Neuroendocrinology (DOI:10.1159/000478742)(Accepted, unedited article not yet assigned to an issue) 

© 2017 S. Karger AG, Basel www.karger.com/nen 

 Advanced Release: June 23, 2017 

Received: April 9, 2017 Accepted after revision: June 15, 2017 

  

Surgical management of patients with neuroendocrine neoplasms of 

the appendix: appendectomy or more? 

Nikhil Pawa* 1, Ashley K Clift* 2, Helai Osmani 1, Panagiotis Drymousis 2, Andrzej Cichocki 3,

Rashpal Flora 4, Robert Goldin 4, Dimitrios Patsouras 1, Alan Baird 5, Anna Malczewska 2,6, James

Kinross 2, Omar Faiz 1, Anthony Antoniou 1, Harpreet Wasan 2, Gregory A Kaltsas 7, Ara Darzi 2,

Jaroslaw B Cwikla 8 & Andrea Frilling 2

1. Department of Surgery, St Mark’s Hospital, London, UK

2. Department of Surgery and Cancer, Imperial College London, London, UK

3. Department of Surgical Oncology, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw,

Poland

4. Department of Pathology, Imperial College London, London, UK

5. Department of Cellular Pathology, London North West Hospitals NHS Trust, London, UK

6. Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice,

Poland

7. Department of Pathophysiology, National University of Athens, Greece

8. Department of Nuclear Medicine, Faculty of Medical Science, University of Varmia and Mazury,

Olsztyn, Poland

* NP and AKC contributed equally as first authors

Corresponding author: Professor Andrea Frilling, Department of Surgery and Cancer, Imperial

College London, Hammersmith Campus, Du Cane Road, London, W12 0HS

a.frilling@imperial.ac.uk Phone: 00 44 203 133 210 Fax: 00 44 203 132 037

Short title: Surgery for ANEN

Key words: appendix, neuroendocrine tumours, neoplasms, appendectomy, hemicolectomy

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 2   Abstract

Background: Appendiceal neuroendocrine neoplasms (ANEN) are mostly indolent tumours treated

effectively with simple appendectomy. However, controversy exists regarding the necessity of

oncologic right hemicolectomy (RH) in patients with histologic features suggestive of more aggressive

disease. We assess the effects of current guidelines in selecting surgical strategy (appendectomy or

RH) in the management of ANEN. Methods/aims: Retrospective review of all ANEN cases treated

over a 14 year period at 3 referral centres and their management according to consensus guidelines of

the European and the North American Neuroendocrine Tumor Societies (ENETS and NANETS,

respectively). The operation performed, the tumour stage and grade, extent of residual disease and

follow-up outcomes were evaluated. Results: Of 14,850 appendectomies, 215 patients (1.45%) had

histologically confirmed ANEN. Four patients had synchronous non-ANEN malignancies. One

hundred and ninety-three patients had index appendectomy. Seventeen patients (7.9%) had LN

metastases within the mesoappendix. Forty-nine patients underwent RH after appendectomy. Thirty-

day morbidity and mortality post-RH were 2% and 0%, respectively. Twelve patients (24.5%)

receiving completion RH were found to have lymph node metastases. Two patients had liver

metastases, of them both synchronous. Median follow-up was 38.5 months (range 1-143). No patient

developed disease recurrence. Five year and 10-year overall survival for all patients with ANEN as the

only malignancy were both 99.05%, respectively. Conclusions: Current guidelines appear effective in

identifying ANEN patients at risk of harbouring nodal disease, but question the oncological relevance

of ANEN lymph node metastases. RH might present an overtreatment for a number of patients with

ANEN.

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 3   Introduction

Neuroendocrine neoplasms (NEN) are a diverse collective of tumours most commonly arising from

the gastroenteropancreatic and bronchopulmonary tracts. Appendiceal NEN (ANEN) comprise 38% of

all gastrointestinal NEN, and represent up to 87.9% of all tumours originating from the appendix [1].

