CARCINOID TUMORS- great article from OncologyStat (click title for link to article)

Carcinoid Tumors

Surg Oncol Clin N Am. 2006 Jul;15(3), Rebecca S. Sippel, Herbert Chen

(Note: I have seen Dr Chen- March 2009 @ U Wisconsin Medical Center- good Carcinoid MD, very upfront, but I didn't want to do the experimental drug we was offering me......)

ABSTRACT

Background

In 1888, Otto Lubarsch provided the first description of the small multicentric tumors now know as carcinoid tumors, but Oberndorfer [1] was the first to apply the term karzinoid in 1907, describing a tumor that resembled an adenocarcinoma, yet behaved in a more benign fashion. The hormonal production of these tumors was not discovered until much later. In 1954, Thorson was the first to describe the clinical carcinoid syndrome. Four years later, Lembeck identified serotonin as the major hormone responsible for that syndrome.

Carcinoids are derived from Kulchitsky or enterochromaffin cells, which are part of the diffuse neuroendocrine cells of the gut. The estimated prevalence of carcinoid tumors is 1 to 2 cases per 100,000 people, accounting for just 0.5% of all malignancies [2]. Most carcinoids are found in the gastrointestinal (GI) tract (67.5%), with pulmonary carcinoids accounting for the next largest group [3]. The most common locations in the GI tract are the small bowel (25%), rectum (14%), and appendix (12%) [3,4]. The epidemiology of carcinoids has evolved over the past several decades. The number of appendiceal carcinoids has decreased, whereas the number of rectal and stomach carcinoids have dramatically increased. A major reason for this shift is the increased use of upper and lower endoscopy. Lesions that may not have been identified previously are being identified at a very early, presymptomatic stage.

The diagnosis of a carcinoid tumor is based on histology with confirmation by immunohistochemical staining with neuroendocrine markers. Various substances are secreted by carcinoid tumors (Box 1). Serotonin or 5-hydroxytryptamine (5-HT) is the most commonly secreted substance and can cause the symptoms of the classic carcinoid syndrome, consisting of flushing, diarrhea, bronchoconstriction, and ultimately valvular heart disease.

Unfortunately, histologic examination cannot predict the aggressiveness or metastatic potential of carcinoid tumors. Malignancy is based on the presence of metastatic disease. The most common sites of metastases are the lymph nodes, the liver, and, less frequently, bone.

The prognosis of carcinoid tumors varies greatly depending on the location of the tumor and the extent of spread at diagnosis. Despite having a reputation as an indolent tumor, the 5-year survival for these tumors is only 63%, and 13% of patients already have metastatic disease at diagnosis [3].

Several classification systems have been proposed to subdivide carcinoid tumors into groups to predict their behavior [5]. The oldest classification system, first proposed in 1963 by Williams and Sandler [6], divided carcinoids into subgroups based on their embryologic site of origin, including foregut (lung, stomach, pancreas), midgut (small bowel, appendix, proximal colon), and hindgut (distal colon and rectum). They based this division on the fact that tumors in each group had similar staining characteristics when stained with silver. The problem with this classification system is that it groups tumors together that clearly behave differently clinically. For example, appendiceal and cecal carcinoids are considered midgut tumors but have very different prognoses. Because of this concern, many authors have chosen to subdivide carcinoid tumors based on their organ of origin. A third classification system uses only histologic criteria to define tumors as either typical or atypical. Typical carcinoids are well differentiated and have clear neuroendocrine features, whereas atypical carcinoids have increased nuclear atypia, have higher mitotic activity, and contain areas of necrosis.

With all of these classification systems being applied in the literature, comparing studies and determining the efficacy of interventions is difficult. To clarify the classification of carcinoid tumors and provide a system that would enable clinicians to compare patients and predict outcomes, the World Health Organization developed a revised classification system in 2000 [7]. The new classification system incorporates the site of origin and histologic features. To minimize confusion, the term carcinoid is now discouraged and these tumors are simply referred to as neuroendocrine tumors. The tumors are divided into three main categories based on histologic features and malignant potential: (1) well-differentiated neuroendocrine tumor (benign vs. uncertain malignant potential), (2) well-differentiated neuroendocrine carcinoma (low-grade malignancy), and (3) poorly differentiated neuroendocrine carcinoma (high-grade malignancy). The tumors are then further subdivided by organ of origin.

