Neuroendocrine Tumors (NETs) of the Colon: Serial Case Reports

Warsinggih, Liliyanto, Kusuma M. Ihwan

Department of Digestive Surgery Faculty of Medicine, Universitas Hasanuddin,
Wahidin Sudirohusodo Hospital, Makassar

Abstract
Neuroendocrine tumors (NETs) which previously called carcinoid tumors are neoplasms
of enterochromaffin/neuroendocrine cell origin which display neurosecretory capacity that may
result in the carcinoid syndrome. An analysis of the Surveillance, Epidemiology and End Results
(SEER) database estimated that the incidence of neuroendocrine tumors in the United States was
6.98 cases per 100,000 people in the year 2004; yet many NETs remain asymptomatic and
clinically undetected. A majority of NETs follows a benign course; however some will display
malignant characteristics. NETs most commonly occur in the gastrointestinal tract (67.5%) and
bronchopulmonary system (25.3%). Gastrointestinal NETs occur within the stomach, small
intestine, liver, colon and rectum. We report a retrospective study of 2 subjects: neuroendocrine
tumors (NETs) at descending colon and sigmoid colon. The diagnosis, imaging, biochemical
testing, surveillance, treatment and review of the literature are presented.

Keywords: neuroendocrine, carcinoid, gastrointestinal, tumors

INTRODUCTION

Neuroendocrine tumors (NETs) are a group of very rare and heterogenic. NETs are
characterized histologically with endocrine tissue intracellular marker, like chromogranin A,
synaptophysin, and neuron specific enolase (NSE), which can be used to diagnose these tumors.
These tumors can occurred everywhere in body, but the most common site is in gastrointestinal
tract which commonly called carcinoid tumor. The term “carcinoid” (karzinoide) had been
introduced since 1907 by Oberndorfer as an identification for a group of ileum tumors, which are
originated from enterochromaffin (EC) which produced serotonin, these kind of tumors are

1
associated with a better prognosis than that of adenocarcinoma. 1 The most common use tumor
markers are general marker neuroendocrine (NE) (for all kind of NE cell),protein gene 9.5 or
granulation marker like chromogranin A (CgA), and synaptophysin. NET cells which need
immunohistochemistry hormone are NETs that can cause hyperfunctional syndrome (functional
NETs).2 NETs which show immunopositivity for endocrine marker and or serum marker but
without clinical symptom are called non functioning NETs. 2-6 Nowadays, the World Health
Organization (WHO) has issued a classification for NETs. The classification is well
differentiated endocrine tumors (low grade / G1, intermediate grade / G2, high grade / G3) and
poorly differentiated (high grade / G3).
The incidence of NETs are 2 cases per 100.000 population and estimated 0.5% from all
malignancies. Even NETs are found most commonly in gastrointestinal tract, carcinoid tumor
and other NETS are only estimated 1.5% and 0.3% of all gastrointestinal malignancies in USA.
Neuroendocrine tumors are rarely found in children and often occur in patients over 50 years of
old. The incidence is twice as much in men compared to women. 7-9 The incidence of NETs has
increased, probably because of better diagnosis and the availability of very specific and sensitive
modalities, like endoscopy, computed tomography (CT scan), magnetic resonance imaging
(MRI), ultrasonography (USG), and scintigraphy.
In 2005, epidemiological studies of these tumors were conducted in Japan and the
incidence of Pancreatic endocrine tumors (PETs) was around 1.01 per 100,000 and the incidence
of gastrointestinal neuroendocrine tumors (GI-NETs) was 2.01 per 100,000.10 In Indonesia,
accurate data regarding this tumor have not been obtained. In this article, we want to report 2
cases of NETs found in Wahidin Sudirohusodo Hospital in 2018.

CASE REPORT
This case series describe a wide spectrum of benign gastrointestinal NET originating in the
descending colon andsigmoid.

Patient 1
A 66-year-old male came with a history of laparotomy surgery at Barru Hospital,
Makassar. Before the surgery, the patient had history of abdominal distension for 3 days and

2
diarrhea for 2 weeks. The patient was diagnosed with peritonitis in Barru Hospital. On August
13th 2018, sigmoidectomy (Hartmann’s procedure) and primary closure of perforated caecum had
been performed in Barru Hospital, Makassar. The post-surgical diagnosis was peritonitis caused
by perforated caecum and distal sigmoid colon tumor. The histopathology results on August 29 th
2018 showed neuroendocrine carcinoma with a near incision edge still containing tumors and
was positive on 2 colon lymph nodes and was compared with Alveolar Rhabdomyosarcoma. The
patient came to RSUP Dr. Wahidin Sudirohusodo on November 12 th 2018, reevaluation had been
done with the results of examination: abdominal ultrasound showed no sign of metastasis were
seen, other intra-abdominal organs within normal limits. On thoracic x-ray examination showed
that there was no sign of metastasis in the chest radiograph with dilatation of aorta. Lopography:
Lopography result was within normal limits, the distance of the rectosigmoid colon with distal
colon descending 9.5 cm. Laboratory tests were obtained: Hb: 12.3 g/dl, leukocytes: 16,010/ul,
platelets: 493,000/ul, Ureum: 27 mg/dl, Creatinin: 0.90 mg/dl, SGOT: 23 U/L, SGPT: 19 U/L,
albumin, 3.2 gr/dl, CEA: 43.15 ng/m, HBsAg: Non reactive, Electrolyte: Na : 143 mmol/L, K:
3.0 mmol/L, Cl: 106 mmol/L. We planned to close the stoma.