Depending upon geographic region and ethnicity an annual incidence of 0.03 - 0.16 cases per 100,000

[2,3] has been reported, and in absolute terms, the incidence of ANEN has increased by 70-133% [4].

There is no gender-specific difference in incidence. Appendiceal NEN are often discovered

incidentally on histopathological examination of appendectomy specimens or during abdominal

surgery for other indications. Often considered indolent, the risk of disease dissemination remains, as

shown in a recent analysis of the Surveillance, Epidemiology, and End Results (SEER) Program

database demonstrating that 49% of reported appendiceal tumours (albeit not all ‘pure’ NEN) had

lymph node metastases [5,6]. Approximately 9% may have distant metastases, the risk of which is

directly proportional to tumour size, particularly evident in >2cm tumours [5]. Existing data on

incidence and tumour stage derived from cancer registries should be taken with caution since small

ANEN are sometimes considered as uniformly benign and not recorded. Furthermore, other types of

more aggressive appendiceal tumours such as goblet cell cancers (GCC) or mixed adeno-

neuroendocrine carcinoma (MANEC) are frequently included in the same group. This is reflected in

the observation that the rates of distant and regional metastases of 12% and 28%, respectively,

reported in the SEER database for appendiceal NEN are higher than those reported in case series that

include solely ANEN [7].

The mainstay of treatment for ANEN remains surgical, with simple appendectomy or right-

hemicolectomy (RH) with lymphadenectomy according to oncologic principles. The latest consensus

guidelines proposed by the European Neuroendocrine Tumor Society (ENETS) published in 2016 [8]

(initial guidelines in 2012 [9]) suggest that well-differentiated ANEN 2%) and/or angioinvasion, and all patients with tumours exceeding 2cm

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 4   should receive an oncological RH within 3 months after appendectomy [8]. According to the North

American Neuroendocrine Society (NANETS) consensus guidelines, RH is recommended in the

presence of tumour invasion at the base of appendix, for tumours >2 cm in size (or when size cannot

be clearly estimated), if there is evidence of lymphovascular or mesoappendiceal invasion, in patients

with mesenteric lymph node metastases, and for intermediate or high-grade tumours [3].

The data pertaining to recurrent disease in ANEN is scarce due to both the rarity and indolent nature of

the disease, and studies demonstrating a survival benefit associated with a RH compared to simple

appendectomy only are lacking. Therefore, controversy exists regarding the indications for further

segmental colonic resection, and there is debate as to whether the use of RH constitutes over-treatment

or if it is oncologically adequate. This uncertainty is most marked for intermediate-sized lesions, i.e.

those between 1cm and 2cm in size [8]. The uncertainty is further fostered by reports on lymph node

metastases in patients who underwent RH for tumours 2.0 cm and negative lymph nodes [13]. Differences in current TNM staging

systems for ANEN, e.g. The Union for International Cancer Control (UICC)/American Joint

Committee on Cancer (AJCC) versus ENETS (Table 1) methods may further contribute to the

controversy.

Here, we report a retrospective review of patients undergoing appendectomy at 3 centres: St Mark’s

Hospital (SMH), London, UK, Imperial College London Healthcare NHS Trust (ICLHNT), London,

UK and Maria Sklodowska-Curie Memorial Cancer Center (MCS-MCC), Warsaw, Poland, which

identified patients with a confirmed diagnosis of ANEN. We evaluate the management of ANEN

patients in light of the most recent guidelines and analyse disease recurrence and overall survival

outcomes[3,8].

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 5   Patients and methods

We retrospectively reviewed all consecutive patients who underwent an appendectomy either as an

isolated procedure or as a part of another abdominal surgical procedure at SMH, ICLHNT and MCS-

MCC between July 2001 and December 2015. All three institutions are tertiary referral centres for

NEN and the two UK sites are partners within the Imperial College London ENETS Centre of

Excellence. Patient data were entered into a prospectively maintained database at all sites. Study

inclusion criteria included: histologically confirmed ANEN according to standard histopathology

criteria (other appendiceal tumours, e.g. GCC or MANEC, were excluded), and undergoing an

abdominal surgical procedure involving appendectomy. All histopathology reviews were by one

specialist pathologist at each institution. Basic demographics, biochemical data, and histopathological

information including grading and TNM staging (with histology and imaging) according to

ENETS/WHO [14] and UICC/AJCC [15] classifications, respectively, were collated from individual

patient notes. In case of potential disagreement between classification systems, the ENETS

classification was considered. Approval for the collection and analysis of patient data in this

retrospective study was obtained from the institutional audit/ethical boards of each participating centre

in accordance with national standards, including approval REC07/MRE09/54 at Imperial College

London.

