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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_927_Библиотеки_им_академика_М_И_Перельмана.pdf
A
BC
FIGURE 75-3 Heineke-Mickulicz (A), Finney (B), and Michelassi (C) strictureplasties. (Reprinted with
permission, Cleveland Clinic Center for Medical Art & Photography copyright 1998-2016. All Rights Reserved.)
ManageMent of SMall Bowel Crohn DiSeaSe392
major complication rate is 3% to 5%. Although many patients will
require a repeat procedure, surgery can be avoided in more than half
of patients during the ensuing 5 years.
OUTCOME
Early complications (≤30 days) associated with an operation for small
bowel Crohn disease include bowel obstruction, intestinal hemorrhage, sepsis, and death. Small bowel obstruction occurs during the
postoperative period in 2% to 5% of cases and is usually managed
conservatively because the obstruction spontaneously resolves in
most patients, and a repeat operation more than 7 to 10 days aer
the initial surgery is oen associated with accidental creation of
enterotomiesas aresult of dense adhesions.Intestinalhemorrhage
complicates 3% to 7% of the operations and is usually self-limited.
Septic complications (e.g., an anastomotic leak and an intra-abdominal abscess) arise in 8% to 11% of patients and are managed with
laparotomy plus fecal diversion or CT-guided drainage, depending
on the patient’s clinical scenario. e overall 30-day mortality rate is
approximately 0.4% for elective procedures but higher for emergency
operations.
Disease recurrence eventually aects most persons and can be
classied as follows:
• Endoscopicrecurrencedenedasmucosaldiseaseconsistent
with Crohn disease
• Clinicalrecurrencedenedassymptomaticdiseaserequiring
medical therapy
• Surgicalrecurrence dened assymptomaticdisease warrant-
ing further operative intervention
Endoscopic recurrence aecting the neoterminal ileum is noted
in 70% to 90% of patients who undergo a colonoscopy 1 year aer an
ileocecectomy. Approximately 50% of patients will experience clinical recurrence within 5 years of surgery, and 70% of patients require
an additional operation within 10 years of their initial surgery. Risk
factors for recurrence include active smoking, penetrating Crohn disease, and extensive (>50 cm) upper gastrointestinal disease. Smoking cessation should be strongly encouraged and supported in active
smokers to delay the onset of recurrence. Prophylactic medical therapy is prescribed for high-risk patients and anyone demonstrating
endoscopic recurrence during follow-up colonoscopy 6 to 12 months
aer surgery.
SUMMARY
Crohn disease of the terminal ileum and upper gastrointestinal tract
is initially managed with medical therapy, but surgery is eventually
warranted in most patients. Patients requiring an elective procedure
should be evaluated with endoscopic and imaging studies, and they
should be clinically optimized as dictated by their clinical condition.
Resection and strictureplasty are commonly used as complementary
procedures through a laparoscopic approach, with eorts focusing on
small bowel conservation. Eorts to prolong the disease-free interval
should be employed in patients at increased risk for the disease recurrence that ultimately aects most patients.
S e l e c t e d R e a d i n g
Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590–1605.
Buisson A, Chevaux JB, Allen PB, etal. Review article: the natural history
of postoperative Crohn’s disease recurrence. Aliment Pharmacol er.
2012;35:625–633.
Fazio VW, Marchetti F, Church J, et al. Eect of resection margins on the
recurrence of Crohn’s disease in the small bowel. A randomized controlled
trial. Ann Surg. 1996;224:563–573.
Feagins LA,HolubarSD, Kane SV, Spechler SJ. Current strategies in the man-
agement of intra-abdominal abscesses in Crohn’s disease. Clin Gastroen-
terol Hepatol. 2011;9:842–850.
HeX, Chen Z,HuangJ, etal. Stapled side-to-side anastomosis might be better
than handsewn end-to-end anastomosis in ileocolic resection for Crohn’s
disease: a meta-analysis. Dig Dis Sci. 2014;59:1544–1551.
HeshamW, Kann BR. Strictureplasty. Clin Colon Rectal Surg. 2013;26:80–83.
Reese GE, Purkayastha S,TilneyHS, etal. Strictureplasty vs resection in small
bowel Crohn’s disease: an evaluation of short-term outcomes and recur-
rence. Colorectal Dis. 2007;9:686–694.
Rosenfeld G,Qian H, Bressler B. e risks of post-operative complications
following pre-operative iniximab therapy for Crohn’s disease in patients
undergoing abdominal surgery: a systematic review and meta-analysis. J
Crohns Colitis. 2013;7:868–877.
TilneyHS, Constantinides VA,HeriotAG, etal. Comparison of laparoscopic
and open ileocecal resection for Crohn’s disease: a metaanalysis. Surg En-
dosc. 2006;20:1036–1044.
S B
N
Susan L. Gearhart
INTRODUCTION
Neoplasms of the small intestine are rare, accounting for 3% to 6% of
gastrointestinal neoplasms overall and 1% to 3% of primary gastrointestinal cancers. e incidence of small bowel cancer is higher in
North American and Western European men compared with Asian
men and women, and a higher incidence also has been noted in
African American men and women. e prevalence of small bowel
cancer, particularly carcinoid tumors, is increasing. e mean age
at presentation is 65 years, with the incidence increasing aer age
40 years.
