Keywords
carcinoid - neuroendocrine - tumor - gastric
Gastric neuroendocrine tumors (gNETs) were first reported by Askanazy in 1923.[1] gNETs have an incidence of 1 to 2 cases per 1,000,000 people[2] as per a study by Dias et al. It accounts for 8.7% of all neuroendocrine tumors
(NETs)[3] and 1.8% of all gastric tumors.[2] They are rare and have an indolent behavior with a neuroendocrine differentiation.
Their incidence is increasing due to the widespread use of upper gastrointestinal
endoscopy (UGIE) and the technical refinement of endoscopists.[2] Therefore, a suspicion of a NET must be kept in mind for a patient presenting with
self-limiting hematemesis with a polyp on UGIE.
Case Presentation
History and Examination
A 38-year-old man presented to the surgery clinic with complaints of upper abdomen
pain for 1 year. The pain was dull aching with episodes of increased severity lasting
for 1 to 2 hours. The pain was relieved with oral analgesics. This was associated
with occasional black tarry stools. The patient also complained of easy fatigability,
breathlessness, and palpitations. He had a history of repeated blood transfusions
for severe anemia. He was a chronic smoker and tobacco chewer.
His clinical examination revealed pallor. The rest of the examination was unremarkable.
Investigations
The patient had severe anemia with hemoglobin of 5.7 g/dL for which he was transfused
with two units of packed cells. Subsequently, his hemoglobin improved to 8.3 g/dL.
UGIE showed a 1 × 1 cm polyp with central umbilication along the greater curvature
of the body of the stomach. There was no active bleeding. The mucosa of the rest of
the stomach appeared normal. An impression of a gastrointestinal stromal tumor or
NET was kept. The serum chromogranin A (CgA) level was 304 ng/L (normal value = 28–94 ng/mL).
Contrast enhanced computed tomography (CECT) showed evidence of a hyperenhancing polypoidal
lesion along the greater curvature measuring 1.1 × 0.7 cm ([Fig. 1]). There were no enlarged lymph nodes visualized. Gd-68 DOTATATE scan showed a somatostatin
receptor (SSTR) expressing small polypoidal soft tissue density in the body of the
stomach along the greater curvature ([Fig. 2]).
Fig. 1 Contrast enhanced computed tomography of the abdomen showing polypoidal lesion on
the greater curvature of the stomach (black arrow).
Fig. 2 Gd-68 DOTATATE scan showing somatostatin receptor expressing polypoidal lesion on
the greater curvature of the stomach (black arrow).
Subsequently, the patient underwent resection of the polyp under a second endoscopy
([Fig. 3]) which was sent for histopathological examination (HPE).
Fig. 3 Upper gastrointestinal endoscopy showing polyp.
HPE showed a polypoidal structure lined by gastric mucosa ([Fig. 4]). The mucosa and submucosa were infiltrated by a tumor that was arranged in an acinar
pattern. The tumor cells were monomorphic with a moderate amount of cytoplasm and
salt and pepper nuclear chromatin. Occasional mitotic figures were seen. The base
of the polyp was free of tumor cells. The tumor was diffusely positive for synaptophysin
and CgA on immunohistochemistry ([Fig. 5]). Ki-67 index was 3%. The impression made from the above findings was NET of the
World Health Organization (WHO) grade II.
Fig. 4 Histopathological examination showing tumor cells arranged in acinar pattern (black
arrow).
Fig. 5 Chromogranin positive tumor cells.
The patient was immediately relieved of symptoms following polypectomy and was discharged
2 days later. His hemoglobin after 2 weeks on follow-up was 10.5 g/dL. He is currently
asymptomatic.