ENETS criteria for surgical therapy of ANEN [9] were used to evaluate all study subjects – these

guidelines are detailed in Table 2. In cases of patients undergoing colonic resection as a second

intervention, results of specific diagnostic work-up (i.e. cross-sectional imaging, somatostatin

receptor-based imaging, NEN-specific biochemistry) preceding RH were recorded. To attain optimal

information regarding disease stage, and for better surgical planning, all patients considered for RH

underwent somatostatin receptor targeted imaging, either with 99mTc-[HYNIC, Tyr3]-Octreotide whole

body WB-SPECT/CT (Tektrotyd ® NCBJ, Polatom, PL) or 68Ga-DOTATATE PET/CT. The

management of patients was discussed within multidisciplinary team settings at all centres.

Thirty-day morbidity and mortality data were collated. Length of follow-up was calculated from the

date of the surgery involving appendectomy. Follow-up protocols were according to ENETS

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 6   guidelines and uniform among the three institutions. For patients undergoing simple appendectomy

alone (i.e. those with tumours smaller than 1cm, with R0 resection), no specific follow-up was carried

out. For those patients who underwent oncological RH for tumours smaller than 2cm, with no lymph

node metastases or residual disease, there was no specific follow-up. In patients with lymph node or

any other metastases, follow-up occurred 6-12monthly and thereafter annually with CT or preferably

MRI and tumour biochemistry – if there were any pathologic increases in tumour markers or findings

on morphologic imaging, 68Ga-DOTATATE PET/CT or Tektrotyd ® whole body WB-SPECT/CT

would be carried out. Patients who were eligible for, but did not receive completion RH were also

followed 6-12monthly initially, and then annually with CT or preferably MRI, and tumour-specific

biochemistry.

Patient survival status at the last follow-up date (31st December 2015) was ascertained by reviewing

patient notes, contacting the patient’s general practitioner, or the patients themselves. Patients lost to

follow-up were deemed ‘alive’ at last known clinical encounter. Survival was only formally assessed

with Kaplan-Meier methodology for patients with ANEN as the only malignancy, i.e. patients with

synchronous second malignancies were not included in these analyses. The unpaired t test was used in

the comparison of means, whilst associations between categorical variables were assessed with

Pearson’s chi-squared test. Statistical analyses were performed in IBM SPSSTM (v.24), or R (v.3.3.2).

We performed a sub-group analysis in all patients that underwent RH to evaluate the guidelines in

terms of appropriately selecting ANEN patients for further surgical intervention [3,8].

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 7   Results

During the study period, 14,850 appendectomies were performed within the 3 units and 215 patients

(1.45%) had a histologically confirmed diagnosis of ANEN. Four included patients (1.86%) had

synchronous second abdominal malignancies; colonic adenocarcinoma in two cases and ileal

neuroendocrine neoplasia in two cases). There were no significant differences between the patients

from each centre in terms of gender, age at diagnosis, tumour grade or the incidence of lymph node or

distant metastases (all p>0.05), thus enabling analysis as a single cohort.

The mean age of the ANEN cohort was 33.2 years (range 9-79), and 130 (60.5%) were female. Index

appendectomy was performed in 193 cases (89.8%). In 16 patients (7.4%), RH was performed as the

index operation for a colonic adenocarcinoma (n=2), ileal NEN (n=2), perforated colon (n=2), right

sided diverticular disease (n=3), suspected and histologically confirmed ANEN >2cm (n=2), an

identified caecal pole abnormality (n=2), inflammatory bowel disease (n=1), colonic polyps (n=1) or

an enlarged appendix identified on CT pneumocolon (n=1). One patient underwent a subtotal

colectomy and two with familial adenomatous polyposis underwent a panproctocolectomy within

which a tumour within the appendix was identified. The 3 remaining cases underwent abdominal

surgery for gynaecological indications, wherein an abnormal appendix was resected. Table 3

demonstrates the demographic, operative and pathological characteristics of the ANEN patients.