Tumors by organ site of originPulmonary carcinoid tumorsPulmonary carcinoids account for 2% of primary lung tumors and approximately 25% of all carcinoid tumors [2,8]. These tumors can be classified as typical or atypical based on their histologic features. Two thirds of pulmonary carcinoids are considered typical, are found in a perihilar location, and most commonly occur in the fifth decade. Carcinoid syndrome occurs in fewer than 5% of these patients, with more common symptoms being recurrent pneumonia, cough, hemoptysis, or chest pain [8]. These tumors are found to be metastatic in approximately 12% of cases and have a 5-year survival rate of 93% [9]. Atypical carcinoids, defined by their increased cellular atypia, typically occur in the periphery of the lungs and arise in older patients [10,11]. Their course is more aggressive, with up to 50% having lymph node metastasis, leading to a 5-year survival rate of only 40% to 75% [9–11].Gastric carcinoid tumorsThe incidence of gastric carcinoid tumors has increased in recent years, probably because of the increased use of upper endoscopies in evaluating patients. The three main types of gastric carcinoids have separate causes and very different prognoses. Type 1 gastric carcinoids are the most frequent, accounting for 63% to 75% of cases [12,13]. These tumors develop in patients who have type A chronic atrophic gastritis (CAG-A) and are believed to be caused by overproduction of gastrin. These tumors tend to be nonfunctional and asymptomatic [14]. Type 1 gastric carcinoid tumors rarely metastasize [12]. Type 2 gastric carcinoids are rare (0%–10%) and arise in the setting of multiple endocrine neoplasia 1 and Zollinger-Ellison syndrome [12]. These tumors are often multiple and display a low grade of malignant behavior [13]. Hypergastrinemia plays an important role in stimulating the growth of type 1 and type 2 gastric carcinoids, although hypergastrinemia alone is not believed to be causative [15]. Type 3 gastric carcinoids are the sporadic variety and account for 13% to 20% of tumors [14]. These tumors are often large (>2 cm) and metastatic with a 5-year survival rate of 75% [12]. Gastric carcinoids may cause an atypical carcinoid syndrome that includes flushing, hypotension, lacrimation, edema, and bronchoconstriction, or they may secrete ACTH. They may secrete small amounts of 5-HTP, but because they lack the enzyme aromatic acid decarboxylase are unable to convert it to its active form of 5-HT. Therefore, 5-HT and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels are often normal in these patients.Small intestinal carcinoid tumorsThe most common location for carcinoid tumors is the small bowel (29%), with more than half occurring in the distal ileum [2]. These tumors present in the sixth or seventh decade and are frequently multicentric [16]. Patients typically present with symptoms of abdominal pain or intestinal obstruction. These lesions can create a characteristic fibrotic reaction in the mesentery that may cause kinking of the bowel, leading to intermittent obstruction or intestinal ischemia. These tumors tend to grow slowly and have a prolonged disease course. The classic carcinoid syndrome is present in only 5% of patients [17]. Most of these lesions have spread to the lymph nodes (39%) or have distant metastases (31%) at diagnosis [2]. The extent of disease spread at diagnosis is closely correlated with the patient's 5-year survival. The presence of liver metastases and significant preoperative weight loss are major negative prognostic factors [18]. The 5-year survival rate is 65% with localized/regional disease, but falls to 36% when distant disease is present [2].Appendiceal carcinoid tumorsMost appendiceal carcinoids are diagnosed incidentally during surgery. More than half of patients who have appendiceal carcinoids present with signs and symptoms that suggest acute appendicitis [19]. Appendiceal carcinoids are most frequently located at the tip of the appendix, although they can be located throughout the appendix [20]. The most common age at diagnosis is in the fourth or fifth decade [2]. The prognosis of appendiceal carcinoids is very good. The 5-year survival rate is 94% for local disease, 85% for regional metastasis, and 34% when distant metastases are present [2].Colonic carcinoid tumorsColonic carcinoid tumors are rare and typically present during the seventh decade. These tumors are more frequent in women and are often symptomatic at diagnosis, with abdominal pain being the most common complaint [21]. The carcinoid syndrome is present in fewer than 5% of patients [21]. These tumors tend to be large and are most commonly located in the right colon [22]. At diagnosis, approximately 44% have spread to the lymph nodes and 38% have spread to