BACKGROUND: Carcinoid or neuroendocrine tumors of the gastrointestinal tract, although characteristically indo- lent, are also quite heterogeneous both with ...
CURRENT STATUS
Gastrointestinal Carcinoid Tumors Current Management Strategies Muhammed Ashraf Memon, M.B.B.S., D.C.H., Heidi Nelson, M.D. From the Division o f Colon a n d Rectal Surge~, Mayo Clinic a n d Mayo Foundation, Rochester, Minnesota BACKGROUND: Carcinoid or neuroendocrine tumors of the gastrointestinal tract, although characteristically indolent, are also quite heterogeneous both with respect to histologic and endocrine features and with respect to clinical presentation and behavior. PURPOSE: This study was undertaken to review and summarize the current literature on classification controversies, site-specific carcinoid presentation and behavior, and diagnostic and management strategies for primary and advanced carcinoid tumors and the carcinoid syndrome. RESULTS: For carcinoid tumors, oncologic results depend on the location of the primary tumor, extent of locoregional and metastatic disease, functioning status of the tumor, and the feasibility of complete surgical extirpation. Whereas favorable survival rates are typically observed for appendiceal and rectal primaries, less favorable rates are often observed for colonic and ileal tumors. A search for additional tumors is generally advised because multiple carcinoids and second neoplasms are not uncommon. Because of the indolent nature of the tumor and because these therapies have been shown to hnprove quality and quantity of life, otherwise fit patients with advanced carcinoid disease should be treated with aggressive medical and surgical therapies. Development of a malignant carcinoid syndrome indicates the presence of a functionally active carcinoid tumor and portends a poor prognosis. CONCLUSION: Gastrointestinal carcinoids, although malignant, behave differently from other carcinomas. Results are highly variable and must be individualized according to the site of the primary tumor, extent of spread, and general condition of the patient. A prolongation of quality life can often be accomplished through aggressive medical and surgical therapies. [Key words: Carcinoid tumor; Carcinoid syndrome] Memon MA, Nelson H. Gastrointestinal carcinoid tumors: current management strategies. Dis Colon Rectum 1997;40: 1101-1118. C
arcinoids, first described in 1888 b y Lubarsch, 1 are indolent tumors of n e u r o e n d o c r i n e cell origin z with the capacity for amine precursor u p t a k e and
Supported by an American Cancer Society Career Development Award. Present address of Dr. Memon; Creighton University School of Medicine, Department of Surgery, Suite 3740, 601 North 30th Street, Omaha, Nebraska 68131. Address reprint requests to Dr. Nelson: Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. 1101
decarboxylation. 3 A l t h o u g h carcinoids m o s t often occur as primary tumors o f the gastrointestinal tract, they can also b e found, albeit m o r e rarely, outside the gastrointestinal tract, in such locations as the bronchus, ovary, lung, thymus, and kidney, to n a m e a few. Carcinoid tumors are extremely h e t e r o g e n e o u s , b o t h with respect to histologic and endocrinologic features a n d to clinical presentation a n d behavior, including metastatic potential. No d o u b t the histologic and endocrinologic h e t e r o g e n e i t y o f these tumors is at least in part responsible for their diverse clinical behavior. To achieve s o m e m e a s u r e of standardization, for purp o s e s of comparative analyses a n d communications, d e m a n d s the application o f a classification s c h e m a capable o f a c c o m m o d a t i n g diverse variables. Alt h o u g h several schemata have b e e n described, few have survived the evolution of k n o w l e d g e specific to this h e t e r o g e n e o u s disease. The best current s c h e m a is that p r o p o s e d b y Capella et al. 4