Discussion
The majority of gNETs are neoplasms derived from the enterochromaffin-like cells (ECL
cells) of the gastric mucosa. The cells comprising these tumors are avid for salts
of silver. These ECL cells play an important role in regulating HCl secretion in the
stomach.[4] An extremely rare form of gNET (type IV) may also arise from the gastrin or serotonin
producing endocrine cells of the stomach.[5]
Patients with this pathology present with upper abdomen pain, bloating, nausea or
vomiting, symptoms of anemia, weight loss, or hematemesis. Further evaluation may
reveal an associated condition such as Zollinger–Ellison's syndrome or multiple endocrine
neoplasia type 1.[4]
Gastric polyps may incidentally be found on UGIE. Their prevalence on UGIE is approximately
6%. The most common type of polyp of stomach is fundic polyp comprising 70 to 90%
of all polyps. They occur due to long-term proton-pump inhibitor (PPI) use. Polypectomy
is recommended for polyps more than 1 cm in size or with a suspicion of malignancy.
Mucosal sampling is also done along with polypectomy to rule out atrophic gastritis
and Helicobacter pylori infection.[6]
gNETs are classified into four distinct types with different characteristics, treatment,
and prognosis ([Table 1]).
Table 1
Types of gNETs[7]
|
Features
|
Type 1
|
Type 2
|
Type 3
|
Type 4
|
|
Prevalence among gNETs
|
70–80%
|
5–10%
|
15–20%
|
Rare
|
|
Number of lesions
|
Multiple
|
Multiple
|
Single
|
Single
|
|
Size
|
1–2 cm
|
1–2 cm
|
>2 cm
|
Largest 16 cm
|
|
Other symptoms
|
Autoimmune polyglandular syndrome
|
MEN-1 (gastrinoma)
|
–
|
–
|
|
Serum gastrin level
|
Raised
|
Raised
|
Normal
|
Normal
|
|
Gastric pH
|
Raised
|
Reduced
|
Normal
|
Normal
|
|
Underlying mucosa
|
Atrophic
|
Hypertrophic
|
Normal
|
Normal
|
|
Invasion
|
Mucosa/submucosa
|
Mucosa/submucosa
|
Any depth
|
Any depth
|
|
Metastasis
|
|
Lymph nodes
|
5–10%
|
10–20%
|
50–100%
|
–
|
|
Liver
|
2–5%
|
10%
|
22–75%
|
100%
|
|
Prognosis
|
Excellent
|
Very good
|
Poor
|
Poor
|
|
Proliferation index (Ki-67)
|
<2%
|
<2%
|
>2%
|
>30%
|
|
Immunohistochemistry
|
CgA, NSE, VMAT 2 positive
|
CgA positive
|
CgA negative
|
Synaptophysin, NSE, PGP 9.5 positive
CgA negative
|
Abbreviations: CgA, chromogranin A; gNET, gastric neuroendocrine tumor; HPF, high-power
field; MEN-1, multiple endocrine neoplasia type 1; NSE, neuron-specific enolase; PGP,
protein gene product; VMAT, vesicular monoamine transporter.
Immunohistochemistry
Confirmation of NETs is brought about by immunohistochemical analysis with the help
of CgA and synaptophysin. This also helps in classifying lesions according to the
WHO histological grades. The proliferative index Ki-67 and the number of mitoses per
high magnification field help predict the prognosis. Prognosis and risk of metastasis
may also relate to p53 and serum enolase biomarkers. The positive predictive rates
for CgA is 40%, 60% for synaptophysin, 60% for CD56, 40% for neuron-specific enolase,
and 100% for p53.[8]
Staging
CECT of the abdomen is necessary for types I and II gNETs more than 2 cm and for all
type III lesions.[2] NETs are rich in SSTRs 2 and 5 which are detected by somatostatin scintigraphy.
Octreoscan is a technetium-based somatostatin scintigraphy test with a high sensitivity
and specificity.[9] A recently developed gallium-labeled octreotide captured by positron emission tomography
scans shows superiority over the octreotide scintigraphy.[2]
Treatment
The treatment of gNETs depends on the type, extent, grade of differentiation, and
presence of poor prognostic factors. The WHO classified these neoplasms into three
histological degrees with graded prognosis ([Table 2]).
