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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
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), 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 5-HIAA 5-HTP Histamine

Tachykinins
Kallikrein Substance P (32%)

Peptides

Other

Pancreatic polypeptide (40%) Prostaglandins Chromogranins (100%)

Neuropeptide K (67%) Neurotensin (19%) 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%

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, 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

Associated with MEN I ~10% cases

Commonly large intestine synchronous adenocarcinoma

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 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, and growth pattern

Gastrointestinal Carcinoid

Most common site (Sabiston)

(Cheek RC et al) According to SEER database of 11,427 carcinoids 19731997


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

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

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 adequate >2cm right hemicolectomy 1 to 2 cm decide by location

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

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)

>2cm

80%

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

Size

Metast asis

1cm
11.9cm >2cm

Rare
~10% >70%

Often to lymph nodes or 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. 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; 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
Majority

are asymptomatic and found incidentally at time of surgery, endoscopy, or autopsy [80%]

When

presentcorrelate 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


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

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)

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, >5000g/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, highresolution 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