More than 40 dierent histologic types of neoplasm may arise in the
small intestine, and nearly 50% are malignant. Kopácová etal found
that 42% of small intestinal neoplasms discovered in 170 patients by
double balloon endoscopy were malignant; adenocarcinoma was the
most common. Other malignancies include carcinoid, lymphoma,
and gastrointestinal stromal tumor (GIST). Benign polyps include
adenomas and hamartomas. Several hereditary syndromes have small
intestinal polyps in their phenotypes (see Fig. 76-1).
e rarity of small bowel neoplasms is likely a result of several
factors. e transit time through the small intestine is rapid, giving a brief mucosal contact time for potential carcinogens. Bacterial
counts in the small intestine are lower than in the colon, so there
is less processing of intestinal contents into carcinogens. A higher
concentration of gastrointestinal lymphoid tissue and higher levels
of immunoglobulin also are present. Finally, small intestinal contents
are alkaline and liquid, which results in less chemical and mechanical
stress on the mucosa and thus less inammation.
Risk factors for small bowel cancer include Crohn disease and
celiac disease. In both, the risk increases with the duration of the disease. In Crohn disease, the incidence of adenocarcinoma is higher
among males with stulizing disease of the distal jejunum or ileum.
Celiac disease is associated with both lymphoma and adenocarcinoma. Lifestyle factors that have been reported in some studies to
increase risk include red meat consumption, alcohol, smoking, and
obesity. Gallstones appear to be associated with a higher risk for carcinoid tumors.
PRESENTATION
e presentation of small intestine neoplasms varies. Symptoms
include gastrointestinal bleeding and abdominal pain, whereas more
advanced disease may present with bowel obstruction and weight
loss. Some tumors are seen incidentally during an imaging study, and
patients with lymphomas may present with fever, weight loss, and
drenching night sweats. A small number of patients with liver metastases from carcinoid tumors present with the carcinoid syndrome,
suggested by ushing, diarrhea, and bronchospasm.
DIAGNOSIS
Until recently, small bowel tumors have been dicult to image or
see. e best available diagnostic tool used to be the poorly tolerated
and relatively inaccurate small bowel enteroclysis. Current methods
for the diagnosis of small bowel tumors are much more eective
and include computerized tomography enterography (CTE), magnetic resonance (MR) enterography, capsule endoscopy, and doubleballoon enteroscopy (DBE).
CTE can only detect lesions that are 0.85 cm or larger. MR
enterography oers greater resolution without the exposure to ionizing radiation and provides information about extraintestinal involvement. It has a sensitivity of 0.86 and specicity of 0.98 for small bowel
neoplasms, and more recent studies have identied imaging characteristics on MR that may help dierentiate benign from malignant
neoplasms. ese characteristics included solitary lesions, nonpedunculated lesions, longer lesions, mesenteric fat inltration, and
enlarged mesenteric lymph nodes.
Both video capsule endoscopy and DBE allow small bowel
tumors to be seen. However, one major limitation of video capsule
endoscopy is the fact that it does not cover the complete small bowel
mucosa in nearly 35% of patients. Furthermore, the average capsule
retention rate is 10% to 25% and is higher in patients with a small
bowel tumor. DBE is more sensitive than CTE and permits suspicious lesions to be biopsied. However, it can be time consuming and
is invasive, with a 1% to 4% complication rate. Understanding the
prevalence and distribution of the dierent types of small bowel
tumors helps in calling the odds. In 1987, adenocarcinoma was the
most common small bowel tumor (45%), followed by carcinoid
(29%), lymphoma (16%), and sarcoma (10%). However, in 2009,
carcinoid was the most common small-bowel tumor. In the three
decades between 1985 and 2005, the proportion of patients with carcinoid tumors increased from 28% to 44%, whereas the incidence
of adenocarcinoma decreased from 42% to 33%. e proportion of
patients with lymphoma and GIST has remained stable. A small proportion of small intestinal malignancies are metastases from lung,
breast, prostate, and melanoma.
e location of tumors of the small intestine is relatively consistent and is demonstrated in Figure 76-2. Adenocarcinoma is most
frequently found in the duodenum. When an adenocarcinoma is
associated with an inammatory disease (Crohn disease, celiac disease, and Meckel diverticulum), the lesion is most commonly found
in the ileum. Primary intestinal lymphoma parallels the distribution
of lymphoid tissue and tends to be found in the lymphoid-rich terminal ileum. Carcinoid tumors are most commonly found in the
ileum within 60 cm of the ileocecal valve. Endoscopically, a small
protrusion within the submucosa is seen. A desmoplastic reaction in the submucosa is common and can be seen on CT imaging
(see Fig. 76-3). Small bowel carcinoids can be associated with
393
Small Bowel NeoplaSmS394
Cancer
Duodenum
Adenoma
Adenocarcinoma
Benign Malignant Hereditary syndromes
• Inflammatory polyp
• Lipoma
• Adenoma
• Hamaratoma
• Granular cell tumor
• Lymphangioma
• Adenocarcinoma
• Carcinoid
• Lymphoma
• Gastrointestinal stromal tumor
(GIST)
• Melanoma
FIGURE 76-1 Common types of small intestinal neoplasms.
