of appendicular NEN (well differentiated neuroendocrine tumour). T1a T1b T2 T3 T4 N1
1 cm >1e2 cm >2e4 cm OR with extension to the caecum >4 cm OR with extension to the ileum Perforates peritoneum OR other organs or structures Regional
B. Amr et al. / EJSO 41 (2015) 1243e1246
five patients (29.4%) were staged T1b. All patients were successfully treated with a simple appendicectomy that was subsequently followed by a right hemicolectomy in two patients. None of the patients developed evidence of metastases or recurrence with a median follow-up of 2.9 years (range: 0.92e5.8). Follow-up measures included laboratory testing of Chromogranin A and B in three patients. An elevated level of Chromogranin A (96 pmol/L) with a normal Chromogranin B (59 pmol/L) was noticed in one patient six months following surgery in clinic. This was not followed-up with further tests or imaging. Three patients were followed up by laboratory measuring 24-H urinary 5-hydroxyindoleacetic acid (5-HIAA). These levels were elevated in two patients on their follow-up appointments more than 6 weeks post-operatively but returned to normal on future follow-up analysis. All patients were symptom free on follow-up. Follow-up imaging included normal Magnetic Resonance Imaging (MRI) in two patients, normal Computed Tomography (CT) scan in two patients and normal Octreotide scan in two patients. One patient aged 8 years was referred to a paediatric oncologist. All patients were followed up and remained tumour free with no evidence of recurrence or metastatic disease within the period of the study. The median follow-up was 2.9 years (range: 0.92e5.8). Only one patient who was 75 years old with metastatic prostate cancer died at 21.6 months following his surgery. Discussion The rare incidence of appendicular NEN was mirrored in this series, which was found to be as low as 0.6%. Tumour size was less than 1 cm in diameter in 64% of the cases consistent with previous studies.8e12 These tumours are indolent and have no tumour specific characteristics at presentation making preoperative diagnosis of appendicular NEN challenging unless they present with features of carcinoid syndrome. In our series, all patients presented with clinically suspected appendicitis and none were suspected to have appendicular NEN preoperatively or intraoperatively. The preoperative work-up for these patients included standard laboratory tests for acute appendicitis which could not predict the disease in this series. None of the patients had a computed tomography (CT) scan prior to surgery, however, in a series reported by Coursey et al. none of the tumours could be prospectively identified on the preoperative CT scan.5 The presence of the tumours at the tip of the appendix in the majority of our cases (64.7%) raises suspicions regarding the pathogenesis of the appendicitis through liminal obstruction in this group of patients. Histological examination confirmed features of acute inflammation in only 9 patients (52.9%). Of these, only one specimen showed acute inflammation of appendix with luminal
1245
obstruction secondary to the tumour and one case had acute inflammation around the tumour at the tip. It is therefore unlikely for these tumours to have initiated the process of appendicitis through luminal obstruction.13,14 Serosal invasion was histologically reported in six patients (35.3%) and this does not appear to affect the overall outcome.6 Mesoappendiceal invasion was identified in five cases (29.4%); however, this has no role in the prognosis of the tumours.15 Overall, the diagnosis of appendicular NEN carries a favourable outcome with excellent prognosis compared to NEN tumours of other sites.2,4,11 Only two patients in this series had a right hemicolectomy for tumours less than 2 cm at the base of the appendix due to the risk of mesenteric lymph node metastasis. Simple appendicectomy was curative in the remainder of patients. The National Comprehensive Cancer Network (NCCN) has published clinical practice guidelines for neuroendocrine tumours including appendicular carcinoids in 2013.17 It is recommended that simple appendicectomy is curative for tumours less than 2 cm confined to the appendix with follow-up as clinically indicated. For tumours larger than 2 cm, positive resection margin, or with metastatic nodal deposits, CT or MRI of the chest, abdomen and pelvis is recommended for patient evaluation. These patients would benefit from subsequent right hemicolectomy and follow-up should take place every 3e12 months by means of history and physical examination, 24-H urine 5-HIAA, chromogranin A, CT or MRI. Subsequent follow-up is then scheduled every 6e12 month up to 10 years post resection.17 The consensus guidelines of the European Endocrine Tumour Society (ENETS) published in 2012 also recommend simple appendicectomy for tumours less than 2 cm, which appears to be curative independent of the tumour site and a right hemicolectomy is within 3 months following the initial appendicectomy operation in patients with tumours more than 2 cm.4 For tumours between 1 and 2 cm, a subsequent right hemicolectomy is recommended if there is a positive or unclear margin, deep mesoappendiceal invasion, higher proliferation rate and/or vascular invasion. No follow-up is required for tumours < 1 cm with R0 resection. For well-differentiated tumours of 1e2 cm and R0 resection, the data is insufficient for a clear-cut decision. However, in cases with deep infiltration of the mesoappendix or vascular invasion, imaging may be performed to rule out any residual disease. Patients with larger tumours (>2 cm), metastases or R1 resection, should be followed initially after 6 and 12 months postoperatively and then annually; although this approach has not been validated. The main drawback of our series lies in its retrospective nature. However, the lack of tumour specific symptoms and signs for the non-metastatic, non-carcinoid syndrome tumours, make the prospective studies more difficult to conduct. The small number of cases in our series is due to the low incidence of the disease in general as reported in the literature.3,6 It is difficult to gather information
1246
B. Amr et al. / EJSO 41 (2015) 1243e1246
regarding the macroscopic appearances of the appendixes removed in this series due to poor descriptive documentation in the operative notes. Through examination of the macroscopic appearances in the histology reports, there were no specific features which would suggest a NEN tumour was present. Hence, the authors would recommend the removal of intraoperatively normal looking appendix in the absence of other features to explain the symptoms (such as an ovarian cyst rupture or a Meckel’s diverticulum) to avoid missing an appendicular NEN tumour and the metastatic sequela that would ensue. This study certainly confirms what is already known about appendicular NEN tumours; that they are rare and simple appendicectomy appears to be curative in most cases. Summary Preoperative diagnosis of appendicular NEN is challenging for surgeons with a lack of tumour specific symptoms or signs. Most cases are diagnosed postoperatively with a detailed histological examination. Surgical management with simple appendicectomy seems to be curative for the majority of cases especially with tumours less than 1 cm. Right hemicolectomy is recommended for tumours larger than 2 cm especially those near the base or with nodal metastasis. Conflicts of interest The authors have no conflicts of interest to declare.
References 1. Oberndorfer S. Karzinoide Tumoren des D€unndarms. Frankf Z Pathol 1907;1:426–9. 2. Murray SE, Lloyd RV, Sippel RS, Chen H, Oltmann SC. Post-operative surveillance of small appendiceal carcinoid tumors. Am J Surg 2014;207(3):342–5.
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