Figure 1. The first patient: The lopography result of the first patient is within
normal limit

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 Figure 2. The first patient: Abdominal ultrasound shows no sign of metastases in liver

Patient 2
A 45-year-old woman came to the emergency room at RSUP Dr. Wahidin Sudirohusodo
with complaints of abdominal distentionand unable to defecate since 7 days before entering the
hospital on March 29th 2018. A 3-position abdominal X-ray was performed and showed large
bowel obstruction. Then, left hemicolectomy has been performed with end to end anastomosis.
On March 23rd 2018, prior to surgery, an abdominal CT scan with contrast had been performed
and showed descending colon tumors. Then, the histopathology examination of colon descending
tissue showed malignant tumor which suggesting neuroendocrine carcinoma / carcinino tumor.
Differential diagnosis of poorly differentiated adenocarcinoma or lymphoma had been made.
From May 8th 2018 until August 30th 2018, the patient underwent five cycles of chemotherapy
with 5 FU 700 mg, Cisplatin 98 mg, and Sandostatin LAR 20 mg which was given by the
internist. On November 8th 2018, Chest X-Ray showed the impression of heart and lung were
th
within normal limits, no metastasis was seen on the chest radiograph. On November 13 2018,
colon in loop showed stenotic impression in the lower descending colon and colitis in the
descending colon. On November 13rd 2018, plain abdominal X-ray was also performed with the
impression that there were no radiological abnormalities in this abdomen. On 15 th November
2018, whole abdominal MSCT was performed with the impression of minimal ascites, gall
stones, hepatomegaly accompanied with right hepatic lobe lesions, suggestive of metastatic
tumors, and circular thickening of descending colon suspected of descending colon tumors.

4
Figure no 3. The second patient: Preoperative MSCT-Scan with contrast shows descending
colon tumor

Figure no 4. The second patient: Surveillance MSCT-Scan with contrast shows hepatomegaly
accompanied with right hepatic lobe lesion

DISCUSSION

The incidence of NETs has increased about 40 to 50 cases per million population per
year, probably because of better diagnosis and the availability of very specific and sensitive ways
to measure these tumor products, "immunohistochemistry", and improvement of diagnostic
techniques for tumor detection. Thus, the perceived increase in incidents may not be a real
change in the incidence of this disease.
An analysis of the Surveillance, Epidemiology and End Results (SEER) database
estimated that the incidence of neuroendocrine tumors in the United States was 6.98 cases per
100,000 people in the year 2004.11,12 This analysis suggested that the incidence of neuroendocrine
tumors is increasing, and that the prevalence of individuals with neuroendocrine tumors in the
United States may exceed 170,000.1,2 Other independent analyses of the SEER data base also
found that the incidence of GI neuroendocrine tumors increased from 1975 to 2008. 3,4 The reasons
for this increase are unclear, although it seems likely that improved diagnosis and
classification is one factor.

