The case
A 48-year-old man with a 6 month history of diarrhea, flushing and upper abdominal pain was referred to the neuroendocrine tumor unit by his oncologist. He had experienced a weight loss of 10 kg over this period, as well as exertional dyspnea with resultant diminished tolerance to exercise. Clinical examination revealed cachexia and gross hepatomegaly. Elevated jugular venous pressure, systolic murmur and mild ankle edema were noted.
CT of the abdomen revealed a 15 
9 12 cm tumor in segment 3 of the liver, which was compressing the stomach. Several smaller metastases were present throughout the rest of the liver (Figure 1a). A 3.2 2.2 cm nodule was noted in the small-bowel mesentery, together with thickening of the terminal ileum, suggesting the diagnosis of a primary small-bowel carcinoid tumor with mesenteric involvement. Liver biopsy revealed a well-differentiated neuroendocrine tumor (Figure 1b). Immunohistochemistry demonstrated positive staining for chromogranin, which indicated that the tumor was of neuroendocrine origin with a Ki-67 proliferation index of <2%, indicating a low-grade tumor (Figure 1b). 111In-pentetreotide scintigraphy (Octreoscan™, Mallinckrodt Inc., St Louis, MO) showed avid uptake of radiolabeled somatostatin analog at the tumor sites (Figure 1c). Serum chromogranin A levels were above 1,000 pmol/l (normal range <60 pmol/l). Urinary 5-hydroxyindoleacetic acid (5-HIAA) levels were 800 
mol/24 h (normal range 0–42 mol/24 h).
Figure 1 | Tumor detection and identification.
a | CT of abdomen showing a large deposit in segment 3 of the liver, which is compressing the stomach (arrow). Multiple, smaller bilobar metastases are also present. b | Hematoxylin and eosin stain x 400 (upper panel) demonstrates a well-differentiated carcinoid tumor composed of uniform cells with eosinophilic cytoplasm. Positive staining for chromogranin (lower panel) confirms the neuroendocrine origin of the tumor. c | 111In-pentetreotide scintigraphy (Octreoscan™) demonstrating avid uptake at tumor sites (arrow). d | Macroscopic view of the wedge resection of segment 3 of the liver showing the necrotic, hemorraghic tumor within the liver capsule (arrow).
Echocardiography revealed features consistent with carcinoid heart disease (CHD). Tricuspid and pulmonary valve leaflets were thickened, retracted and fixed. Severe tricuspid regurgitation, moderate pulmonary regurgitation and mild pulmonary stenosis were present. The right ventricle was mildly dilated but had good systolic function (Figure 2).
Figure 2 | Echocardiography and features of carcinoid heart disease.
a | Two-dimensional echocardiogram showing the dilated right ventricle (RV) and right atrium (RA), and thickened, fixed and retracted tricuspid valve (TV) leaflets. b | Color Doppler demonstrating severe tricuspid regurgitation (TR). c | Continuous wave Doppler demonstrating severe tricuspid regurgitation characterized by "Dagger" shaped Doppler pattern.
The patient was commenced on a somatostatin analog (subcutaneous octreotide 1 10-7 kg three times daily). After 2 months of octreotide treatment, his diarrhea improved but flushing and particularly abdominal pain persisted. After a review by the neuroendocrine multidisciplinary team, a decision was made to proceed with resection of the large volume left-lobe liver metastasis. This was in view of the severe local pain caused by the hepatomegaly, and cachexia attributed to gastric compression as well as persistent carcinoid syndrome. This procedure was followed by cardiac valve replacement to relieve cardiac symptoms.
As the raised hepatic venous pressure was likely to result in major and perhaps uncontrollable blood loss during resection of the large and highly vascular liver tumor, a unique surgical strategy was employed. After complete mobilization of the left lobe of the liver, the vascular inflow and outflow of the large liver tumor were blocked by a series of mattress sutures through the entire thickness of the adjacent normal liver. These mattress sutures were ligated at the capsular surface by use of a series of supporting buttresses. This drastically reduced the vascularity to the tumor and allowed the liver parenchyma to be divided in a standard fashion using an ultrasound dissector (Cavitron Ultrasonic Surgical Aspirator [CUSA™], Integra LifeSciences Corporation, Plainsboro, NJ). This device disrupts the liver parenchyma at the resection site, allowing ligation and division of the vessels and bile duct branches. The resected mass showed signs of hemorrhage within the neuroendocrine metastasis and was associated with clear resection margins (Figure 1d). The complex and high-risk nature of this patient's liver resection precluded concomitant removal of his primary tumor.