• Peutz Jeghers
• Familial adenomatous
polyposis (FAP)
• Von Recklinghausen disease
Polyp
Jejunum
Hamaratoma
Lipoma
multiple endocrine neoplasia type 1. Secondary malignancies of the
large bowel, stomach, breast, lung, pancreas, and gallbladder are the
most common tumors associated with carcinoid. GISTs can be found
anywhere in the small intestine, but the ileum is the most common
location. Endoscopically, they are round, submucosal lesions, sometimes with a central ulcer.
e management of benign, small intestinal tumors is either endoscopic or surgical resection. Surgical resection is generally required
for large symptomatic polyps. If the polyp is known to be benign,
simple excision with resection is denitive. Lymphadenectomy
should be considered if malignancy is in question. Surgical resection of all primary small intestinal carcinomas is the treatment of
choice. Fewer than half of small bowel carcinomas are characterized by localized disease, more than one third display nodal spread,
and nearly 20% result in distant metastasis. Key points regarding
the most common malignancies are discussed in the following
sections.
FIGURE 76-2 Location of most common small intestine neoplasms. GIST, Gastrointestinal stromal tumor.
MANAGEMENT
Carcinoid with
lymph nodes
Ileum
Carcinoid
Lymphoma
GIST
Adenocarcinoma without Metastatic Disease
A curative resection includes removal of the regional lymphatics.
If the tumor is located in the terminal ileum, a formal right hemicolectomy should be performed. For tumors of the duodenum, a
pancreatoduodenectomy may be required. If the disease is unresectable, a palliative bypass to relieve the obstruction should be considered. Adjuvant therapy is considered for local regional and distant
metastasis.
Carcinoid Tumors
Carcinoid tumors are generally small (<1.5 cm) and asymptomatic, and they are often identified incidentally. The risk of tumor
spread to the lymphatics increases dramatically with tumor size,
approaching 80% in tumors larger than 2 cm. They arise from
enterochromaffin cells and secrete biochemically active substances, including serotonin, prostaglandin, bradykinin, and a
variety of other hormones. The carcinoid syndrome occurs with
hepatic metastases. This syndrome includes flushing and diarrhea,
FIGURE 76-3 Computerized tomography image of carcinoid tumor
with involvement of the mesentery of the small intestine.
which may be the result of serotonin in the systemic circulation.
Other symptoms include bronchospasm and right heart valvular
disease. The diagnosis of carcinoid syndrome is confirmed by
elevated 5-hydroxyindole acetic acid. Another useful marker of
disease is the chromogranin A level, which is more specific for
carcinoid malignancy than is 5-hydroxyindole acetic acid. Neither
correlates with survival, however.
e management of intestinal carcinoid tumors requires a wide
mesenteric resection and inspection for any other associated malignancies. Structures involved in the desmoplastic reaction that oen
is associated with this tumor should be removed en bloc. Debulking of irresectable metastatic disease can provide symptomatic relief.
Adjuvant therapy for unresectable disease has short-lived ecacy.
e use of long-acting somatostatin analogues provides reliable and
sustainable symptomatic relief for the carcinoid syndrome.
Lymphomas
Types of lymphoma seen in the small intestine vary by age and associated risk factors. Children present with Burkitt lymphoma of the
terminal ileum, whereas adults more commonly have a B-cell lymphoma. e histology of these tumors is most oen diuse, intermediate- to high-grade, non-Hodgkin lymphoma. Lymphomas
associated with celiac disease are found in the jejunum and are of the
T-cell variety. Surgical management is generally for complications:
obstruction, perforation, or hemorrhage. Because of the rarity of the
disease and the acute presentation, the role for primary elective surgical excision is not well established. A recent systematic review of
small intestinal lymphoma recommended that surgery be reserved
for patients with a clinical indication. Chemotherapy is the mainstay
therapy for this disease.
SMALL INTESTINE 395
GIST Tumors
GIST tumors are large solitary masses that frequently become large
without causing symptoms. ey arise from the gastrointestinal cells
of Cajal that regulate the autonomic nerve system of the gastrointestinal tract. Almost all GISTs express the KIT receptor tyrosine
kinase, an important factor in the management of these tumors.
Small intestinal GIST tumors more frequently present with metastasis than gastric GISTs. However, tumors smaller than 5 cm with a
mitotic count less than or equal to 5/50 high-power elds have a very
good prognosis with a risk of metastases of less than 5%. e most
common place for metastasis is the peritoneal cavity and liver, and
rarely the lung. Surgical management is complete excision. Metastatic
disease or unresectable disease is best managed with chemotherapy
targeted at the kit receptor (imatinib [Gleevac]).