distant locations. The overall 5-year survival rate for patients who have these lesions is 25% to 41% [2,21,22].Rectal carcinoid tumorsBecause of enhanced screening, the rectum is quickly becoming one of the most common locations for carcinoid tumors [23]. Approximately 50% of these tumors are diagnosed incidentally on routine endoscopy. The remaining patients typically present with symptoms of rectal pain, bleeding, or constipation [23]. The typical carcinoid syndrome is very rare. The size of these tumors correlates closely with their risk for metastasis and survival rates. The 5-year survival rates for these patients is 81% if only local disease is present, 47% if regional metastases are present, and 18% if distant metastases are found [2].DiagnosisLaboratory testsCarcinoid tumors have been traditionally diagnosed through a 24-hour urine measurement of the serotonin metabolite 5-HIAA. Elevated 5-HIAA levels have been found to have a 100% specificity and a 73% sensitivity [24]. Platelet serotonin levels are more sensitive than urinary 5-HIAA levels and may be useful in patients who have tumors that produce low levels of serotonin [25]. Urinary serotonin levels also can be elevated and seem to correlate with an elevation in platelet serotonin levels [25]. Platelet and urinary serotonin levels are highly specific, although their sensitivity remains modest around 65%. When 24-hour urine 5-HIAA levels are combined with platelet and urinary serotonin levels, 84% of patients will have at least one positive test.The most sensitive biomarker for carcinoid tumors in chromogranin A. Chromogranin A is a glycoprotein that is stored in and released from neuroendocrine cells [26]. Its sensitivity ranges from 87% to 100% [27], but it is limited in its lack of specificity. False-positive results with chromogranin A can occur with liver or kidney failure, inflammatory bowel disease, atrophic gastritis, or the chronic use of proton pump inhibitors [26]. Because midgut carcinoids tend to produce high levels of serotonin, the sensitivity of chromogranin A (87%) is only slightly better than urinary 5-HIAA levels (75%). However, in foregut and hindgut tumors, chromogranin A is substantially more sensitive (87% and 100%, respectively) than urinary 5-HIAA levels (31% and 0%) [27,28]. Chromogranin A levels can be very useful in monitoring patients for recurrence [27]. In fact, a direct correlation seems to exist between chromogranin A levels and tumor burden [26].Imaging testsCT scans are the most commonly used method to image carcinoid tumors and their metastases, but its sensitivity in detecting the primary tumor is poor (44%–55%). CT scanning is much more helpful in identifying the presence of metastatic disease, specifically liver metastases (Fig. 1) [29].Nuclear imaging plays an important role in the localization of carcinoid tumors. Somatostatin receptor scintigraphy (SRS) or octreotide scanning is the most useful localizing procedure for carcinoid tumors. Approximately 87% of carcinoid tumors have somatostatin receptor on their surface and can bind either somatostatin or its analogs [30]. The sensitivity of SRS is estimated to be up to 87%. The positive predictive value of SRS is 100% (Fig. 2). Another nuclear imaging technique that has been used to localize carcinoids is 131I-methyl iodobenzylguanidine scintigraphy (MIBG). MIBG scans are positive in approximately 60% to 70% of all carcinoid tumors [31]. In a study of 20 patients, Taal and colleagues [32] evaluated combined MIBG and SRS and found an overall sensitivity of 95%.Traditional positron electron tomography (PET) scanning has not been useful in localizing carcinoid tumors because of their indolent course and low metabolic rates. However, recent studies have used the serotonin metabolic pathways inherent to these tumors to localize lesions. PET using 11C-labeled 5-hydroxytryptophan was compared with CT in 18 patients and was found to better visualize the tumor in more than 50% of cases [33]. This technique shows promise, although experience is currently very limited.Although endoscopy is not typically used to localize a primary tumor, carcinoids are increasingly being diagnosed as incidental findings during upper and lower endoscopy. Endoscopic ultrasound has also played an important role in localizing tumors within the head of the pancreas and appropriately staging rectal tumors.Upper gastrointestinal and small bowel series are frequently ordered to localize a carcinoid tumor within the small bowel. Although carcinoid tumors can create filling defects, these findings are nonspecific and tumors are frequently missed. Barium enema has a poor sensitivity for rectal lesions, but can be useful in diagnosing more proximal colonic lesions.Surgical treatment of the primary tumor