Mean tumour size was 9.8mm (range 1-50mm) – 100 (46.5%) cases were smaller than 10mm (T1), 52

(24.2%) had lesions between 10-20mm (T2), and 63 (29.3%) tumours were larger than 20mm (T3 or

T4) (TNM staging according to ENETS guidelines [8]). Seventeen patients (7.9%) had lesions

invading the peri-appendicular fat, and 32 (14.9%) demonstrated serosal invasion of the appendiceal

wall (Table 3). Seventeen patients (7.9%) had involved lymph nodes within the appendiceal

mesentery, and 14 (6.5%) demonstrated signs of vascular invasion. A positive resection margin was

seen in 9 (4.2%) cases, all of which subsequently underwent RH.

Regarding ENETS tumour grade (G), 200 patients (93%) had G1 tumours (Ki67

 

  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 8   retrospective immunostaining. All patients with G2 and G3 tumours had loco-regional lymph node

metastases. Two patients had liver metastases (0.9%); ANEN diagnosis was made in both at the time

of explorative laparoscopy for assessment of multifocal liver metastases. The tumour stage was

T2N0M1 in one case and in the other T3N1M1; one patient (stage T2) had a G1 tumour (Ki67 2%)

and the other a G2 (Ki67 8% in the primary tumour and 12% in the lymph nodes and liver metastases,

respectively). In the former, the primary tumour was 8mm in diameter but displayed invasion of both

the muscularis propria and mesoappendix.

Of 193 patients undergoing index appendectomy, 49 (25.4%) underwent subsequent oncologic RH on

the basis of histopathological analysis. In this sub-group, 5 (10.2%) had T1 lesions, 24 (49%) had T2,

16 (32.7%) had T3 and 4 (8.2%) had T4 tumours (according to ENETS criteria [8]). All of the 29

patients with T1 or T2 lesion fulfilled at least one ENETS criterion for RH (Table 2). Lymph node

metastases were present in 12 patients (24.5%), 7 of whom had T1/2 primary tumours. For these 7

patients, the indications for right hemicolectomy were either location at the base of appendix and

inomplete margins (n=4) or angioinvasion (n=3). Thirty-day morbidity and mortality following RH

were 2% and 0%, respectively (all morbidity was Clavien-Dindo grade 1) [16]. Pathological

radiotracer uptake on Tektrotyd ® or 68Ga-DOTATATE PET/CT at any stage of the patient journey

was only observed in the 2 patients with liver metastases. In the patient with a T3 tumour and liver

metastases, hepatic and appendiceal pathologic tracer uptake was seen (Figure 1). Serum

chromogranin A and B were within normal ranges prior to RH in all patients except in the patient with

liver metastases.

After a median follow-up of 38.5 months (range 1-192), no patient that had ANEN as the only

malignancy (n=211) and underwent simple appendectomy as the only procedure, appendectomy in the

context of other abdominal surgery or completion RH developed recurrent disease. Of those

undergoing simple appendectomy, 23 (11.9%) were lost to follow-up; patients were either no longer

registered with their initial GP, not possible to contact, or had moved back to their native country.

There were 5 patient deaths in the entire study cohort. Two patients died at 13 and 31 months post-

surgery, respectively – both underwent RH as an index operation for a known ileal neuroendocrine

neoplasm and incidentally detected ANEN. Another patient was synchronously diagnosed with

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 9   colorectal carcinoma and died 20 months after diagnosis due to colonic cancer progression. A 64-year

old patient with liver metastases of a G2 ANEN had severe carcinoid syndrome and died 9 months

after initial diagnosis despite challenging multimodal treatment with surgery, somatostatin analogues

and chemotherapy. This patient was highly symptomatic with diarrhoea and dehydration. In addition,

he developed adrenal insufficiency (normal adrenal glands on imaging) and required corticosteroid

supplementation. The other ANEN patient with distant metastases aged 58 years survived 23 months

after explorative laparoscopy including appendectomy and underwent treatment with somatostatin

analogues and Lutetium 177 peptide receptor radionuclide therapy.