Long-term outcome data for small intestinal carcinomas are lacking. Most review articles indicate that the 5-year survival rate is best
for carcinoid tumors (60%). GIST tumors have a 50% 5-year overall
survival rate. Lymphoma has a 15% to 50% survival rate over 5 years.
Adenocarcinoma has the poorest prognosis, with a 5-year survival
rate of less than 30%.
CONCLUSION
Small intestinal tumors are rare and dicult to diagnosis. With newer
imaging and endoscopic modalities, it is hoped that earlier diagnosis
will occur. Surgical resection remains the best management for many
of these tumors.
ACKNOWLEDGMENT
I thank Cory Sandone for her artwork on small bowel neoplasms.
S u g g e S t e d R e a d i n g S
Beaton C, Davies M, Beynon J. e management of primary small bowel and
colon lymphoma—a review. Int J Colorectal Dis. 2012;27:555–563.
Bilimoria KY, Betrem DJ, Wayne JD, etal. Small bowel cancer in the United
States: changes in epidemiology, treatment, and survival over the past 20
years. Ann Surg. 2008;249:63–71.
Chen W, Shan G, Zhang H, et al. Double-balloon enteroscopy in small
bowel tumors: A Chinese single-center study. World J Gastroenterol.
2013;19:3665–3671.
Chow J, Chen C, Ahsan H, Neugut A. A population-based study of the inci-
dence of malignant small bowel tumors: SEER, 1973-1990. Int J Epidemiol.
1996;25:722–728.
Kopácová M, Rejchrt S, Bures J, Tacheci I. Small intestinal tumors. Gastroen-
terol Res Pract. 2013;2013:702536.
Manfe AZ, Norbeerto L, Marchesini M, Lumachi F. Usefulness of Chro-
mogranin A, neuron-specic enolase and 5-HIAA measurements in pa-
tients with malignant carcinoids. In Vivo . 2011;25:1027–1029.
Masselli G, Casciani E, Polettini D, etal. Magnetic resonance imaging of the
small bowel neoplasms. Cancer Imaging. 2013;13:92–99.
Pilleul F, Penigaud M, Milot L, etal. Possible small bowel neoplasms: contrast-
enhanced and water-enhanced multidetector CT enteroclysis. Radiology.
2006;241:796–801.
Reynolds I, Healy P, Mcnamara D. Malignant tumors of the small intestine.
Surgeon. 2014;12:263–270.
Van Weyenberg SJ, etal. MR enteroclysis in the diagnosis of small-bowel neo-
plasms. Radiology. 2010;254:765–773.
N
T S
L I
Seraina Faes and Dieter Hahnloser
DEFINITION
Neuroendocrine tumors (NETs) derive from neuroendocrine cells
(also called enterochroman cells or enterochroman-like cells) of
the endoderm of the fore-, mid-, and hindgut. ese cells are diusely
distributed in the epithelium of the gastroenteropancreatic system,
the bronchial system, and the thymus and produce peptide hormones
or neurotransmitters, such as serotonin, tachykinin, kallikrein, histamine, insulin, gastrin, vasoactive intestinal polypeptide, glucagon,
somatostatin, growth hormone–releasing hormone, corticotropinreleasing hormone, adrenocorticotropic hormone, and pancreatic
polypeptide. e entity of these amine- and peptide-producing cells
is very polymorphic.
In 1966, Anthony G. E. Pearse described the neuroendocrine
cells as descending from an amine precursor uptake and decarboxylation system because of their functional resemblance to neurons. He
wrongly suspected a neuroectodermal origin from the neural crest.
e term carcinoid was shaped by the German anatomist Oberndorfer in 1907 as “cancerlike” in order to distinguish these tumors from
cancer because of their relatively benign behavior and slower growth
patterns compared with carcinomas. is term was abandoned in
favor of terms such as neuroendocrine tumor or neuroendocrine neo-
plasm. e term carcinoid syndrome is reserved for symptomatic
serotonin-producing tumors. ese symptoms are present in only
approximately 10% of NETs and occur when secretory products
gain access to the systemic circulation either by bypassing hepatic
metabolism as a result of liver metastases or by direct access in locally
advanced tumors (i.e., retroperitoneal inltration). is occurrence is
more frequent in small intestinal NETs because of their more aggressive behavior compared with NETs of the appendix, colon, or rectum.
NETs were formerly classied with respect to their origin into NETs
of the fore-, mid-, and hindgut. However, lately this classication has
been replaced by the more appropriate allocation to the organ where
they are found.
INCIDENCE, EPIDEMIOLOGY, AND RESEARCH
NETs are rare, with an incidence of 5.0 to 5.5 per 100,000 per year.
ey account for approximately 0.5% of all malignant neoplasms.
e anatomic distribution reects the localization of neuroendocrine cells. Most NETs originate in the gastroenteropancreatic
system, with one quarter originating in the bronchopulmonary
system and a minority in other sites. e incidence of gastrointestinal NETs has increased during the past 40 years and now ranges
from 1.3 to 1.4/100,000/year. e site of predilection has changed
from a historical preponderance of appendiceal NETs to a preponderance of pancreatic and small intestinal NETs. e incidence of
rectal NETs in particular has increased. Depending on the source
of information, appendiceal NETs account for only 4% of NETs;
396
however, data on anatomic distribution vary widely. According
to most publications, the predominant intestinal origins are the
ileum, followed by the appendix, jejunum, rectum, and colon.