The preferred treatment for carcinoid tumors is surgical resection. The extent of resection for the primary tumor is determined by the size of the tumor and its location (Table 1) [34]. The prognosis after surgery is based on not only the location of the primary tumor but also the extent of the disease and the histology of the tumor. Retrospective studies have attempted to identify variables that may help define prognostic significance. In a review of 188 patients with carcinoid tumors, McDermott and associates [35] identified several significant negative prognostic factors: increased tumor size, increased depth of invasion, small bowel location, and the presence of either lymph node or hepatic metastases. Positive prognostic factors included female gender and incidental discovery of the tumor. In a multivariate analysis of 150 patients, Shebani and associates [16] found in that age older than 50 years, the presence of metastases, and male gender were all significant predictors of death. Histochemical indicators of a poorer prognosis include increased expression of Ki-67 and p53 [36].

Pulmonary carcinoid tumorsPulmonary carcinoids are treated with surgical resection. If the tumor is smaller than 2 cm, a wedge or segmental resection can be performed. If the tumor is larger than 2 cm the treatment of choice is a segmental resection or lobectomy.Gastric carcinoid tumorsType 1 tumors are usually asymptomatic. If they are smaller than 2 cm, they can be either observed or removed endoscopically [14]. Tumors larger than 2 cm can be either removed endoscopically if amenable or surgically resected. Because hypergastrinemia is a major stimulus for the growth of type 1 and type 2 carcinoids, antrectomy has been suggested as a treatment adjunct for large or recurrent tumors [37,38]. Antrectomy with subsequent normogastrinemia has been shown to cause regression and stabilization of type 1 and type 2 tumors [39,40]. Type 2 carcinoids develop in the setting of multiple endocrine neoplasia 1 and Zollinger-Ellison syndrome [12]. Because multiple lesions are frequently present, the treatment of these tumors is controversial. If lesions are smaller than 2 cm, they can be either observed, especially if multiple, or endoscopically removed if isolated. When the tumors are larger than 2 cm, the lesions may be excised either endoscopically or surgically. When these tumors become larger, gastrectomy is the preferred treatment. For type 3 gastric carcinoids, the prognosis is much poorer and the preferred treatment is total gastrectomy regardless of tumor size [12,41].Small intestinal carcinoid tumorsNodal disease is present in most patients who have small bowel carcinoids. Mesenteric metastases can encase the mesenteric vessels and lead to a fibrotic reaction that can cause acute or chronic mesenteric ischemia or obstruction. Hence, the preferred treatment for these tumors is a small bowel resection with the associated mesentery [42]. These tumors are often slow-growing with a prolonged course of disease, making surgical treatment very important in the long-term management of these patients. Because of the complications of obstruction and ischemia, an aggressive surgical approach to the resection of mesenteric disease should be taken [18,43]. Resection of the primary tumor and the mesenteric lymph nodes leads to a significant reduction in tumor-related symptoms. Hellman and colleagues [18] showed that resection of mesenteric lymph nodes can also cause a prolongation in survival. Most patients who have small bowel carcinoids will ultimately be treated with octreotide, which is associated with a high incidence of cholelithiasis. Because of this side effect, surgeons should consider performing a cholecystectomy in any patient undergoing a laparotomy to treat a carcinoid.Appendiceal carcinoid tumorsWhen tumors are smaller than 1 cm, simple appendectomy is considered adequate treatment. Tumors larger than 2 cm have an approximately 33% risk for lymph node metastasis, so most experts would advocate a right hemicolectomy as the appropriate treatment option [19,44]. The optimal treatment for tumors 1 to 2 cm is greatly debated. The mesentery should be careful evaluated for invasion or lymph node metastasis and, when present, a right hemicolectomy should be performed. Many clinicians lean toward a more aggressive approach in younger patients.Colonic carcinoid tumorsApproximately half of these tumors have lymph node involvement at diagnosis; hence, a formal hemicolectomy with mesenteric resection is the preferred treatment. Occasionally very early tumors found incidentally during colonoscopy may be treated with local excision [22].Rectal carcinoid tumorsThe size of these tumors is closely correlated with their risk for metastasis and survival rates. Metastases occur in fewer than 5% of patients who have a tumor smaller than 1 cm, and these tumors can be treated successfully with local excision [23,45]. Tumors larger than 2 cm are usually associated with metastatic disease and most have been treated with a low anterior resection or an abdominal perineal resection [45]. However, some experts have questioned the role of extensive surgery in these patients because no survival advantage over local excision alone has been shown [46,47].Surgical debulkingBeyond surgical resection, treatment options are limited for patients who have carcinoid tumors. Because these tumors often have a protracted course, surgery plays an important role in managing these patients at all stages of disease. Bowel obstruction secondary to peritoneal carcinomatosis is a major cause of mortality in these patients. Aggressive surgical debulking for patients who have advanced disease has been advocated by many experts [48–51]. Although surgery may not be curative, it can significantly improve symptom control and patient quality of life. In a recent study, mesenteric encasement leading to intestinal ischemia was successfully relieved in 10 of 12 patients [50]. Surgical debulking may also lead to a prolonged survival [42,49].Carcinoid syndrome and carcinoid heart disease

Carcinoid syndrome occurs because of the overproduction of 5-HT and tachykinins [14]. This syndrome, characterized by flushing, diarrhea, bronchoconstriction, and valvular heart disease, can be provoked by tyramine-containing foods, stress, or alcohol [5]. Carcinoid syndrome occurs in fewer than 10% of patients and almost exclusively in the presence of liver metastases [5].