Administration of anesthesia or performing interventional/surgical procedures may precipitate a carcinoid crisis, characterized by the release of large quantities of vasoactive amines into the circulation, causing hypotension, wheezing and flushing. An intravenous infusion of 5 10-8 kg/h octreotide was administered for 12 h before surgery and 48 h post surgery in order to prevent a potential carcinoid crisis. The patient had an uneventful postoperative recovery. His appetite improved and he gained more than 5 kg in weight over the next few months. The symptoms of diarrhea, flushing and abdominal pain had resolved. Serum chromogranin A and urinary 5-HIAA levels dropped to 34 pmol/l and 46 mol/24 h, respectively. The octreotide dose was titrated up to 2 10-7 kg three times a day and he subsequently received a long-acting monthly formulation (Sandostatin LAR® [Novartis Pharmaceuticals Corporation, East Hanover, NJ] 20 mg).
Six months later he underwent cardiac valve surgery to replace his tricuspid and pulmonary valves. His cardiac status improved and his ankle edema disappeared. Two years after his valve replacement he remains in functional New York Heart Association Class I. Presently, the patient has declined further surgical intervention to remove his primary small-bowel carcinoid tumor.
Diagnosis
Carcinoid tumors commonly originate in the gastrointestinal tract with an incidence ranging from 2.5 to 5 cases per 100,000 population.1 The small bowel (including the appendix) is the most common location for gastrointestinal carcinoids. Small-bowel carcinoid tumors can be asymptomatic for many years but may present with obstructive features such as abdominal pain, nausea and vomiting. Carcinoid syndrome characterized by diarrhea, flushing and bronchospasm may develop when the tumor metastasizes to the liver. It is thought that the release of vasoactive substances, including 5-hydroxytryptamine (5-HT), tachykinins and bradykinins, are responsible for the development of this syndrome.1
Chromogranin A is a glycoprotein released by tumor cells. The level of chromogranin A is raised in more than 80% of patients with carcinoid tumors. Levels of this glycoprotein can correlate with tumor load. Measurement of 5-HIAA (a 5-hydroxytryptamine metabolite) levels in urine during a 24 h collection is used as a specific marker in carcinoid syndrome. Certain foods such as bananas and avocado, and certain cough medications affect urinary excretion of 5-HIAA and should be excluded before collection.2
The ability to detect primary tumors and secondary tumor deposits depends on the imaging modalities used and also varies according to the extent, nature and location of a patient's tumor. A multimodality approach is usually required. The sensitivities of CT, MRI and ultrasonography for the detection of primary carcinoid tumors are 46%, 56% and 64%, respectively and 83%, 85% and 88%, respectively for the detection of liver metastases.3 The best imaging modality for carcinoid tumors, however, is 111In-pentetreotide scintigraphy (Octreoscan™, Mallinckrodt Inc.), which is used because carcinoid tumors express high levels of somatostatin receptors, especially types 2 and 5, which can bind to somatostatin analogs. Octreoscan™ (Mallinckrodt Inc.) is positive in 80–90% of patients, which can help to identify both the primary tumor and nodal metastases. It is currently the most sensitive imaging modality for identification of hepatic metastases.3 Histological examination of a biopsy sample is required for diagnostic confirmation and determination of the histological grade of the tumor.
CHD occurs in over 50% of patients with carcinoid syndrome.4 Vasoactive substances are thought to be produced by metastatic tumor cells in the liver. These substances are able to reach the right side of the heart and are associated with the deposition of fibrotic plaques on the endocardial surfaces of the right side of the heart. This deposition results in damage to valve structures, producing valvular regurgitation and/or stenosis. Involvement of the left-sided heart valves is not common because 5-HT is deactivated by the lungs. Metastatic spread to the heart is rare.4
Although the signs and symptoms of right-sided heart failure, including fatigue, shortness of breath, ascites and peripheral edema, will eventually ensue, the onset of symptoms may be insidious. Echocardiography remains the gold standard for diagnosis of CHD in patients with carcinoid syndrome.
Differential diagnosis
There can often be a delay of several years before the diagnosis of carcinoid syndrome is made. Patients might not present with the classical array of symptoms. Patients with vague, intermittent abdominal pain or diarrhea, after extensive investigation, might be diagnosed as having functional gastrointestinal disorders such as irritable bowel syndrome. This may be due, in part, to the limitation of imaging modalities in detecting the primary tumor and small liver metastases.