NETs of the stomach, esophagus, biliary tract, thymus, and ovaries
are very rare.
e clinical characteristics of NETs of the small and large intestine
are outlined in Table 77-1.
An incidence of 0.32 to 1.12/100,000/year is reported for small
intestinal NETs. However, the incidence in postmortem studies is
higher. NETs constitute between one third and half of small intestinal
malignancies. e site of predilection is the ileum (the terminal ileum
in particular). Twenty percent to 50% of small intestinal NETs display
malignant behavior, and approximately 30% have metastasized at the
time of diagnosis. Age at diagnosis is usually in the sixth and seventh
decade. Prevalence is probably similar for both genders; however, a
slight male preponderance is possible.
NETs of the appendix show an incidence of 0.15 to 0.60/100,000/
year. Depending on the source of information, they are nearly as frequent as small intestinal NETs, although newer data suggest a lower
frequency. With a percentage of approximately 80%, NETs constitute
the most common appendiceal neoplasm. An incidental diagnosis at
appendicectomy is frequent, with 3 to 9 NETs per 1000 appendicectomies. Approximately 70% are localized at the tip of the appendix,
followed by the middle third and then the appendiceal base. Patients
are considerably younger than other patients with intestinal NETs,
with a mean age of 40 to 50 years at diagnosis.
NETs of the colon have an incidence of 0.1 to 0.2/100,000/year
and represent about 4% to 8% of all NETs. ey are frequently malignant and can occur in association with adenocarcinomas.
Rectal NETs are usually small tumors that are diagnosed in
younger patients (the mean age at diagnosis is 56 years) at screening sigmoidoscopy. Persons with a black or Asian ethnic background
seem to be more frequently aected by rectal NETs. Rectal NETs are
oen localized on the anterior or lateral wall of the upper and middle
rectum.
Multicentricity is frequent with small but not with large intestinal
NETs. Second primary tumors, particularly colorectal adenocarcinomas, occur frequently with all intestinal NETs and increase with the
patient’s age.
Mechanisms of carcinogenesis of NETs are not well known. Chromatin remodeling, DNA damage, apoptosis inhibition, and RAS
signaling are suggested oncogenic mechanisms. Ki67 and mutated
p53 correlate with adverse prognosis and metastasis. Clinical trials
target the PI3K/AKT/mTORC1 pathway (with the mTOR inhibitor
everolimus).
Familial clustering is rare in intestinal NETs. Sporadic mutations were discovered in the FGFR2, MEN1, HOOK3, EZH2,
MLF1, CARD11, VHL, SRC, and SMAD genes. Germline mutations, as in the case of multiple endocrine neoplasia type 1
(MEN1) syndrome with a loss of heterozygosity of the tumor
suppressor gene MEN1 as a result of inactivating mutation of p16
SMALL INTESTINE 397
TABLE 77-1: Clinical Characteristics of Neuroendocrine Tumors of the Small and Large Intestine
Jejunum + Ileum Appendix Colon Rectum
Portion of NET 30%-40% 4%-19% 4%-8% 5%-18%
Portion of tumors at site 27%-34% 77%-88% 0.9% 0.5%
Incidence 0.3-1.1/100,000 0.2-0.6/100,000 0.1-0.2/100,000 0.9/100,000
Gender preference M ≥ F M < F M = F M = F
Ethnic preponderance Black Caucasian Black Asian and black
Age at diagnosis (yr) 60-65 40-50 55-65 56
Predominant hormone(s) Serotonin Serotonin Serotonin* Serotonin/glucagon*
Carcinoid syndrome 60%-80% <10% Very rare 3%-13%
Predominant location (Terminal) ileum Distal third Right hemicolon Upper and middle
rectum
Tumor multicentricity 20% 4% Rare Rare
5-year survival 50%-60% 70%-85% 40%-50% 75%-88%
Metastasis at diagnosis 30% 3%-5% 30%-45% 2%-8%
Second primary 29%-52% 13%-32% 20%-35% 5%-32%
F, Female; M, male; NE T, neuroendocrine tumor.
*e majority are hormonally inactive.
and chromosomal instability or in the case of von Hippel–Lindau
disease with mutations of the von Hippel–Lindau tumor suppressor gene, are associated with pancreatic but not intestinal NETs.
Genetic counseling or germline or somatic DNA testing are not
indicated in intestinal NETs.
CLINICAL PRESENTATION
Intestinal NETs are frequently asymptomatic, particularly if they are
in the colon or rectum, because of their rare hormonal activity and
the larger diameter of the bowel. Symptoms occur in persons with
advanced disease and are oen nonspecic (e.g., abdominal pain,
anorexia, bowel dysmotility, fatigue, and intestinal bleeding). Visceral
brosis may be responsible for more pronounced symptoms because
of bowel obstruction or ischemia.
