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 (carcinomamalignant potential or particularly benign features)

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 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), (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
5HT

Tachykinins
Kallikrein

Peptides

Other

Pancreatic polypeptide (40%) Prostaglandins

5-HIAA

Substance P (32%)

Chromogranins (100%)

5-HTP

Neuropeptide K (67%) Neurotensin (19%)

Histamine

HCG (28%) HCG Motilin

Dopamine

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
Localization Stomach, duodenum, pancreas, bronchus Trabecular Argyrophil 5-HT, serotonin, histamine, multiple polypeptides Stomach 20-25% 20-

Midgut
Jejunum, ileum, appendix, ascending colon Solid mass of cells Argentaffin Serotonin, prostaglandins, polypeptides Small intestine 35% Asc colon 60% Appendix 2% Classical

Hindgut
Transverse and descending colon, sigmoid, rectum Mixed Variable None

Histology Silver Staining Secretory products

Metastasis to liver

Rectum <10% of tumors >2cm Rare

Carcinoid syndrome

Atypical

Pathology


Grossly, small, firm submucosal nodules, yellowyellow-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 20(multicentricity exceed other malignant neoplasms of GIT) 1010-20% 2nd primary neoplasm
Commonly large intestine synchronous adenocarcinoma

Associated with MEN I ~10% cases

HISTOLOGY


Typical Well-differentiated, containing small regular Wellcells 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\ 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 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.

Variable malignant potential

Related to size, location, depth of invasion, size, location, and growth pattern

Gastrointestinal Carcinoid


Most common site (Sabiston)

1. Appendix (45%)** (45%)** 2. Small intestine (28%) (last 2ft of ileum) 3. Rectum (16%)

(Cheek RC et al)  According to SEER database of 11,427 carcinoids 197319731997

Small intestine (45%)** (45%)** Rectum (20%) Appendix (16%) Colon (11%)


Similar results database study from a Swedish registy

5,184 carcinoid tumors 1958-1998 1958-

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 adequate  >2cm 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


Tumor size Metastasis <1cm 1-2cm >2cm 2% 50% 80%

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)

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 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

Size 1cm 11.9cm >2cm

Metast asis Rare ~10% >70%

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 enterochromaffin 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 (Zollingersyndrome) 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 5and 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
 Majority

are 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) brightDiarrhea (76%)** episodic, explosive, watery, occur after meals Hepatomegaly (71%) Cardiac lesions-Right heart valve (41 to 70%) PS, TR, TS lesionsAsthma/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 5 Elevation of humoral factors basis in those with carcinoid syndrome


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

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) (99+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 5Urinary 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 5May be predictor of prognosis (301 pts, >5000g/L=poor overall survival)

Blood Serontonin
Helpful when U5-HIAA testing is equivocal U5-

Diagnosis
Others  Plasma substance P, neurotensin, neurokinin A, and neuropeptide however, not elevated in all patients


Provocative test- pentagastrin, calcium, or testepinephrine 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 Indiumscintigraphy) 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, highhighresolution 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 5regression (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 LongLong-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 245Treatment and prognosis dependent of size and location of primary tumor Resection is tumor increased overall survival Metastases correlate with location and size of tumor