Table 2
WHO 2010 classification of NETs[5]
|
Differentiation
|
Grade 1 (well)
|
Grade 2 (moderately)
|
Grade 3 (poorly)[a]
|
|
Metastases
|
−
|
−
|
+
|
|
Muscularis propria invasion
|
−
|
±
|
+
|
|
Tumor size (cm)
|
≤2
|
>2
|
Any
|
|
Mitoses/10 HPF[b]
|
<2
|
2–20
|
>20
|
|
Ki-67 index %
|
≤2
|
3–20
|
>20
|
|
Angioinvasion
|
Never
|
Late
|
Always
|
Abbreviations: HPF, high-power field; NET, neuroendocrine tumor; WHO, World Health
Organization.
a Grade 3 is divided into small cell and large cell neoplasms.
b HPF: High Power Field.
Poor prognostic factors include: lesion ≥2 cm, deep submucosal invasion or beyond,
Ki-67 ≥3%, lymphovascular invasion, poorly differentiated and presence of atypia or
necrosis.[2]
Carcinoid crisis is provoked by tumor manipulation before or during surgery that can
be prevented by subcutaneous or intravenous octreotide.[2]
The first-line treatment for any polyp that is more than 1 cm or suspicious of malignancy
is endoscopic polypectomy. Endoscopic polypectomy is adequate for types 1 and 2 gNETs.
Further surgical treatment is necessary for type 3 gNETs and type 1 or 2 gNETs where
endoscopic treatment is not feasible or there is presence of poor prognostic factors.
Total or subtotal gastrectomy allows adequate removal of G-cells that is not attainable
by antrectomy. Lymphadenectomy is added in the presence of poor prognostic factors
or extragastric disease.[2] Octreotide decreases the gastrinemia but discontinuation of this treatment allows
a rise in serum gastrin levels at 1 year follow-up. This treatment is reserved for
patients unfit for surgery.[10] Vitamin B12 supplementation is given in all cases.[2]
The latest development includes netazepide (YF476) that is a potent and highly selective
cholecystokinin 2 receptor antagonist belonging to the benzodiazepine class. They
cause regression of type 1 gNETs and normalize CgA levels.[6]
Extrahepatic metastasis or recurrent symptomatic disease is treated with systemic
therapy consisting of cytotoxic chemotherapy (streptozocin combined with 5-fluorouracil
or cyclophosphamide, doxorubicin mono drug or with 5-fluorouracil, dacarbazine or
temozolomide, oxaliplatin with capecitabine or 5-fluorouracil with leucovorin) or
molecular-targeted agents (bevacizumab, sorafenib, sunitinib, pazopanib, and everolimus).[11] These tumors also reportedly benefited from targeted radiotherapy with 177Lu octreotide.[12]
Carcinoid Syndrome
Carcinoid syndrome occurs in type 3 gNETs due to the release of histamine from the
tumor cells. This causes erythema, itching, diarrhea, and bronchospasm. Symptoms are
controlled with somatostatin analogs (octreotide or lanreotide) and low-dose interferon-alfa
for refractory cases.[3]
Follow-up
Median survival of gNETs ranges from 13 months to more than 10 years.[2]
The recommendation of the National Comprehensive Cancer Network for follow-up consists
of history, physical examination, UGIE, abdominal CECT or magnetic resonance imaging,
and serum CgA every 6 months for 1 to 2 years, annually for 4 years and then every
2 years until 10 years after surgery. Types I and II lesions <2 cm and without poor
prognostic factors or features suspicious of malignancy may only be followed with
history, physical examination, and UGIE every 6 to 12 months.[2] Serum CgA is used to monitor any recurrence following chemotherapy. However, somatostatin
analogs and PPIs may alter these levels thereby reducing their sensitivity.
Overall, the following algorithm may be used to treat gNETs ([Fig. 6]).
Fig. 6 Treatment algorithm for gNETs. CgA, chromogranin A; gNET, gastric neuroendocrine
tumor; HPE, histopathological examination; UGIE, upper gastrointestinal surgery.
Conclusion
gNETs consist of a rare complex disease that includes different subtypes with distinct
management and prognosis. Correct identification of the clinical type and histological
grade allows for a tailored management. A suspicion of gNET must be kept in mind in
a patient presenting with vague symptoms of abdomen pain and self-limiting hematemesis
with a polyp on UGIE.