5
 In Indonesia, accurate data regarding this tumor has not been obtained. In RSUD dr.
Soetomo, Surabaya for a period of 2 years (2008-2010) obtained 5 cases. Whereas in Dr. RSUP
Wahidin Sudirohusodo during 2018 there were 2 cases. In most neuroendocrine tumors, the
symptoms that appear are only a consequence of the growth of the tumor itself. With more than
100,000 cases, NETs have a higher prevalence rate than gastric and pancreatic cancer.
Most of the NETs occur in the gastrointestinal tract (67.5%) and in the respiratory tract
(25.3%).13 The most common location of NETs in the GI tract among patients in the United
States is the small intestine (38%), followed by the rectum (34%), colon (16%), stomach (11%),
and unknown sites (1%), according to analysis of the Surveillance.14
The diversity of tumor subtypes is reflected in the complicated and often confusing
nomenclature for their classification, for example, adenocarcinoid, goblet cell, crypt cell,
mucous, and mixed carcinoid-adenocarcinoma. Each subtype of tumor appears to have different
biological and clinical behavior. For example, pure carcinoid tumors tend to be slow growing
and have a relatively indolent course, whereas adenocarcinoid tumors are very aggressive and
fast growing.15Neuroendocrine tumors (NETs) arise from the neuroendocrine or amine precursor
uptake and decarboxylation (APUD) cells that are scattered through out the mucosa of the
gastrointestinal tract.16
NETs can be further divided into either functional (secretory) or nonfunctional
(nonsecretory) groups depending upon whether a hormonal-related recognizable clinical
syndrome is present. Functional NETs include those that over-secrete amines and/or peptides
such as well-differentiated and intermediate-grade tumors. Functioning NETs are characterized
by the hormones they produce and/or the symptoms they cause; clinical symptoms are typically
observed following metastasis to the liver.17 Different from functional NETs, nonfunctional GI-
NETs are not associated with a distinct hormonal syndrome so are more difficult to detect than
functioning GI-NETs; due to this, patients generally present late with large primary tumors and
advanced disease. However non-functioning GI-NETs may secrete bioactive amines at
subclinical levels, or secrete compounds that lead to other, still under-recognized hormonal
syndromes.17
Many NETs of non-pancreatic origin release vasoactive peptides and amines, such as
serotonin and tachykinins, into the systemic circulation and cause a characteristic set of
symptoms called ‘carcinoid syndrome’. The term carcinoid is also used in this review because of

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its common usage in the literature to describe GI-NETs, and we primarily deal with the well-
differentiated, serotonin-producing NETs to which this term refers.17
The incidence of GI-NETs is twice as much in men compared to women. 14,15
Neuroendocrine tumors are rarely found in children and often occur in patients over 50 years of
old.18 A retrospective study which was conducted by Kojima et al from 760 cases of GI-NETs
showed in total, 60.7% patients were men and 39.3% were women, with a mean age of
58.7 years.19 In our cases, we couldn’t compare our cases according to gender because we had
only two patients (one male and one female patient)with GI-NETs. Our patients are 66 years old
and 45 years old respectively, these findings were consistent with the literature which stated that
GI-NETs are most common in people over or near to 50 years old.
There are many types of NETs and these tumors can be found everywhere in the body.
Most of the NETs are found in the gastrointestinal tract and this age group is known as
gastroenteropancreatic neuroendocrine tumors (GI-NETs), which include carcinoid tumors and
pancreatic neuroendocrine tumors (pNET).
The majority of NETs are asymptomatic at the time of discovery. In most patients with
these tumors, the discovery is made incidentally at the time of surgery orother diagnostic
evaluations.20-24 In one series, carcinoid tumors were found in 1.22% of 16,294 autopsies in
Malmo, Sweden, and 90% were incidental findings.25
NETs can be cancerous or benign. If NETs are malignant, the tumor will have the
potential to metastasize, although the tumor itself grows very slowly. Symptoms that do occur
tend to be vague and nonspecific, and more often these symptoms are related to the mass effects
of the tumor. These can include vague abdominal pain, abdominal distention, weight loss,
bleeding, obstruction, and constipation, although the majority of the patients have no symptoms.
Non-functional tumors can cause symptoms such as abdominal pain (68-78%), weight loss (32-
50%), jaundice due to biliary obstruction or metastasis (21-50%) or 36% vomiting.2
About 10% of patients with NETs will cause carcinoid syndrome caused by the
overproduction of serotonin or other hormones secreted by some NETs, often presenting after
cancer spreading to other body parts. Common symptoms are gut hypermotility (diarrhea), hot
red flushing from the face, palpitation, and asthma attacks. These symptoms occur in less than
10% of all patients, as the syndrome requires the presence of hepatic metastases.2

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 Data shows that nearly 22% of functional non-carcinoid NETs are found with distant
metastasis when diagnosed is established, whereas carcinoid tumors that appear are accompanied
with metastatic process approximately 19%. If distant metastasis is found when NETs is
diagnosed for the first time, the 5-year life expectancy is estimated to be around 27% in patients
with NETs which accompanied with liver metastasis when the diagnosis is made.2
Clinical presentation of colonic NETs includes change in bowel habits, gastrointestinal
bleeding, abdominal pain, weight loss, and asymptomatic lesions found during screening
colonoscopy is generally indistinguishable from other mass lesions of the colon. When present in
rectum, symptoms may include change in bowel habits, gastrointestinal bleeding, anorectal
discomfort, and pruritus ani. There may be nonspecific local effects of the tumor. For example,
fibrosis from carcinoid tumors may cause obstruction from adhesions or stricture of the
intestinal lumen,26 hydronephrosis and subsequent renal failure, or even mesenteric ischemia
from constriction of the mesenteric vessels.27 The pathogenesis of this fibrosis is poorly
understood.
In our cases, the first patient, a 66-year-old man were presented with a history of
sigmoidectomy and primary closure of perforated caecum. The patient had history of no specific
abdominal symptom, like abdominal distention for 3 days and diarrhea for 2 weeks. The tumor
was found in sigmoid colon at the time of surgery and was confirmed by histopathology study as
neuroendocrine tumor. The history of this patient is consistent with the literature that in some
patients with NETs can experience abdominal distention and change in bowel habit.
Different from the first patient, our second patient, a 45-year-old woman was presented
with abdominal distention and unable to defecate for 7 days. This patient experienced obstructive
symptom of NETs. In this case, liver metastasis of descending colon tumors were also found
approximately 8 months after left hemicolectomy.
Patients with suspected NETs should undergo biochemical evaluation. In the past, several
plasma, serum and urine markers have been evaluated as predictors of tumor progression in
NETs, such as chromogranin A (CgA), serotonin , 5-hydroxyindoleacetic acid (5-HIAA) ,
neurokinin A, neuropeptide K , neuron-specific enolase (NSE), or E-cadherin. Currently, CgA
and 5-HIAA widely used in the clinical routine for diagnosis and follow-up of patients with
NETs. 