Hormone-specic symptoms are less frequent, and given the
hepatic metabolism of hormones secreted into the portal circulation, they usually occur only in persons with metastatic disease or
bulky tumors only. NETs of the terminal ileum are the most frequent
cause of hormone production, followed by NETs originating from
the appendix and jejunum. Hormonally active NETs of the colon
and rectum are very rare. Serotonin is the predominant hormone in
intestinal NETs; however, many intestinal NETs are inactive. Symptoms caused by serotonin, tachykinin, and kallikrein are referred to
as the carcinoid syndrome and include abdominal cramps, secretory
diarrhea, ushing, and bronchial wheezing. Furthermore, these hormones may cause carcinoid heart disease, also called Hedinger syndrome, which is present in 25% to 50% of patients with carcinoid
syndrome. It can lead to right heart failure or cardiac arrhythmias
as a result of an endocardiac brosis and bears a poor prognosis.
Rare but potentially life-threatening is the carcinoid crisis, which
may occur with stimuli such as surgery, anesthesia, or chemotherapy.
Other conditions attributed to hormone-producing NETs include the
Whipple triad (hypoglycemia, neurohypoglycemia that immediately
improves with administration of glucose, and glucose <4 mmol/L)
caused by insulin (pancreatic NETs), acromegaly caused by growth
hormone– releasing hormone (bronchial and pancreatic NETs),
Cushing syndrome caused by corticotropin-releasing hormone or
adrenocorticotropic hormone (bronchial and pancreatic NETs),
Zollinger-Ellison syndrome (multiple ulcers, diarrhea, and reux
disease) caused by gastrin (pancreatic, duodenal, and gastric NETs),
diabetes and necrolytic migratory erythema caused by glucagon
(pancreatic and rectal NETs), Werner Morrison syndrome (watery
diarrhea, hypokalemia, and achlorhydria—i.e., WDHA syndrome)
caused by vasoactive intestinal polypeptide (pancreatic NETs), and
diabetes, steatorrhea, and cholelithiasis caused by somatostatin (pancreatic and duodenal NETs).
DIAGNOSIS
Given the frequently asymptomatic presentation or nonspecic
symptomatology, metastasis has occurred in 27% to 73% of patients
at the initial diagnosis (possibly higher percentages in specialized
centers because of preselection; particularly NETs of the colon and
small intestine). A high threshold of suspicion, proactive intent, and
expedient workup are essential, because early detection and treatment remain the best ways of improving outcome.
e mainstay of diagnosis is a complete history and physical
examination accompanied by a biochemical workup, imaging (with
radiology and nuclear medicine), and endoscopy.
A sensitive but nonspecic test is the measurement of chromogranin A, which is stored in the membrane of secretory granules. It is
used as a tumor marker, because it correlates with prognosis and may
indicate recurrence. e biochemical analysis should further include
urinary 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite
of serotonin. e measurement of the hormones is not a sensitive
diagnostic tool because they are regular products of neuroendocrine cells. Neuron-specic enolase and synaptophysin, which are
NeuroeNdocriNe Tumors of The small aNd large iNTesTiNe398
cytoplasmic components independent of hormone specicity, may
complete the laboratory workup.
Computed tomography (CT) and magnetic resonance imaging
(MRI) are used to image the primary tumor and, in particular, lymphatic and distant metastases. MRI and endoanal/rectal ultrasound
are of particular importance in the local staging of rectal NETs.
Somatostatin receptor imaging can be performed either by planar scintigraphy and single photon emission computed tomography
(SPECT) or positron emission tomography (PET) and is able to detect
NETs because of an overexpression of somatostatin receptor subtype 2
at the cell membrane of most NETs. e applied somatostatin analogue
(octreotide, DOTA-d-Phe(1)-Tyr(3)-octreotide [DOTATOC], DOTA
-Tyr(3)-octreotate [DOTATATE], DOTA-Nal(3)-octreotide [DOTANOC]) is linked to radionuclides (i.e., 111-indium for SPECT and
68-gallium for PET), which are visualized by the gamma detector. Sensitivity and specicity are 90% or higher. Receptor-negative NETs (especially insulinomas, NETs of the colon, or poorly dierentiated NETs), as
well as lesions smaller than 1 cm, may be missed. e new tracers 11-carbon-5-hydroxytryptophane and 18-uoro-dihydroxyphenylalanine are
being evaluated and are not widely available. Less specic radionuclear
diagnostics such as 123-iodine-metaiodobenzylguanidine-PET (for the
detection of neurosecretory granules) or 18-uoro-DOPA can be used
to complement prior imaging. Fusion with a CT scan is performed on a
regular basis to determine the exact anatomic localization.
Endoscopy (colonoscopy for colorectal lesions, push enteroscopy,
video-capsule endoscopy, and double-balloon enteroscopy for small
bowel lesions) is indicated for screening in cases of negative radiologic
imaging, for endoscopically guided biopsy, and to exclude synchronous
colorectal adenocarcinomas and (less frequently) multifocal disease.