Otherwise, there were no ANEN-specific deaths either in the appendectomy-only group, or in the sub-

set undergoing RH after initial appendectomy. Five year and 10-year overall survival for all patients

with ANEN as the only malignancy (n=211) were both 99.05%, respectively. Recurrence-free survival

at 5- and 10-years was 100%.

Retrospectively applying current guidelines throughout the study period would have resulted in 15

additional patients in whom completion oncologic RH would be indicated, but was not performed. Of

these, 1 had a T1 tumour, 2 had T2 tumours, 9 had T3 tumours and 3 had T4 tumours with no evidence

of lymph node metastases on imaging. All 3 patients with T1 or T2 tumours fulfilled at least one

ENETS criterion for RH (Table 2). Reasons for not undergoing further resection comprised patient

choice (reluctance to have a second, more invasive procedure which may be overtreatment),

significant co-morbidities conferring unacceptable surgical risk, or lack of consensus within the

multidisciplinary team regarding the benefits of RH. None of these patients developed imaging-

detectable loco-regional or distant disease recurrence, or died during a median follow-up of 31months

(range 14-138). Figure 2 summarises the treatments and outcomes of the cohort.

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 10   Discussion

Although ANEN are mostly considered as indolent tumours that can be treated with simple

appendectomy, a number may still develop metastatic disease to regional lymph nodes and rarely to

the liver and abdominal cavity [12]. The presence of a number of histopathological features has been

thought to identify patients at risk and RH has been proposed as their further surgical approach (Table

4). However, the additional value of RH has been evaluated in only a small number of studies with

cohort sizes not exceeding 30, demonstrating that approximately 30-40% may have residual disease

[11,13,17]. Our review of more than 200 appendectomies performed for ANEN is the largest reported

non registry-based analysis of a surgical cohort. We found that when recently suggested criteria for the

treatment of ANEN are employed: 1) simple appendectomy is a curative measure in approximately

90% of patients with G1 tumours; 2) of patients selected for subsequent RH, approximately a quarter

will be found to have lymph node metastases at re-operation; 3) liver metastases are present in less

than 1% of patients (2 out of 211 who had only ANEN), and; 4) disease recurrence does not seem to

occur despite presence of lymph node metastases at index appendectomy and/or completion RH.

Furthermore, we have demonstrated the limitations of currently available imaging and biochemical

technology for the presently recommended follow-up for patients with ANEN.

The predictive value of tumour size has been reported in numerous studies and is considered in the

ENETS and NANETS guidelines as a reliable guide for surgical management of ANEN [8,18-21].

Additionally, the presence of small vessel invasion (SVI) has been identified to be a significant arbiter

of dissemination. In the largest single-centre series of ANEN reported in the past 2 decades (n=79),

Kleiman et al. demonstrated that tumours smaller than 2cm in size but with SVI had the same

metastatic potential as tumours 2cm or larger [22].

The seminal papers by Moertel [23,24] comprised 150 patients with ANEN followed for 25 years.

None of the patients with 2cm tumours managed initially with appendectomy developed local and nodal

recurrence 29 years later, underwent RH and remained disease free for a further 17 years. The

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 11   remainder of patients with >2cm tumours remained disease free. Only 2 patients from a group of 7

with tumours >2cm managed with RH had micrometastases in the regional lymph node basin, but

remained disease free within a median follow-up period of 11years.

