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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)
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
Tachykinins
Kallikrein Substance P (32%)
Peptides
Other
Dopamine
HCG, Human chorionic gonadotropin; 5-HIAA, 5-Hydroxyinoleacetic acid; 5-HT, 5-Hydroxytryptamine; 5-HTP, 5-Hydroxytryptophan
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
Metastasis to liver
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
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
Lewin, KJ, Appelman, HD. Tumors of the esophagus and stomach. Atlas of tumor pathology (electronic fascicle), 1996.
Gastrointestinal Carcinoid
1. Appendix (45%)** 2. Small intestine (28%) (last 2ft of ileum) 3. Rectum (16%)
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
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
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
Carcinoid of ileum
Colon
7th decade Presenting with abdominal pain, anorexia, or weight loss Carcinoid syndrome uncommon Majority in right colon
Cecum
Colon
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%
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
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
venous drainage from a metastatic tumor in the liver goes directly into the systemic circulation and bypasses hepatic inactivation
Liver metastases
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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%)
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
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
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
Staging
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