Furthermore, CT or MRI enteroclysis may help detect the primary
tumor. An endoscopically guided biopsy of intestinal lesions and a
sonography guided biopsy of liver metastases allow histologic dierentiation. NETs contain uniform cells in rosettes and cribriform patterns.
ey possess neurosecretory granules and express neuroendocrine
markers. e malignant potential of the primary tumor is dened by
inltration, which is dicult to detect at biopsy. For dierential diagnosis, use of immunohistochemistry for the hormone, chromogranin,
synaptophysin, or neuron-specic enolase is possible. Histopathologic
workup includes evaluation of the Ki67 index and mitotic index. e
possibility of a subtype of mixed adenoneuroendocrine carcinoma
(goblet cell carcinoid/carcinoma) must be evaluated.
In cases of negative diagnostic studies when suspicion is still high,
a diagnostic laparoscopy or explorative laparotomy is indicated.
CLASSIFICATION
NETs are clinically classied into functional and nonfunctional NETs
(or hormonally active and inactive NETs). Functional tumors have a
storage deciency with the consecutive secretion of the hormone or
neurotransmitter. Nonfunctional NETs demonstrate positive somatostatin receptor imaging in 80% of cases.
e TNM classication of malignant tumors of the Union of International Cancer Control is the most accepted classication. e seventh
edition was released in November 2009 with an updated classication
for NETs (Table 77-2). Changes include a separate staging by site. e
classication for appendiceal NETs is based on size, and that for small
intestinal NETs is based on the aected layer of the bowel wall.
e World Health Organization classication discerns the three
grades as 1 to 3 using the criteria Ki67 index and mitotic index (mitoses/10 high-power elds):
Grade 1: Well-dierentiated NET (low grade)
Ki67 index ≤2%, mitotic index <2
Grade 2: Well-dierentiated NET (intermediate grade)
Ki67 index 3% to 20%, mitotic index 2 to 20
Grade 3: Poorly dierentiated neuroendocrine carcinoma
Ki67 index >20%, mitotic index >20
SURGICAL TREATMENT
A multidisciplinary approach to treatment is key, and a thorough
discussion and evaluation at interdisciplinary tumor boards is
compulsory. Complete resection of the primary tumor and locoregional lymph nodes is the only curative measure that has been
shown to significantly improve survival. The clinical setting in
which a complete resection of all tumor sites is possible is referred
to as curative in Figures 77-1 to 77-4. The required extent of resection depends on the tumor location. A laparoscopic approach
should be considered if it is feasible. A complete intraoperative
exploration of the intestinal tract is mandatory because of the
frequent occurrence of multicentricity and secondary malignancies. Surgery may be complicated by a desmoplastic reaction with
mesenteric fibrosis or by mesenteric infiltration. The risk of a carcinoid crisis and the presence of carcinoid heart disease must be
considered prior to surgery, and thus a screening echocardiography is highly recommended.
Small Intestine
A radical approach with oncologic resection of the aected bowel
segment and central lymphadenectomy is recommended independent of tumor size because of the high metastatic potential (Fig.
77-1). A right hemicolectomy may be indicated in cases of NETs of
the terminal ileum.
Appendix
Appendicectomy is regarded as sufficient for distal tumors measuring less than 1 cm (Fig. 77-2). If they are incidentally diagnosed after appendicectomy, completely resected NETs that are
1 cm or smaller without invasion of the serosa or 3 mm or larger
of the mesoappendix can be regarded as cured without a risk of
recurrence and with 100% 5-year survival rates. Tumors smaller
than 1 cm at the appendiceal base can be managed by resecting a
portion of the distal cecum; however, performing a right hemicolectomy is also valid. A radical right hemicolectomy is indicated
for appendiceal tumors larger than 2 cm because of the risk of
lymph node and distant metastases and recurrence. For the intermediate size group of 1 to 2 cm, the situation is less clear-cut, and
a more aggressive surgical approach should be considered with
care, taking comorbidities and the operative risk into account. A
hemicolectomy is indicated when there is infiltration of the mesoappendix greater than 3 mm, lymphovascular or angioinvasion,
lymph node involvement, location at the base of the appendix, and
tumor grades G2 or G3.
Colon
NETs with a size less than 2 cm and grade 1 or 2 can be treated
endoscopically without an increased risk of recurrence or metastasis
(Fig. 77-3). Incidentally diagnosed colonic NETs with the aforemen-
tioned criteria that are discovered in a polypectomy specimen can be
regarded as cured if they are completely resected. All colonic NETs
greater than 2 cm or that are grade 3 require oncologic resection of
the colon and lymph node drainage.
