Carcinoid Tumor

Marcelyn Coley
Surgery IV Conference
Mount Sinai School of Medicine
 History
1888 – First described by Labarsch
1907 – Oberndorfer coined term
“Karzinoide” (carcinoma-like, lack of
malignant potential or particularly benign
features)
 Carcinoid Tumor
 5thto 7th decade of life
 Incidence 2.47 and 2.58 per 100,000 for
men and women, respectively (series
reported to NCI
 4.48 and 3.98/100,000 Black M/F
 Occurrence rate 1:300 autopsies
 Reported in a number of organs
– Lungs, bronchi, GI tract, ovaries
 Carcinoid Tumor
 Arises from enterochromaffin cells (Kulchitsky
cells) type of enteroendocrine cell distributed
throughout the digestive tract.
– Ability to stain with potassium chromate (chromaffin),
a feature of cells that contain serotonin
 Found in crypts of Lieberkuhn (intestinal glands)
 secretes serotonin among other peptides
 PICTURE/GRAPH of secretions
 Secretory products of carcinoid
Amines Tachykinins Peptides Other
5HT Kallikrein Pancreatic polypeptide (40%) Prostaglandins

5-HIAA Substance P (32%) Chromogranins (100%)

5-HTP Neuropeptide K (67%) Neurotensin (19%)

Histamine HCGα (28%)

HCGβ

Dopamine Motilin

HCG, Human chorionic gonadotropin; 5-HIAA, 5-Hydroxyinoleacetic acid; 5-HT, 5-Hydroxytryptamine; 5-HTP, 5-Hydroxytryptophan
 Classified by embryologic origin
– Foregut (respiratory tract, thymus, stomach)
– Midgut (small intestine, appendix, prox colon)
– Hindgut (distal colon, rectum, GU tract)
 1/3 of midgut tumors symptomatic
– 10% assoc with carcinoid syndrome
 Hindgut rarely cause carcinoid,
asymptomatic, even when metastatic
 Characteristics of carcinoids
Foregut Midgut Hindgut
Localization Stomach, Jejunum, ileum, Transverse and
duodenum, appendix, ascending descending colon,
pancreas, bronchus colon sigmoid, rectum
Histology Trabecular Solid mass of cells Mixed

Silver Staining Argyrophil Argentaffin Variable

Secretory products 5-HT, serotonin, Serotonin, None

histamine, multiple prostaglandins,
polypeptides polypeptides
Metastasis to liver Stomach 20-25% Small intestine 35% Rectum <10% of
Asc colon 60% tumors >2cm
Appendix 2%
Carcinoid syndrome Atypical Classical Rare
Pathology
 Grossly, small, firm
submucosal nodules,
yellow-tan on cut
surface
 Grow slowly
 Pathology
 After serosal invasion often an intense
desmoplastic reaction producing mesenteric
fibrosis, intestinal kinking, and intermittent
obstruction
 Small bowel – multicentric 20-30% patients
(multicentricity exceed other malignant
neoplasms of GIT)
 10-20% 2nd primary neoplasm
– Commonly large intestine synchronous
adenocarcinoma
 Associated with MEN I ~10% cases
 HISTOLOGY

 Typical
– Well-differentiated, containing small regular
cells with rounded nuclei
 Atypical or anaplastic
– Increased nuclear atypia, mitotic activity,
areas of necrosis
 Five distinct patterns recognized
– Insular, trabecular (ribbon like), glandular,
undifferentiated, and mixed\
 Biologic behavior does not always correspond to
histologic characteristics
– Distinction between benign and malignant is
based upon presence or absence of
metastasis
– correlates to size and site of primary tumor
 The two types of silver staining used to
histologically identify neuroendocrine cells
are argyrophil and argentaffin in addition
to immunohistochemical stains such as
chromogranins, synaptophysin and
enolase
 Poorly differentiated gastric
carcinoid

•sheets of poorly differentiated tumors cells with •marked nuclear pleomorphism and
areas of necrosis (arrow). hyperchromasia.

