Carcinoid Tumor Marcelyn Coley Surgery IV Conference Mount

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Carcinoid Tumor

• Marcelyn Coley
• Surgery IV Conference
• Mount Sinai School of Medicine

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History

• 1888 First described by Labarsch
• 1907 Oberndorfer coined term Karzinoide
  (carcinoma-like, lack of malignant potential or
  particularly benign features)

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Carcinoid Tumor

• 5th to 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 1300 autopsies
• Reported in a number of organs
• Lungs, bronchi, GI tract, ovaries

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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

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Secretory products of carcinoid
HCG, Human chorionic gonadotropin 5-HIAA,
5-Hydroxyinoleacetic acid 5-HT,
5-Hydroxytryptamine 5-HTP, 5-Hydroxytryptophan
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• 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

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Characteristics of carcinoids
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Pathology

• Grossly, small, firm submucosal nodules,
  yellow-tan on cut surface
• Grow slowly

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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

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HISTOLOGY

• Typical
• Well-differentiated, containing small regular
  cells with rounded nuclei
• Atypical or anaplastic
• Increased nuclear atypia, mitotic activity, areas
  of necrosis

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• 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

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• 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

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Poorly differentiated gastric carcinoid

• sheets of poorly differentiated tumors cells with
  areas of necrosis (arrow).

• marked nuclear pleomorphism and hyperchromasia.

Lewin, KJ, Appelman, HD. Tumors of the esophagus
and stomach. Atlas of tumor pathology (electronic
fascicle), 1996.
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• Variable malignant potential
• Related to size, location, depth of invasion, and
  growth pattern

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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

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Appendix

• Most common location
• Majority in 40s to 50s
• FgtM
• 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

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Appendix Surgery

• Depends on the site of primary tumor
• Appendix
• Prognosis best predicted by size
• lt1cm Simple appendectomy adequate
• gt2cm right hemicolectomy
• 1 to 2 cm decide by location
• Base of appendix or invading mesentery ?Right
  hemicolectomy
• Appendectomy alone if tumor can be fully resected
• Mesoappendiceal invasion regardless of tumor size
  Right hemicolectomy
• Studies show that recurrence unlikely with small
  tumors with this feature treated by appendectomy
  alone.
• (Kulke. N Engl J Med 1999)

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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

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Small intestine

• Often metastasis to lymph nodes or liver
• Treatment
• Resection of involved segment and mesentery
• Even in known metastasis

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Carcinoid of ileum
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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

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Colon

• 5-yr survival based on metastasis
• Local - 76
• Regional - 72
• Distant - 30
• Small localized tumors likely cured by resection

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Rectum

• 6th decade
• Majority found incidentally on rectal exam or
  endoscopy
• Uncommon presentation includes rectal bleeding or
  pain
• Carcinoid syndrome rare
• Size correlates with metastasis
• Often to lymph nodes or liver

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Rectum

• Treatment
• lt1cm Local excision (clear margins)
• 1-2cm more controversial, some recommend more
  extension resection in those with muscular
  invasion or symptoms
• gt2cm Low anterior resection or abdominoperineal
  resection
• (similar to txt for adenocarcinoma)
• This aggressive approach has been challenged
  since survival is not consistently improved

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Prospective study
FIGURE 2. BerksonGage 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 791294
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• 5-yr survival rates
• Localized (90)
• Regional (49)
• Distant metastasis (26)

SEER database
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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

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Gastric Carcinoids
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• Type 1
• 6th and 7th decade, FgtM
• Carcinoid syndrome rare
• Usually indolent and generally benign condition
• Metastases lt10 of tumors lt2cm
• 20 present in larger tumors

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• Type 2
• Associated with gastrinomas (Zollinger-Ellison
  syndrome) or MEN type 1
• lt5 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

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• 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

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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

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Clinical Manifestations

• Majority are asymptomatic and found incidentally
  at time of surgery, endoscopy, or autopsy 80
• When presentcorrelate with location and extent
  of tumor
• Carcinoid Syndrome

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Malignant Carcinoid Syndrome

• Occurs in lt10 with tumors
• Commonly tumors of gi tract, esp. small bowel
• Other locations described
• gt90 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

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Liver metastases
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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)

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Malignant Carcinoid Syndrome

• Metastasis to liver
• Malabsorption and pellagra (dementia, dermatitis,
  and diarrhea) occasionally present thought due
  to excessive diversion of dietary tryptophan

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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

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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 gt100mg/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)
• Incd 5-HIAA excretion in urine and inc serotonin
  uptake by platelets
• Urinary serotonin is normal or slightly increased

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Diagnosis

• Chromogranin A protein made in the secretory
  granules of a variety of neuroendocrine tissues
  (specificity not well established
• Elevated in gt80 cases (with or without the
  syndrome?)
• Generally parallels 5-HIAA
• May be predictor of prognosis (301 pts,
  gt5000µg/Lpoor overall survival)
• Blood Serontonin
• Helpful when U5-HIAA testing is equivocal

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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

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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

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CT malignant carcinoid of ileum
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Small bowel follow through

• Polypoid mass of the terminal ileum

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Somatostatin receptor scintigraphy
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Staging

• No standard system for describing spread of
  gastrointestinal carcinoids

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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

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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

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• 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)

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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

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Summary

• gt80 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