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 In the literature it is said that there are various tumor markers including neuron-specific
enolase (NSE) and chromogranin A (CgA) which have been evaluated as a tool to detect NETs
and as an indicator of tumor development and response to therapy. Neuron-specific enolase has
varying sensitivity (43-100%) and low specificity (65%) as a serum marker for NETs.
Chromogranin A is a secreted protein that may be elevated in patients
with neuroendocrine tumors; elevated levels have been associated with
poorer prognosis. Chromogranin A is sometimes used as abiochemical marker in non-
functioning tumors. Whereasone meta-analysis calculated the sensitivity and specificity of
chromogranin A to be 73% and 95%, respectively, for diagnosis of neuroendocrine tumors,
others have questioned its value.Increased circulating CGA levels are found in about 60-80% in
NETs both functional and non-functional, even in non-neoplastic cases, such as renal
insufficiency, hepatic impairment, chronic atrophic gastritis, therapy with proton pump inhibitors
can give false positive results, so in general should not be relied upon in isolation as a diagnostic
test.2,4
The most commonly employed marker in patients suspected of having a carcinoid
tumoris the urinary 5-hydroxyindole acetic acid (5-HIAA). Serotonin is a neurotransmitter that is
produced mainly in the brain, also in the bronchi and gastrointestinal tract. After use, serotonin is
degraded in the liver and its metabolite 5-HIAA is excreted through urine.
Usually 5-HIAA is only present in small amounts in the urine, but can be increased in
carcinoid syndrome.The 5-HIAA sensitivity was obtained at 100% with a specificity of 88%. 28
However, 5-HIAA assays have the benefit of being widely available. 5-HIAA, a metabolite of
serotonin, in a 24-hour urine or plasma sample may also be considered as a biochemical marker
in some cases, particularly in patients with metastatic small-intestinal neuroendocrine tumors.
During monitoring of patients after treatment of a neuroendocrine tumor, decreasing levels of 5-
HIAA indicate a response to treatment, whereas increasing or excessive concentration indicates
that the treatment has not been successful. However, a patient with symptoms may still have a
neuroendocrine tumor even if the concentration of 5-HIAA is normal. Diet and a variety of drugs
can affect the 5-HIAA test. Therefore, patients should be advised not to eat avocados, bananas,
cantaloupe, eggplant, pineapples, plums, tomatoes, hickory nuts/pecans, plantains, kiwi, dates,
grapefruit, honeydew, or walnuts for 48 hours before the start of and during urine collection. 29

9
Medications that can increase 5-HIAA include acetaminophen, ephedrine, diazepam, nicotine,
glycerylguaiacolate (an ingredient found in some cough medicines), and phenobarbital.
In our cases, two of our patients didn’t undergo any biochemical screening, such as
chromogranin A (CgA), serotonin, 5-hydroxyindoleacetic acid (5-HIAA), neurokinin A,
neuropeptide K , neuron-specific enolase (NSE), or E-cadherin.
Imaging has an important role in localizing the primary tumor, identifying the location of
metastases and assessing the response to treatment. In this case series the initial imaging was
carried out to determine tumor reaction and assess the resectability of the tumor. Starting from an
ultrasound examination, CT scan and MRI. For carcinoid and pancreatic tumors CT and MRI are
very good in determining the extent of metastasis and assessing response to treatment. Both
techniques seem to have the same sensitivity to detect these tumors, ranging from 30% to 94%.
Endoscopy Ultrasound has an important role in the preoperative assessment of the pancreas
where there is a possibility of a small functioning tumor or the suspicion of multiple tumors. This
technique is very successful in the hands of experts with a sensitivity of 79-100%.29
Functional imaging modalities such as somatostatin receptor scintigraphy (SRS,
Octreoscan), have a large impact on patient management by providing a tool for better tumor
staging, visualization of occult tumors and feasibility evaluation for somatostatin analogues
(SSA). Even in NETs which commonly express somatostatin receptors and by radiolabelled
SSA, tumors can be sought by scintigraphy. SRS is a very special examination with sensitivity
for tumors greater than 1 cm of approximately 80-90% (with the exception of insulinomas that
excrete somatostatin receptors in only 50% of cases). SRS also detects distant metastasis with
sensitivity that can reach 96%.2,4
NETs can be classified according to several ways, based on histology, tumor existence,
and place of origin.29,30 In the description of histopathology examination results, some important
information is needed, including: anatomical site of the tumor, diagnosis, grade, mitotic rate, size
of tumor, presence of multicentric disease, presence of vascular invasion, presence of perineural
invasion, presence of other pathological components, lymph node metastasis to include the total
number of positive nodes and total number of nodes examined, margin status (positive or
negative), and TNM stage according to the TNM AJCC system. 30 Several numbers of optional
information that can be useful are immunohistochemical staining for general neuroendocrine
markers, presence of non ischemic tumor necrosis, presence of unusual histologic features (eg,