CLASSIFICATION The classification s c h e m a for n e u r o e n d o c r i n e tumors described b y Capella et al. 4 (Table 1) is b a s e d o n site o f origin (lung, pancreas, small intestine), t u m o r size (---0.9, 1,2, ->2 cm), extension into s u r r o u n d i n g tissue, angioinvasion, biologic b e h a v i o r (low, intermediate, or high grade), a n d histologic differentiation (well, moderately, or poorly) c o m b i n e d with functioning or n o n f u n c t i o n i n g status o f the tumor. "Functioning" in this context refers to the clinical presentation o f carcinoid s y n d r o m e s y m p t o m s in addition to elevated s e r u m h o r m o n e concentrations. In replacing the previous classification schema, Capella and colleagues c h a n g e d the w o r d carcinoid to n e u r o e n d o crine to reflect m o r e accurately the nature of the neoplasm. This s c h e m a incorporates all of the presently r e c o g n i z e d factors that influence prognosis. To better u n d e r s t a n d the influence of these individual
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Table 1. General and Cell-Specific Neuroendocrine Markers and Associated Syndromes and/or Symptoms General Markers
Cytosolic markers Neuron-specific enolase Protein gene product 9.5
Specific Markers
Peptides Adrenocorticotropin hormone (Cushing's syndrome) Calcitonin (hypercalcemia)
7B2
Motilin (diarrhea)
S-1 O0
Vasoactive intestinal peptide (vipomas) Parathyroid hormone (hyperparathyroidism) Neurotensin (neurostensinomas) Enteroglucagon (enteroglucogonomas) Insulin (insulinomas) Human chorionic gonadotropin
Small vesicle-associated markers
Synaptophysin Secretory granule-associated
Neuropeptide K Glucagon (glucagonomas) Gastrin (gastrinomas, Zollinger-Ellison's syndrome) Pancreatic polypeptide (somatostatinomas, pancreatic polypedidomas) Amines Dopamine (aberrant metal status) Serotonin (carcinoid syndrome) Hydroxytryptophan Histamine
markers
Chromogranins A, B, and C (secretogranin II) Leu 7
Kinin
Kallikrein
Growth hormone (acromegaly) Substance P (flushing attacks) Melanocyte-stimulating hormone (hyperpigmentation) Antidiuretic hormone
factors on patient prognosis, histologic and marker studies are discussed here, and clinical factors, such as size and location, are discussed below under each separate gastrointestinal location. Unique to carcinoid tumors are the neuroendocrine markers. It is not surprising, therefore, that key to understanding and classifying neuroendocrine tumors is the identification of neuroendocrine markers, 4 specifically markers that determine tumor phenotype. Markers help to establish the diagnosis for tumors that do not produce or secrete specific messengers. These neuroendocrine markers are divided into cytosolic markers, small vesicle-associated markers, and secretory granule-associated markers. Cell-specific or secretory neuroendocrine products 5 are typically peptides or amines that usually act as hormones or neurotransmitters. Elevated levels are usually responsible for producing side effects such as diarrhea, wheezing, and flushing (Table 1). Histologic growth patterns definitely influence survival. Five distinct histologic growth patterns have been identified for carcinoid tumors, r variably referred to as A t o D 7 or I to IVs (Table 2). Soga and Tazawa 7 demonstrated that histologic growth patterns and histochemical findings differ according to site.
Other Prostaglandins
They observed that foregut carcinoids were predominantly Type B, and argyrophilic or nonreactive, midgut carcinoids were Type A and argentaffin, whereas hindgut carcinoids were a mixed nonreactive type. Johnson et al. 9 in their retrospective analysis of 138 cases demonstrated the mixed growth (43 percent) pattern as the most prevalent diagnosis followed by insular (33 percent), trabecular (18 percent), undifferentiated (4 percent), and glandular (2 percent). Their data showed that among pure growth patterns, the best prognosis was observed in the insular and trabecular varieties, whereas the glandular and the undifferentiated had the worst prognosis. For the mixed growth pattern, insular and glandular patterns have the best prognosis, even better than the two pure varieties (Table 2). Although it can be concluded that the histologic growth pattern can be considered an independent prognostic factor, Johnson et al. 9 failed to show any difference in patient outcome w h e n different treatments were used based on histologic growth patterns. As yet, histologic growth patterns do not so much influence therapy as they predict outcome. Although the heterogeneity and complexity of these tumors must not be understated, a few generalizations can be made to guide clinical therapies.