Carcinoid heart disease, rather than tumor growth, is the cause of death in approximately one third of these patients [27]. Carcinoid heart lesions consist of endocardial thickening and fibrosis that classically involves the right side of the heart [8]. These lesions cause tricuspid regurgitation and pulmonary stenosis, with subsequent development of pulmonary hypertension [52]. Right-sided valvular heart disease is a late complication of the disease and is believed to be caused by chronic overproduction of serotonin [52]. Patients who have heart disease tend to have higher levels of serotonin, although whether serotonin is directly responsible for the damage is unclear. The recent discovery of similar heart lesions in patients taking the anorectic drug fenfluramine, which interferes with serotonin metabolism, suggests that the role of serotonin is essential in the pathogenesis of these lesions [53,54]. These findings have also been confirmed in a murine model of carcinoid heart disease [55]. The left side of the heart is typically spared because of the enzymatic breakdown of serotonin, which occurs in the lungs. Valve surgery is the only definitive treatment for carcinoid heart disease [56]. However, this surgery is associated with a significant mortality rate, especially in older patients, and requires careful preoperative risk stratification [57].

Management of metastatic disease

Surgery is the mainstay of treatment for all patents who have carcinoids. However, a significant number of patients present with synchronous or metachronous metastatic lesions. Multiple treatment options are available for managing hepatic metastasis and widespread disease [58]. Many of these therapies have the goal of improving quality of life by controlling hormonal symptoms. The management of metastatic disease is discussed separately elsewhere in this issue.

The role of octreotideSomatostatin mediates its actions through five different receptors. The receptor subtypes that are recognized by the clinically used somatostatin analogs are subtypes 2 and 5 [59]. Somatostatin analogs bind to the somatostatin receptors and inhibit hormone production. The two commercially available somatostatin analogs are octreotide and lanreotide. Octreotide has a short half-life and requires subcutaneous injection two to three times per day to reach therapeutic levels. Lanreotide is a long-acting somatostatin analog that can be administered through intramuscular injection two to three times per month.Numerous studies have shown that octreotide and lanreotide are highly effective in reducing tumor markers and controlling symptoms in patients who have carcinoid tumors [60–63]. Comparison studies have shown that these treatments are equally effective in controlling symptoms and reducing tumor markers [61,64,65]. A clinical trial at the Mayo Clinic found that supplemental subcutaneous octreotide is needed for approximately 2 weeks after initiation of a long-acting treatment until steady-state levels from the long-acting formulation are achieved [65]. In a crossover study comparing the two drug regimens, 68% of patients preferred lanreotide over octreotide, largely because of its simplified mode of administration [61].Several studies have suggested an antitumor effect of octreotide therapy [66–69]. In a study of 35 patients, Aparicio and associates [68] found that octreotide stabilized disease in 57% of patients for a median duration of 11 months, and that a slow tumor growth rate was the best predictor for a good response to octreotide therapy. Unfortunately, the antitumor effect of octreotide seems to be transient, with diminishing effectiveness over time [67]. Although most reports show disease stabilization with octreotide, some have shown actual tumor shrinkage, but this occurs in fewer than 10% of patients [63].Several reports have shown the usefulness of octreotide in managing and preventing the complication of carcinoid crisis at surgery [70–72]. Because of these data, the perioperative use of octreotide for preventing and managing carcinoid crisis is an essential part of patient care.The most common side effect of octreotide is cholelithiasis, which can occur in up to 50% of patients [29]. Because of the high incidence of cholelithiasis, surgeons should consider performing a cholecystectomy with any intra-abdominal surgical resection. Other side effects include nausea, vomiting, abdominal pain, dizziness, and steatorrhea.The future

Therapies directed at pathways that regulate carcinoid tumor growth and hormone secretion may become available in the future [73–77]. Several compounds have shown some efficacy in in vitro and in vivo models of carcinoid tumor progression [78,79]. More research is needed into the factors that regulate carcinoid tumor proliferation and differentiation.

Summary

Carcinoid tumors can present a difficult diagnostic and therapeutic dilemma. Despite their reputation as indolent tumors, they frequently metastasize and can cause significant symptomatology. The only curative therapy remains surgical resection. The prognosis and treatment of carcinoids vary based on location and histology, and therapy must be tailored to each patient.