10
oncocytic, clear cell,gland forming), exact distance of tumor to margin(s) if less than 0.5 cm,
background pathology of organ (ie, PanIN, ECL cell hyperplasia).30
NETs classification is based on the existence of the tumor, namely local disease (an
isolated focus of primary NETs of the small intestine), regional disease (primary NETs in the
small intestine with mesenteric spread), distant disease (primary NETs in the small intestine with
mesenteric spread and liver metastasis).29,30
NETs classification is based on its place of origin, namely pancreatic NETs (gastrinoma,
insulinoma, VIPoma, somatostatinoma and pancreatic polypetidoma) and other NETs (foregut:
lungs, stomach, and first duodenum pars), midgut (second pars duodenum, jejunum, ileum, and
ascending colon) and hindgut (transverse colon, descending colon, sigmoid colon and
rectum).15,16,29
The World Health Organization (WHO) has issued a classification based on
histopathology and biological characteristics including grading of tumor cells, size and location
of primary tumors, proliferation of tumor cell markers, local and vascular invasion, and
production of active biological substances. The classification is well differentiated endocrine
tumors (low grade / G1, intermediate grade / G2, high grade / G3) and poorly differentiated (high
grade / G3).15,16,29,30
Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67
proliferation index. In fact, most commonly used histologic classification schemes, including
both the European Neuroendocrine Tumor Society and WHO systems, incorporate mitotic rate
and Ki-67 index.23-25 Numerous studies have confirmed that increased mitotic rate and high Ki-67
index are associated with a more aggressive clinical course and worse prognosis. 25-28 In most
cases for GI and pancreatic neuroendocrine tumors, well-differentiated, low-grade tumors have a
mitotic count of less than 2/10 high-power field (HPF) and/or a Ki-67 index of less than 3%.
Well-differentiated, intermediate-grade tumors usually have a mitotic count of 2 to 20/10 HPF
and/or a Ki-67 index of 3% to 20%. In high-grade tumors, the mitotic count usually exceeds
20/10 HPF and/or the Ki-67 index exceeds 20%.29-37

Table 1. WHO Classification of NETs30-33

Differentiation Grade Gastrointestinal NET
(excluding pancreas)
Low Grade (G1) <2 mitoses/10 HPF AND/OR

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 Well-differentiated <3% Ki-67 index
Intermediate Grade (G2) 2–20 mitoses/10 HPF AND/OR
3–20% Ki-67 index
High Grade (G3)
Poorly differentiated High Grade (G3) >20 mitoses/10 HPF AND/OR
>20% Ki-67 index

Grade is generally defined by mitotic count and/or Ki-67 index, whichever is higher. If
both mitotic rate and Ki-67 index are used and these are discordant, it is currently recommended
that the higher grade be used to assign classification. 38-40 A key recommendation is that tumor
differentiation, mitotic rate, and Ki-67 index should all be included in the pathology report.
Doing so allows the treating physician to factor these data into the clinical picture to make
appropriate treatment decisions.
The characteristic of NETs in our patients were described in the histopathology report
which was summarized in table 2.
Table 2. The Histopathology and Biological Characteristics of NETs in Our Cases
Histopathology examination Case 1 Case 2
Anatomical site of tumor Sigmoid colon Descending colon
Diagnosis 1. Peritonitis caused by 1. Mechanical bowel
caecum perforation obstruction
Grade - -
Mitotic rate High mitotic rate Low mitotic rate
Size of tumor 4 x 10 cm -
Presence multiform disease - -
Presence vascular invasion -
Presence of perineural - -
invasion
Lymph node metastases Two positive lymph nodes -
Margin status + -