Lewin, KJ, Appelman, HD. Tumors of the esophagus and stomach. Atlas of tumor pathology (electronic fascicle), 1996.
 Variable malignant potential
– Related to size, location, depth of invasion,
and growth pattern
 Gastrointestinal Carcinoid
 Most common site (Sabiston)
– 1. Appendix (45%)**
– 2. Small intestine (28%) (last 2ft of ileum)
– 3. Rectum (16%)
(Cheek RC et al)
 According to SEER database of 11,427 carcinoids 1973-
1997
– Small intestine (45%)**
– Rectum (20%)
– Appendix (16%)
– Colon (11%)
 Similar results database study from a Swedish registy
– 5,184 carcinoid tumors 1958-1998
 Appendix
 Most common location
 Majority in 40s to 50s
 F>M
 Majority asymptomatic, located distal 1/3 of appendix
 Symptomatic case tend to larger tumor, at the base of
the appendix (10%) and metastatic disease
– Obstruction, appendicitis, or carcinoid syndrome with tumor
mets to liver
 5-yr survival overall 71%; 10 to 30% with distant
metastasis
 Appendix: Surgery
Depends on the site of primary tumor
Appendix
 Prognosis best predicted by size
 <1cm – Simple appendectomy Tumor size Metastasis
adequate
 >2cm – right hemicolectomy
 1 to 2 cm decide by location
– Base of appendix or invading <1cm 2%
mesentery Right hemicolectomy
– Appendectomy alone if tumor can be
fully resected 1-2cm 50%
 Mesoappendiceal invasion regardless
of tumor size – Right hemicolectomy
– Studies show that recurrence unlikely >2cm 80%
with small tumors with this feature
treated by appendectomy alone.
(Kulke. N Engl J Med 1999)
 Small Intestine
 ~1/3 of small intestine neoplasms
 Commonly within 60cm of ileocecal valve
 6th and 7th decade, present with
abdominal pain or SBO
 Carcinoid syndrome in 5 to 7% of patients
 Multiple tumors in up to 30%
 5-yr survival 36% with distant metastasis
 Small intestine
 Often metastasis to lymph nodes or liver
 Treatment
– Resection of involved segment and mesentery
– Even in known metastasis
Carcinoid of ileum
 Colon
 7th decade
 Presenting with abdominal pain, anorexia, or
weight loss
 Carcinoid syndrome uncommon
 Majority in right colon
– Cecum
 Asymptomatic until tumor becomes large
– In 2 studies, at diagnosis, average tumor size – 5cm
– 2/3 patients had local nodal or distant metastasis
 Colon
 5-yr survival based on metastasis
– Local - 76%
– Regional - 72%
– Distant - 30%
 Small localized tumors likely cured by
resection
 Rectum
 6th decade Size Metast
 Majority found asis
incidentally on rectal
exam or endoscopy 1cm Rare
 Uncommon presentation
includes rectal bleeding
or pain
1- ~10%
 Carcinoid syndrome rare
 Size correlates with
1.9cm
metastasis
– Often to lymph nodes or
>2cm >70%
liver
 Rectum
 Treatment
– <1cm – Local excision (clear margins)
– 1-2cm – more controversial, some recommend more
extension resection in those with muscular invasion or
symptoms
– >2cm – Low anterior resection or abdominoperineal
resection
(similar to txt for adenocarcinoma)
 This aggressive approach has been challenged
since survival is not consistently improved
 Prospective study

FIGURE 2. Berkson–Gage survival analysis for tumor size and distant

metastasisfree survival of the 31 patients presenting without metastasis.
Increasing tumor size was associated with significantly decreased
metastasis free survival. Tumor size was not available for three
patients.

Koura et al. Carcinoid tumors of the rectum. Cancer 1997; 79:1294

 5-yr survival rates
– Localized (90%)
– Regional (49%)
– Distant metastasis (26%)

SEER database
 Stomach
 Three Categories
– Type 1
 70 to 80% of gastric carcinoids
 Associated with chronic atrophic gastritis and often
pernicious anemia
 Derived from enterochromaffin-like (ECL) cells
 Hypothesized that ECL cells develop into carcinoid
after chronic stimulation by high gastric levels i.e.
pts with atrophic gastritis
Gastric Carcinoids
 Type 1
– 6th and 7th decade, F>M
– Carcinoid syndrome rare
– Usually indolent and generally benign
condition
– Metastases <10% of tumors <2cm
– ~20% present in larger tumors
– Type 2
 Associated with gastrinomas (Zollinger-Ellison
syndrome) or MEN type 1
 <5% of gastric carcinoids
 ECL cells
 MEN1 gene locus (11q13) appears to be involved
in the pathogenesis of many of these tumors
(Debelenko et al.)
 Behave similar to type 1
– Type 3
 “sporadic carcinoids” – not associated with any
other disease process
 20% of gastric carcinoids
 Most aggressive – local or hepatic metastases up
to 65% of patients
 May be associated with carcinoid syndrome
– Often produce 5-Hydroxytryptophan in contrast to type 1
and 2, often produce serotonin
 Other sites
 Lung
 Ovary
– **produce carcinoid syndrome without metastases
secondary to direct drainage into the systemic
circulation
– Often arise in cystic terotoma or dermoid tumor
– In one report, 189 or 329 ovarian carcinoids(57%)
coexisted with cystic teratomas/dermoid tumors.
– Compared to carcinoids without associated germ cell
tumors, these were significantly smaller, less likely to
have metastases or carcinoid syndrome
 Clinical Manifestations
 Majorityare asymptomatic and found
incidentally at time of surgery,
endoscopy, or autopsy [80%]

 When present—correlate with location

and extent of tumor
 Carcinoid Syndrome
 Malignant Carcinoid Syndrome
 Occurs in <10% with tumors
 Commonly tumors of gi tract, esp. small bowel
 Other locations described
 >90% with carcinoid syndrome have metastatic
disease, exceptions are bronchial and ovarian
tumors
 Patients with the syndrome almost invariably
have hepatic metastases
– venous drainage from a metastatic tumor in the liver
goes directly into the systemic circulation and
bypasses hepatic inactivation
Liver metastases

http://www.meddean.luc.edu/lumen/MedEd/me
dicine/pulmonar/images/hussain1/scan1.jpg
 Malignant Carcinoid Syndrome
 CLASSIC SYMPTOMS
– Vasomotor
– Cardiac
– Gastrointestinal