More recent studies have implied a favourable tumour biology and questioned the relevance of

positive nodal status. In the analysis of Mullen et al. 10-year survival for patients with lymph node

metastases from any size primary tumour were above 90% [5]. In the study of Kleiman et al. [22]

which advocated RH for tumours 2cm [25]. In the

analysis of 114 cases of paediatric ANEN by de Lambert et al. 10 had tumours larger than 2cm and 20

had extension into the mesoappendix, including 5 with lympho/vascular invasion [26]. Ten of twenty-

nine cases with indications for hemicolectomy underwent further resection, however no specimens

demonstrated evidence of residual disease. The authors concluded that appendectomy is alone

curative, with any further resection or follow-up unnecessary. From all these studies, there appears to

be a discrepancy between residual disease and overall outcome – although patients with residual

disease and thus at risk for recurrence are identified, it appears to exert no major effect on overall

survival.

The ENETS and NANETS consensus guidelines recognise the difficulty associated with intermediate

sized lesions (T2, 1-2cm) insofar as lymph node or distant metastases can possibly develop although

they are not common [8]. Therefore, in the event of other high-risk features such as tumour location at

the base of the appendix, mesoappendiceal invasion, or a positive resection margin, a right

hemicolectomy is recommended by both NANETS and ENETS guidance. Grozinsky-Glasberg et al.

evaluated the ENETS recommendations with their series of 28 patients in whom RH was performed

for ANEN, showing that in 18% of them residual disease would be missed if they were operated on

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 12   according to ENETS criteria [11]. However, there is no data regarding the long term effect of residual

disease on either recurrence-free or overall survival rates.

Our results suggest that current guidelines are effective in identifying ANEN patients at risk of

harbouring nodal disease, but bring into question if lymph node metastases of ANEN have the same

oncologic relevance as those of other intestinal NEN. Lymph node metastases were identified in 7/29

patients (24.1%) with tumours between 1 and 2cm in size who underwent a subsequent RH, apparently

supporting consideration of oncologic resection in selected patients with such intermediate sized

lesions. With the caveat of the limited sensitivity of currently utilised follow-up measures, no patients

demonstrated disease recurrence, even those patients who were managed with an appendectomy who

under the (later introduced) ENETS guidelines would have been selected for hemicolectomy.

In our patient set, all patients undergoing RH for non-distantly metastatic ANEN as the only

malignancy were alive and disease-free at last follow-up; indeed the only deaths post-RH occurred in

patients with second primary malignancies and concomitantly discovered ANEN, or synchronous liver

metastases. These data are in line with those of Steffen et al. who demonstrated in their cohort of 79

patients that such second primary tumours exert a significant detriment to long-term survival, but they

could not demonstrate a statistically significant influence of extended operations for ANEN on

prognosis [27]. The fact that 14.9% of our patients with ANEN as the only malignancy had tumours

invading the serosa but no peritoneal deposits as often seen in colorectal cancer in this stage of disease

further underlines the unique biological behaviour of ANEN. We are aware that a relatively short

follow-up of the patients in this study might limit our conclusions driven from the results.

In our cohort, somatostatin receptor based imaging and standard tumour markers for NEN were not

useful in patient management, most probably due to the fact that the volume of loco-regional disease

was very low and below the sensitivity thresholds for these methods. It is questionable whether these

modalities can be used with high predictive value in at-risk patients, as they were negative even when

employed in patients who were later found to have residual disease. We speculate that in the future,

measurement of circulating tumour transcripts or other “omics” based novel biomarkers may be

helpful to identify neuroendocrine tumour disease in this setting [28]. Although we studied the roles of

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 13   biochemical and radiological follow-up in our cohort, the optimal follow-up strategy remains elusive

in this tumour type.

The surgical management of ANEN remains controversial, particularly for intermediate-sized

tumours. Given the predicaments pertaining to predicting the behaviour of ANEN as aforementioned,

it is likely that for some patients a right hemicolectomy represents over-treatment. Probable too is that

in some patients undergoing simple appendectomy, undetected lymph node metastases remain in situ,

or may develop later but remain clinically silent. Such phenomena question the impact of lymph node

metastases on the outcome of patients with this challenging disease. Another “dark area” is the true

incidence of distant metastases in ANEN since the quality of data available in the literature do not

provide enough evidence for any robust conclusion. In our cohort only 2 patients had liver metastases.