Histopathology study of both patients in our cases didn’t include Ki-67 index in the
examination.
The American Joint Committee on Cancer (AJCC) has made staging definitions
according to T, N, M. The TNM Staging System for Neuroendocrine Tumors from Colon and
Rectum (colonal and carcinoid tumors) [well differentiated neuroendocrine tumors G1, G2 and
G3 are found in tables 3 and 4.41

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Table 3. Definitions for T,N,M41
T PRIMARY TUMOR
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor invades the lamina propria or submucosa and is ≤2 cm
T1a Tumor <1 cm in greatest dimension
T1b Tumor 1–2 cm in greatest dimension
T2 Tumor invades the muscularispropria or is >2 cm with invasion of the lamina propria or
submucosa.
T3 Tumor invades through the muscularispropria into subserosal tissue without penetration of
overlying serosa.
T4 Tumor invades the visceral peritoneum (serosa) or other organs or adjacent structures.
* Note: For any T, add “(m)” for multiple tumors [TX(#) or TX(m), where X = 1-4 and # =
number of primary tumors identified**]; for multiple tumors with different T, use the highest.
** Example: If there are two primary tumors, only one of which invades through the
muscularispropria into the subserosal tissue without penetration of the overlying serosa, we
define the primary tumor as either T3(2) or T3(m).
N REGIONAL LYMPH NODES
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M DISTANT METASTASIS
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to liver
M1b Metastases in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph node,
peritoneum, bone)
M1c Both hepatic and extrahepatic metastases

Table 4. AJCC Prognostic Group

T N M
Stage I T1 N0 M0
Stage IIA T2 N0 M0
Stage IIB T3 N0 M0
Stage T4 N0 M0
IIIA
Stage IIIB T1 N1 M0
T2 N1 M0
T3 N1 M0

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 T4 N1 M0
Stage IV Tx, T0 Any N M1
T1 Any N M1
T2 Any N M1
T3 Any N M1
T4 Any N M1

We classified the first patient in our cases as cT4N0M0 (stage IIIA) based on clinical
characteristic and pT4N1M0 (stage IIIB) according to histopathology finding. Different from the
first patient, the patient in our second case had a history of liver metastases with ascites, gall
bladder stones, and hepatomegaly which was found in surveillance eight months after initial
surgery. We classified our patient in the second case as T4N0M1 (stage IV).
If possible, radical surgery is the standard therapy for NETs. If there is locoregional or
liver metastasis, debulking surgery can be performed in patients with the possibility of the tumor
being removed almost 90%. It is recommended to perform palliative surgery in the following
clinical situations, which is in primary tumors with non-operable liver metastases (especially in
functional NETs) because symptoms correlate with neoplastic masses; if the primary tumor is
localized in the small intestine, because it can cause intestinal obstruction; and in the context of
cases of surgery which allow for subsequent multimodal treatment.2,4
Resection of the gastrointestinal neuroendocrine tumor must be followed by adequate
regional lymph node resection (including all palpable tumors and through exploration of the
associated primary tumor). Resection of gastrointestinal neuroendocrine tumors should include
adequate regional lymph node resection (including all palpable disease where feasible) and
thorough exploration of synchronous primary tumors (15%–30% incidence).
a. Resection of recurrent locoregional disease, isolated distant metastases, or a previously
unresectable tumor that has regressed should be considered for selected patients with
adequate performance status.
b. Patients with symptomatic recurrence from local effects or hormone hypersecretion can
be effectively palliated by subtotal resection of a large proportion of the tumor (typically
more than 90%); however, experienced judgment is required for management of patients
with an unresectabletumor and/or distant metastases. Planned cytoreductive, incomplete
(R2) resection of advanced disease in patients with asymptomatic or non-functional
disease is controversial.

14
c. Wide surgical resection with lymph node dissection is recommended for management of
colonic NETs as metastatic disease is common at the time of diagnosis. Local excision
may be considered for tumors < 2 cm in size; however, data regarding metastatic disease
in this setting are limited.38.39
d. Rectal NETs 1-2 cm in size may be managed with wide surgical excision if there is no
evidence of muscularis invasion or lymph node metastasis. 38 Low anterior resection or
abdominoperineal resection is recommended for tumors > 2 cm as the risk of metastatic
disease increases with tumors > 2 cm in size and with invasion of the muscularis
propria.40,41

In our first case, we performed Hartmann’s procedure and primary closure on perforated
caecum because the tumor location was in sigmoid colon, while our second patient underwent
left hemicolectomy with end to end anastomosis because of descending colon tumor.The surgical
treatment we performed was consistent with NCCN recommendation forlocoregionaldisease,that
is bowel resection with regional lymphadenectomy.
Ideally, within 3-12 months after the operation, it is necessity to do GI-NETs
surveillance, that consist of history taking and physical examination, biochemical marker
examination as clinically indicated, abdominal + pelvic multiphasic CT or MRI as clinically
indicated, chest CT with or without contrast as clinically indicated.