Treatment and management
Initial therapeutic options aim to provide symptomatic relief from the effects of excessive hormone secretion with biotherapy. Somatostatin analogs, designed to reduce circulating tumor metabolites, including 5-HT, are the mainstay of management. A biochemical and symptomatic response is achieved in 50–70% of patients and an antitumoral response in 5–10%. Interferon-
has a similar effect to somatostatin analogs on symptom control but is generally regarded as a second-line therapy owing to its adverse-effect profile.5
Patients with unilobar or bilobar liver metastases, but without extrahepatic spread, should be assessed for the possibility of curative surgical resection. The 5 year survival rate is greater than 60% in patients who undergo resection of liver metastases compared with 30% in unresected historical controls, and over 90% of patients who undergo resection achieve relief of symptoms.6 Whenever surgery is possible resection of the primary tumor and liver metastases is recommended, either as a one or two-step procedure.6, 7 Palliative resection should be considered in patients who remain symptomatic despite the use of medical therapy if more than 90% of the tumor load can be removed, as this can achieve survival benefit and good symptom control.6, 7, 8 When liver metastases are clearly unresectable, removal of the primary tumor should still be considered as this might prevent subsequent local complications of small-bowel obstruction or mesenteric ischemia. In patients with liver metastases who are not suitable for surgery, transarterial embolization or radiofrequency ablation offer good symptom control, although improved survival has yet to be demonstrated with these approaches.7 In patients with diffuse unresectable liver metastases, systemic therapy or, in selected cases, liver transplantation are also options.
In patients with liver metastases and extrahepatic spread or those patients who are not suitable for surgical intervention, systemic therapy is recommended in those who remain symptomatic or have progressive disease despite somatostatin or interferon- use. Radionuclide targeted therapies (for example, 131I metaiodobenzylguanidine, 90Y or 177Lu labeled somatostatin analogs for peptide receptor targeted therapy) in patients with an avid uptake on Octreoscan™ (Mallinckrodt Inc.) have produced symptomatic response in up to 80%. A partial tumor response in up to 35% of patients and disease stabilization in up to 56% of patients has been reported. Myelosuppression after radionuclide targeted therapy is generally mild and transient. Renal dysfunction is uncommon and associated with the total dose and type of isotope used. Co-administration of amino acids might reduce the risk of developing renal dysfunction.9 Chemotherapy drugs, either used as single agents or in combination (streptozotocin, 5-fluorouracil, doxorubicin) are rarely effective, and produce responses in less than 15% of patients.9 Newer agents, including monoclonal antibodies targeted to VEGF, tyrosine kinase inhibitors, and inhibitors of mammalian target of rapamycin signaling pathways, are currently being evaluated. Initial reports of a partial response in up to 20% of patients have been documented (Figure 3).1
Figure 3 | Management algorithm for patients with metastatic midgut carcinoid tumor.
Abbreviations: mTOR, mammalian target of rapamycin; RFA, radiofrequency ablation; TAE, transarterial embolization.
In CHD, medical treatment consists mainly of diuretic therapy. In severe cases cardiac valve replacement improves functional capacity and survival.10, 11 Concerns regarding the high perioperative risk associated with valve surgery in patients with CHD and the risk of bioprosthetic valve degeneration (owing to redeposition of fibrotic plaques) may have restricted referrals for valve surgery. Modern antitumor therapies might protect the valves from degeneration. The perioperative mortality caused by cardiac surgery for treating CHD has reduced from over 20% in the 1980s to less than 10% in recent years.11
Valve surgery should ideally be carried out before major liver resection as this provides greater hemodynamic stability during a major surgical procedure. In this particular case, liver resection was carried out before valve surgery because of intractable pain, uncontrolled carcinoid syndrome and progressive cachexia. Prior valve surgery avoids the grossly elevated right-sided heart pressures, which result in catastrophic and uncontrollable bleeding from hepatic vein branches within the transected liver parenchyma unless an individualized surgical approach is adopted, as seen in the present case. The procedure of buttress suturing of the liver is well established and was originally described in 1897.12 This procedure has been used in the management of liver trauma.13 Potential complications of the technique are liver parenchymal necrosis from compression, which can lead to sepsis.14 Buttress suturing has largely become obsolete with modern surgical techniques for parenchymal transection replacing this approach.15 This case highlights the importance of having a wide experience of surgical techniques when dealing with complex liver resections in patients with carcinoid liver disease. The principle of intraoperative surgical devascularization can supplement modern surgical techniques in the management of vascular tumors at other sites.
Conclusions
This case illustrates how the management of each patient with metastatic carcinoid tumor is unique, requiring a stepwise approach using a variety of modalities, within the setting of a multidisciplinary team, to provide timely, coordinated and effective patient-focused care.