Of note, in both cases there were synchronous bilobar metastases and both patients died due to disease

progression within two years after diagnosis despite multimodal treatment. We are aware that this is an

unexpectedly low survival for patients with G1/G2 neuroendocrine liver metastases offered

multimodal treatment. One of these patients had carcinoid syndrome, which is exceptionally rare in

ANEN and limited to scarce case reports. Accurate classification and staging of these tumours is

pivotal for treatment decisions, however the optimal management algorithm is yet to be elucidated,

and as aforementioned the role of formal follow-up for ANEN is unclear [8].

Further research into the biology of ANEN and novel information beyond standard staging/grading

data is required, together with large scale international collaboration to identify factors predicting

metastatic spread and survival benefit of further resection. Elevated tumour tissue expression of

NAP1LI, MAGE-D2 and MTA1 has been reported in “malignant appendiceal carcinoids” and GCC

(i.e. with local invasion, nodal metastases or liver metastases) compared to “non-invasive carcinoids”

incidentally identified at surgery for acute appendicitis, suggestive of differential molecular signatures

for aggressive and indolent ANEN [29].

Ideally, the contention surrounding surgical approach would be addressed by a randomised clinical

trial comparing survival and recurrence outcomes in patients treated with appendectomy only and

additional oncologic resection. However, due to the protracted follow-up period required as well as the

relatively rarity of the disease, such a trial would in all likelihood be unrealistic. Presently,

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 14   consideration of current guidelines for surgical management of ANEN patients and a detailed

counselling should be the “gold standard”, bearing in mind that a number of patients may be over

treated. A long-term follow-up of the cohort presented in this study – if technically possible – may

contribute to the understanding of the risk of recurrence in ANEN.

Overall, the management of ANEN represents a conflicting clinical situation: the risk of disease

recurrence in the long-term may be low, but the impact of such a recurrence may be significant and

must be balanced against the risks of surgical morbidity/mortality. Our data offer a platform to

reconceive present surgical management and follow-up of ANEN patients and have the potential to

stimulate revision of guidelines.

Acknowledgements

Funding: No specific funding for the purposes of this manuscript. AF is supported by Dr Heinz-Horst

Deichmann Stiftung. AM is supported by ENETS Fellowship. AM and AF are supported by Cancer

Research UK. AF and PD are supported by European Union, FP7-MC-IEF funding scheme.

The results of this study were presented in part at Digestive Disease Week 2016, May 21-24, San

Diego.

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 15   References

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 18   

Figure 1. Findings on CT and Tektrotyd ® whole body WB-SPECT/CT in a 64 year old male patient

with liver metastases from an appediceal neuroendocrine tumour (G2 ANEN, Ki67 = 8%). (A):

increased radiotracer uptake corresponding to a 23mm appendiceal tumour is evident (arrow). (B):

computed tomography showing no clear abnormality in the same region. (C and D): foci of increased

radiotracer uptake corresponding to hepatic metastases (arrows). The uptake in the spleen is within

physiological range.

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 19   

Figure 2. Outcomes for patients eligible for completion right hemicolectomy in our study cohort.

ANEN = appendiceal neuroendocrine neoplasm, LN= lymph nodes, RH = right hemicolectomy,

ENETS = European Neuroendocrine Tumor Society.

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 20    Table 1. TNM staging system for appendiceal neuroendocrine neoplasms, as proposed by the European Neuroendocrine Tumor Society

TNM stage component Criteria

T- primary tumour X Primary tumour not assessed/assessable0 No evidence of primary tumour1 Tumour ≤1 cm with infiltration of submucosa and muscularis

propria2 Tumour ≤2 cm with infiltration of the submucosa, muscularis

propria and/or minimal infiltration (≤3 mm) of the subserosa and/or mesoappendix

3 Tumour >2 cm and/or extensive infiltration (>3 mm) of the subserosa and/or mesoappendix

4 Tumour with infiltration of the peritoneum and/or other neighbouring organs

N- regional lymph node metastases Nx Regional lymph nodes not assessed/assessableN0 No evidence of regional lymph node metastasesN1 Evidence of locoregional lymph node metastases

M – distant metastases Mx Distant metastases not assessed/assessableM0 No evidence of distant metastasesM1 Evidence of distant metastases

Adapted from reference [8].