15
 Both of the patients in our cases underwent surveillance within less than 1 year after the
resection. The first patient underwent surveillance at three months after the resection. The
surveillance included abdominal ultrasound showed no signs of metastases, chest x-ray found no
sign metastases, and lopographic result was within normal limit with distance between proximal
and distal colon was 9.5 cm. Our second patient underwent surveillance at eight months after the
resection. The surveillance included chest X-ray showed heart and lung were within normal
limit; colon in loop showed colitis and stenosis in lower descending colon; and whole abdominal
MSCT showed minimal ascites, gallbladder stones, and right hepatic lesions which was
suggestive of metastases tumor.
The prognosis for patients with neuroendocrine tumors varies according to the stage at
diagnosis, histologic classification, and primary site of the tumor. Most tumors are > 2 cm in size
with invasion into the muscularis propria at the time of diagnosis and overall prognosis is poor
with 5-year survival rates of only 33%-42%.87 Frequently found as small, asymptomatic
submucosal tumors during endoscopic evaluation, rectal NETs have an excellent overall
prognosis with 5-year survival rates of 87%.42,43 The first patient in our case was classified as
stage III B with histopathology characteristic of 2 positive lymph nodes, high mitotic rate, and
the primary site of the tumor was in sigmoid colon. The second patient was classified as stage IV
with liver metastases, histopathology characteristic of low mitotic rate, and the primary site was
in descending colon. Both of the patients in our cases had poor prognosis because of
muscularispropria invasion and had 5-year survival rates of only 33%-42%.

Conclusion
GEP-NET are relatively rare neoplasms of the gastrointestinal tract with variable clinical
presentation, morbidity, and mortality dependent on tumor location, metastatic potential, and
functional biologic status. Staging and classification systems for GEP-NET are likely to continue
to evolve along with further development of tumor directed diagnostic and therapeutic modalities
as our understanding of GEP-NET continues to expand over time.

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REFERENCES
1. Aaron I, Eugene A, Richard R, et al. NANETS Consensus Guidelines for Diagnosis of
Neuroendocrine Tumor. Pancreas. 2010;39:713-714.
2. Mougey A, Adler D. Neuroendocrine Tumors: Review and Clinical Update. Hospital
Physician2007;51:12-20.
3. Kaltsas G, Rockall A, Papadogias D, et al. Recent advances in radiological and radionucleotide
imaging and therapy of neuroendocrine tumors. Eur J Endocrinal. 2004;151:15-27.
4. Massironi S, Seiola V, PeracchiM,et al. Neuroendocrine tumors of the gastro-entero-pancreatic
system. World J Gastroenterol. 2008 ; 14:5377-5384.
5. Kaltsas G, Besser G, Grossmn A. The diagnosis and medical management of advanced
neuroendocrine tumors. Endocrine Review. 2004;25:458-511.
6. Warner RR. Enteroendocrine Tumors Other Than Carcinoid: A Review of Clinically Significant
Advances. Gastroenterology. 2005; 128: 1668-1684.
7. Vilar E, Salazar R, Perez-Garcia J, et al. Chemotherapy and role of the proliferation marker Ki-67
in digestive neuroendocrine tumors. Endocr-Relat Cancer. 2007;14:221-232.
8. Chung IP, Hunt SR. Carcinoid and neuroendocrine tumors of the colon and rectum. Clin Colon
Rectal Surg. 2006; 19:45-48.
9. Poston GJ. Jones LE. Carcinoid tumors. Gastrointestinal oncology evidence and analysis. 2007;
317-336.
10. Ito T, Sasano IL, Tanaka M, et al. Epidemiological study of gastroenterohepatic neuroendocrine
tumors in Japan. J Gastroenterol. 2010;45:234-243.
11. Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid
tumour. Lancet 1998;352:799–805
12. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its
tumors: the WHO classification. Ann NY AcadSci 2004;1014:13–27.
13. Yao JC, Hassan M, Phun A, et al. One hundreds years after “carcinoid” epidemiology of and
prognostic factor for neuroendocrine tumors in 35,825 cases in the United States. J ClinOncol.
2008; 26”3063-3072.
14. Kim JY, Hong SM. Recent updates on neuroendocrine tumors from the gastrointestinal
and pancreatobiliary tracts. Arch Pathol Lab Med May 2016;140:437-448.
15. Zhao J, de Krijger RR, Meier D, et al. Genomic alterations in well-differentiated gastrointestinal
and bronchial neuroendocrine tumors (carcinoids): marked differences indicatingdiversity in
molecular pathogenesis. Am J Pathol 2000;157: 1431–1438.