Rectum
Given the low metastatic potential of small rectal NETs, an endoscopic
resection or wide local excision is recommended for tumors with a
size less than 1 cm (Fig. 77-4). A radical oncologic approach with
low anterior or abdominoperineal resection should be considered for
SMALL INTESTINE 399
TABLE 77-2: TNM Classification of the Union of International Cancer Control, 7th Edition
Localization TNM Stage
UICC Stage
Small intestine
(jejunum and ileum)
T1 Lamina propria/submucosa
size <1 cm
T2 Muscularis propria
size >1 cm
T3 Subserosa
T4 Perforates serosa or adjacent structures
N0 No lymph nodes aected
N1 Regional lymph nodes
M0
M1
No metastases
Distant metastases
Stage I
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IV
M1
T1
T2
T3
T4
Any T
Any T
N0
N0
N0
N0
N1
Any N
Appendix T1a
T1b
T2 >2 cm but ≤4 cm
≤1 cm
>1 cm but ≤2 cm
Extension to cecum
Stage I
Stage II
Stage III
Stage IV
T3 >4 cm
Extension to ileum
T4 Perforates peritoneum or other
organs or structures
N0
N1
M0
M1
No lymph nodes aected
Regional lymph nodes
No metastases
Distant metastases
Large intestine T1 Lamina propria/submucosa and <2 cm Stage I
T1a
T1b
T2 Muscularis propria or >2 cm
T3 Subserosa or pericolorectal tissues
T4 Perforates serosa or adjacent structures
<1 cm
1-2 cm
Stage IIA
Stage IIB
Stage IIIA
Stage IIIB
Stage IV
N0 No lymph nodes aected
N1
M0
M1
TNM, Tumor, node, metastasis; UICC, Union of International Cancer Control.
Regional lymph nodes
No metastases
Distant metastases
T1
T2/3
T4
Any T
Any T
T1
T2
T3
T4
Any T
Any T
N0
N0
N0
N1
Any N M1
N0
N0
N0
N0
N1
Any N M1
tumors greater than 1 cm. e balance of operative risk and clinical
benet is delicate with tumors between 1 and 2 cm. If a complete
resection of lesions measuring between 1 and 2 cm is feasible with a
limited surgical procedure, this option might be better for the patient.
Apart from the tumor size, histologic criteria such as muscularis propria invasion, cellular atypia, a high mitotic index, and lymphatic,
vascular, and perineural invasion should be taken into consideration.
Lesions larger than 2 cm bear an increased metastatic risk of approximately 60% to 80% and should be treated with radical resection.
Locally Advanced and Metastatic Disease
Surgery is indicated in persons with advanced or metastatic disease if
a complete resection is feasible to improve survival (5-year survival
increases from 30% without surgery to 60% to 80% with curative resection) and quality of life. e recurrence rate is high, with a median
time to recurrence of 18 months. In palliative cases, when a complete
resection of all tumor seeds (primary tumor and metastases) is not
feasible, a debulking operation can be considered to relieve tumor- or
hormone-associated symptoms (see the palliative arm in Figs. 77-1 to
77-4). However, given the good symptom control with somatostatin ana-
logues and interferon, this indication is reserved for persons with medically intractable symptoms. Some studies suggested improved outcome
aer reduction of tumor load; however, further studies will need to prove
this possible benet. In palliative cases in which obstruction is present or
imminent, bowel function must be secured by palliative resection, stoma
formation, or bypass (see the palliative arm in Figs. 77-1 to 77-4).
An algorithm for the treatment of liver metastases is outlined in
Figure 77-5. A combined resection of the primary tumor and liver
metastases may be performed in cases of small metastases. In more
extensive metastatic disease, a two-staged procedure must be considered. Liver metastases can be resected anatomically or nonanatomically depending on their spread and size. Ablative and reductive
strategies such as radiofrequency ablation, laser-induced thermotherapy, and transcatheter arterial (chemo) embolization, as well as a twostep surgery (possibly combined with right portal vein embolization/
ligation), should be considered in cases of bilobar disease. Persons
with diuse liver metastases usually receive medical therapies; however, liver transplantation can be an option in highly selected cases.
NeuroeNdocriNe Tumors of The small aNd large iNTesTiNe400
*Risk factors: infiltration of the mesoappendix >3 mm, G2/3, lymphovascular or
angioinvasion, lymph node involvement, localization at the appendiceal base.
• Jejunum and ileum
• Any size
• Terminal ileum
• Any size
Curative situationPalliative situation
Small intestinal NETs
• Present or imminent
obstruction
• Tumor or hormoneassociated symptoms
FIGURE 77-1 Treatment algorithm for small intestinal neuroendocrine tumors (NETs).
Oncologic segmental
resection and central
lymphadenectomy
Onocologic right
hemicolectomy
Segmental resection,
split-stoma or bypass
Evaluate debulking
operation
Appendiceal NETs
• Size <1cm
• Size 1– 2cm
• Size <2 cm
Curative situationPalliative situation
• Present or imminent
obstruction
• Tumor or hormoneassociated symptoms
Appendicectomy
– Risk factors*
+ Risk factors*
Oncologic right
hemicolectomy
Ileocecal resection or
terminal ileostomy
Evaluate debulking
operation
FIGURE 77-2 Treatment algorithm for appendiceal neuroendocrine tumors (NETs).