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 21    Table 2. Summary of guidelines and cohort-based recommendations for treating appendiceal neuroendocrine neoplasms

Tumour size

Moertel et al., [24], 1987

Goede et al., [30], 2003

Alexandraki et al., [17], 2010

Bamboat and Berger, [13], 2006

Mullen et al., [5], 2011

ENETS consensus guidelines [8], 2012

NANETS guidelines3

3 mm

Simple appendectomy, unless: invasion of base of appendix, indeterminable tumour size, lymphovascular or mesoappendix invasion, intermediate/high-grade tumours

1–2 cm Simple appendectomy

Simple appendectomy RH for: tumours at base with positive margin, mesoappendix involvement, high proliferative rate Relative indications for RH: Angioinvasion, mucin producing tumours

Simple appendectomy + regular follow-up for 5 years RH if: tumours at base of appendix, infiltration of caecum, positive resection margin, mesoappendix involvement, presence of undifferentiated/ poorly differentiated cells

Simple appendectomy

RH if: young patient, mesoappendix involvement

RH if: positive/unclear margins, deep mesoappendix invasion, Ki67 ≥3%, angioinvasion

RH if:invasion of base of appendix, indeterminable tumour size, lymphovascular or mesoappendix invasion, intermediate/high-grade tumours

>2 cm Simple appendectomy: elderly/high risk patients RH: young patients

RH RH Simple appendectomy RH: young patients

RH RH RH

RH, right hemicolectomy.

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 22   

  Table 3. Clinicopathological characteristics of patients diagnosed with appendiceal neuroendocrine

neoplasms in the study cohort (n=215). ENETS = European Neuroendocrine Tumor Society. *at initial

diagnosis, **available for 210 patients.

Parameter Number (%) Total number of patients 215 Mean age 33.2 years (range 9-79) Gender Male Female

85 (39.5) 130 (60.5)

Index operation performed Simple appendectomy Right hemicolectomy Sub-total colectomy Panproctocolectomy Other

193 (89.8) 16 (7.4) 1 (0.5) 2 (0.9) 3 (1.4)

Tumour size 2cm

95 (44.2) 69 (32.1) 51 (23.7)

Depth of invasion Serosal Periappendicular fat Vascular invasion Involved margin

32 (14.9) 17 (7.9) 14 (6.5) 25 (11.6)

ENETS stage* I (T1N0M0) IIa (T2N0M0) IIb (T3N0M0) IIIa (T4N0M0) IIIb (T1-4N1M0) IV (T1-4N0-1M1)

96 (44.7) 52 (24.2) 38 (17.7) 10 (4.7) 17 (7.9) 2 (0.9)

ENETS tumour grade** G1 G2 G3

200 (93) 9 (4.2) 1 (0.5)

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  Neuroendocrinology (DOI:10.1159/000478742)  © 2017 S. Karger AG, Basel 23    

Table 4. Pathological factors capable of influencing surgical strategy in appendiceal neuroendocrine

tumours in reported literature and current guidelines. RH = oncological right hemicolectomy,

“consider” = limited reports across literature, “recommended” = some consensus across literature,

“indicated” = effectively uniform consensus across literature.

       Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships) Journal Editor: Millar R.P. (Edinburgh) ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online) www.karger.com/NEN Disclaimer: Accepted, unedited article not yet assigned to an issue. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center. © 2017 S. Karger AG, Basel  

  

Size Mesoappendix invasion

Ki67 index Angioinvasion Location at base of appendix

< 1 cm If >3mm, consider RH

If ≥3%, consider RH

Consider RH Consider RH

1-2 cm RH recommended If ≥3%, RH recommended

Consider RH RH recommended

> 2cm RH indicated RH indicated RH indicated RH indicated

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