17
16. Pearse AG. The APUD concept and hormone production. ClinEndocrinolMetab 1980;9:211–222.
17. Oberg K.E. Gastrointestinal neuroendocrine tumors. Annals of Oncology 2010;21(7):72-80.
18. Mahayana M, Soetamto PW. Tumor neuroendokrin: kasus serial di RSUD
Soetomo.JurnalBedahNasionalJanuari 2018;2(1): 29-39.
19. Kojima M, Ikeda K, Saito N, Sakuyama N, Koushi K, Kawano S, et al. Neuroendocrine tumors of
the largeintestine: clinicopathological features and predictive factors of lymph node metastasis.
Frontiers in Oncology July 2016;6(173):1-7.
20. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer
2003;97:934–95
21. Hay DJ, Curt JR. Carcinoid tumour as a complication of ulcerative colitis. Postgrad Med J
1979;55:430–432
22. Dodd SM. Chronic ulcerative colitis complicated by atypical carcinoid tumour. J ClinPathol
1986;39:913–916
23. Owen DA, Hwang WS, Thorlakson RH, Walli E. Malignant carcinoid tumor complicating
chronic ulcerative colitis. Am J ClinPathol 1981;76:333–338
24. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case
28–2000. A 34-year-old man with ulcerative colitis and a large perirectal mass. N EnglJ Med
2000;343:794–800
25. Berge T, Linell F. Carcinoid tumours. Frequency in a defined population during a 12-year period.
ActaPatholMicrobiolScand [A] 1976;84:322–330
26. Warner TF, O’Reilly G, Lee GA. Mesenteric occlusive lesion and ileal carcinoids. Cancer
1979;44:758–762
27. Marshall JB, Bodnarchuk G. Carcinoid tumors of the gut. Our experience over three decades and
review of the literature. J ClinGastroenterol 1993;16:123–129
28. Tormey WP, FitzGerald RJ. The clinical and laboratory correlates of an increased urinary 5-
hydroxyindoleacetic acid. Postgrad Med J 1995;71:542–545
29. Bajetta E, Catena L, Procopio G, et al. Is the new WHO classification of neuroendocrine tumors
useful for selecting an appropriate treatment? Ann Oncol. 2005: 16: 1374-80.
30. Bosman FT, Carneiro F, Hruban R H, Theise N. WHO classification of tumours of the digestive
system, fourth edition. France: IARC; 2010 [cited 2018 Jul 10] Available
from: http://www.ncbi.nlm.nih.gov/nlmcatalog/101553728
31. WHO Classification of Tumours of Endocrine Organs. Vol. 10 (ed 4).Lyon, France: International
Agency for Research on Cancer (IARC);2017.

18
32. Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a
consensus proposal including a grading system. Virchows Arch 2006;449:395-401. Available
at:https://www.ncbi.nlm.nih.gov/pubmed/16967267.
33. Rindi G, Kloppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine
tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757-762.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/17674042.
34. Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an
analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J ClinOncol
2002;20:2633-2642. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12039924.
35. Panzuto F, Boninsegna L, Fazio N, et al. Metastatic and locally advanced pancreatic endocrine
carcinomas: analysis of factors associated with disease progression. J ClinOncol 2011;29:2372-
2377. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21555696.
36. Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor
patients: comparison between gastrointestinal and pancreatic localization.
EndocrRelatCancer2005;12:1083-1092. Available at:
\http://www.ncbi.nlm.nih.gov/pubmed/16322345.
37. Pape UF, Jann H, Muller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification
system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008;113:256-265
38. Rindi G, Bordi C, La Rosa S, et al. Gastroenteropancreatic(neuro)endocrine neoplasms: the
histology report. Dig Liver Dis 2011;43Suppl 4:S356-360. Available
at:https://www.ncbi.nlm.nih.gov/pubmed/21459341.
39. Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3)pancreatic neuroendocrine tumor
category is morphologically andbiologicallyheterogenous and includes both well differentiated
andpoorly differentiated neoplasms. Am J SurgPathol 2015;39:683-690.Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25723112.
40. van Velthuysen ML, Groen EJ, van der Noort V, et al. Grading of neuroendocrine neoplasms:
mitoses and Ki-67 are both essential.Neuroendocrinology 2014;100:221-227. Available
at:https://www.ncbi.nlm.nih.gov/pubmed/25358267.
41. Used with permission of the American College of Surgeons, Chicago, Illinois. The original
source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published
by Springer International Publishing.
42. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD.Current status of
gastrointestinal carcinoids. Gastroenterology 2005; 128: 1717-1751 [PMID: 15887161
DOI: 10.1053/j.gastro.2005.03.038]

19
43. Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system
and its tumors: the WHO classification. Ann N Y AcadSci2004; 1014: 13-27 [PMID:
15153416 DOI: 10.1196/annals.1294.002]

20