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Table 2. Histologic Growth Patterns of Carcinoid Tumors Type of Classification Soga and Tazawa 7
Histologic Patterns
Martin
Comments and Prognostic Significance
and Potet 8
A
I
Insular (solid) nests with peripherN palisading
B
II
Trabecular or ribbon-like anastomosing pattern
C
III
D
IV
Glandular pattern characterized by a tubular, acinar, or rosette-like structure Undifferentiated
Mixed
Mixed
Any combination of the above four
First, several factors influence outcome and therapy, including the following: 1) primary tumor location; 2) extent of local disease and presence or absence of complications; 3) extent of metastatic disease and presence or absence of hormonal activity; and 4) surgical resectability. Second, because carcinoids are indolent tumors with generally g o o d five-year survival rates (Table 3), every effort should be m a d e to effect a cure and/or palliation using surgical and nonsurgical therapies. Third, a search for additional tumors should be considered w h e n performing surgical or radiologic evaluations, as multiple tumors and second neoplasms are not u n c o m m o n (Table 3). Mthough general review data provide a useful depiction of overall presentation of these tumors (Table 3), a m o r e precise analysis of their behavior is accomplished w h e n each site is considered separately as detailed below. Appendix Appendiceal carcinoids, arguably the most comm o n site of carcinoids, are most often incidental and, fortunately, have little influence on long-term prognosis. The reported prevalence of these tumors varies b e t w e e n 0.03 and 0.69 percent. 1~ That appendiceal carcinoids occur more frequently in w o m e n reflects the greater exposure of y o u n g w o m e n to surgery and incidental appendectomy. 1~ 15, 16 W h e n corrected for risk of incidental surgery, the overall male to female
Most frequent pure growth pattern Favorable prognosis Second frequent pure growth pattern Favorable prognosis Least frequent pure growth pattern Poor prognosis More common than glandular variety Poor prognosis A + C most frequently observed and most favorable prognosis A + B the next frequent mixed growth pattern, also have favorable prognosis All other infrequently observed mixed growth patterns have relatively unfavorable prognoses
ratio is equal. The average age of onset is 41 years. 13 Carcinoids most often present at the tip of the appendix (60-70 percent) and less often present within the b o d y (5-21 percent), base (7-10 percent), or diffusely (1.5-3.5 percent). 15-18 The majority of appendiceal carcinoids (60-76 percent) are smaller than 1 cm, with only 4 to 27 percent of them being b e t w e e n 1 and 2 cm and 2 to 17 percent of them being larger than 2 cm.13, 15, 16 Key points regarding the diagnosis and treatment of appendiceal carcinoids are summarized in Table 4. Appendiceal carcinoids are typically not aggressive in behavior, with the risk of metastasis reported as only being b e t w e e n 1,4 and 8.8 percent. 15' 17, 19--23According to a n u m b e r of studies, 13' 15, is, 21, 22, 24, 25 tumors greater than or equal to 2 cm are more often associated with regional and distant metastases (30-60 percent), whereas tumors smaller than 1 cm never metastasize, and tumors b e t w e e n 1 and 2 cm seldom regionally metastasize (0-11 percent). Based on these data, simple a p p e n d e c t o m y is r e c o m m e n d e d for all tumors smaller than 1 cm and right hemicolectomy for tumors larger than 2 cm. Appropriate treatment for tumors b e t w e e n 1 and 2 cm remains controversial. Because regional metastasis is a real possibility, treatment of tumors 1 to 2 cm in size should be individualized according to tumor location, the patient's health and age, presence of angioinvasion and/or subserosal lymphatic invasion, involvement of the
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