 Symptoms
– Cutaneous flushing (80%) *** (diff erythematosus, violaceous,
prolonged flushes, bright-red patchy)
– Diarrhea (76%)** episodic, explosive, watery, occur after meals
– Hepatomegaly (71%)
– Cardiac lesions-Right heart valve (41 to 70%) PS, TR, TS
– Asthma/Bronchoconstriction (25%)
 Malignant Carcinoid Syndrome
 Metastasis to liver

 Malabsorption and pellagra (dementia,

dermatitis, and diarrhea) occasionally
present – thought due to excessive
diversion of dietary tryptophan
 Carcinoid Tumor
 In absence of carcinoid syndrome, symptoms of
carcinoids tumors in small bowel are similar to
other small bowel tumors
 Abdominal pain ± partial/complete obstruction
– often caused by intussusception
– Local desmoplastic reaction (caused by humoral
agents)
 Diarrhea (result of PBO) and weight loss
 Diagnosis
Produce serotonin, which is then metabolized in the liver and the lung to the
inactive 5-HIAA
 Elevation of humoral factors basis in those with carcinoid syndrome

 Urinary excretion of 5-HIAA* - end product of serotonin metabolism

– 75% sensitive and specificity up to 100%
– Errors induced by certain drugs and foods
– Normal 2 to 8 mg/day, Most carcinoids >100mg/day (99-2070) (in one study)
– +tumors, but without carcinoid syndrome 50 to 260 mg/day
– (not useful in foregut carcinoid bronchial, gastric lack aromatic amino
decarboxylase
– 5-hydroxytryptophan is produced instead (assays not available in US labs)
 Inc’d 5-HIAA excretion in urine and inc serotonin uptake by platelets

 Urinary serotonin is normal or slightly increased

 Diagnosis
 Chromogranin A – protein made in the secretory
granules of a variety of neuroendocrine tissues :
(specificity not well established
– Elevated in >80% cases (with or without the
syndrome?)
– Generally parallels 5-HIAA
– May be predictor of prognosis (301 pts,
>5000µg/L=poor overall survival)
 Blood Serontonin
– Helpful when U5-HIAA testing is equivocal
 Diagnosis
Others
 Plasma substance P, neurotensin, neurokinin A,
and neuropeptide – however, not elevated in all
patients

 Provocative test- pentagastrin, calcium, or

epinephrine to reproduce symptoms, but rarely
used today
– Useful when biochemical markers are marginally
elevated
 Diagnosis
 Once syndrome is confirmed, the tumor may be
localized (metastasis)
– Abdominal CT
– Indium-111 octreotide imaging (somatostatin receptor
scintigraphy) higher sensitivity than conventional
imaging i.e. CT
 Other tests –Add picture of BE
– Barium (filling defects) and endoscopic studies
– Video capsule endoscopy, MR, angiography, high-
resolution ultrasonography
CT: malignant carcinoid of ileum
 Small bowel follow through

 Polypoid mass of the

terminal ileum
Somatostatin receptor scintigraphy
 Staging
 No standard system for describing spread
of gastrointestinal carcinoids
 Management
After localization of the tumor…
 Surgery is the mainstay of treatment
 Based on…
– Tumor size
– Tumor site
– Presence or absence of metastatic disease
 Removal of tumor (if no mets)
 Control of carcinoid symptoms if present
 Widespread metastases – palliative resection
 Metastases
 Widespread metastasis
– Surgical debulking indicated, in many series,
provides symptomatic relief
– ? Hepatic resection
Wedge resection or hepatic lobectomy
– Hepatic artery ligation or percutaneous
embolization
– Reports of tumor regression with hepatic
artery occlusion combined with chemo
 Multimodal therapy needs further evaluated
 Carcinoid syndrome
– Octreotide and alpha interferons have been
effective
– In one study of 130 patients with metastatic
carcinoid tumor, interferon alpha resulted in
decreased urinary 5-HIAA (42%) and
regression (15%)
 Prognosis
 Dependent on size, location of primary tumor
 Midgut tumors better survival than foregut and
hindgut
 Resection of a carcinoid tumor localized to its
primary site approaches a 100% survival rate
 5-yr survival ~65 to 67% with regional disease
 25 to 35% with distant metastasis
 Long-term palliation often can be obtain due to
slow growing nature
 Chromogranin A found to be an independent
predictor of an adverse prognosis
 Summary
 >80% asymptomatic, often incidental finding

 Initial diagnostic test 24-hr urinary 5-HIAA

 Treatment and prognosis dependent of size and location

of primary tumor

 Resection is tumor increased overall survival

 Metastases correlate with location and size of tumor