Illustrative Case Series
By Jerome Yates, MD, Hematology/Immunology Unit, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.
A 55-year-old woman presents to her primary physician with worsening diarrhea and abdominal discomfort. Symptoms first occurred 3 months prior to presentation, and were mild. However, for the prior month, the diarrhea had become moderate-to-severe, and was associated with abdominal cramping. She was employed as a medical receptionist, but for the two weeks prior to her visit, she had not been able to work. She had not travelled, and had no unusual change in her diet prior to her illness. No one in her family (husband, children, and grandchildren) was ill. She thought she was experiencing fever, but when she measured her temperature, it was always lower than 99°F. Physical exam in the office revealed a normal blood pressure, heart sounds, lung sounds, and abdominal exam. There was no tenderness, palpable organomegaly, or mass. A complete blood count and serum chemistries were normal.
She was referred to a gastroenterologist, who undertook an evaluation. Colonoscopy and upper endoscopy were normal. Chest, abdominal, and pelvic CT scans revealed two masses within the liver, one in the right lobe measuring 5 cm in diameter and the other in the left lobe measuring 3 cm in diameter. Ultrasound-guided needle biopsy of the lesion in the right lobe revealed a well-differentiated neuroendocrine tumor consistent with carcinoid.
The 24-hour urine 5-hydroxyindolacetic acid (5HIAA) level and serum chromagranin (CGa) were both elevated. The patient was referred to a medical oncologist for additional evaluation and recommendations regarding management.
This patient has a well-differentiated endocrine tumor, presumably carcinoid, and her symptoms are most likely the result of sporadic release of serotonin or other substances, such as tachykinins, prostaglandins, and bradykinins into the circulation. These tumors are uncommon, occurring in approximately 1 in 100,000 per year, and account for approximately 25% of all the neuroendocrine tumors of the upper intestinal tract.1-3 Most of these tumors are well-differentiated and have an indolent course. However, despite this, most are metastatic at the time of diagnosis.
In the current case, it would be reasonable to attempt to define and resect the primary lesion so as to prevent local complications, such as bowel obstruction or vascular compromise. To this end, imaging studies, including MRI and somatostatin receptor scintigraphy, could be very instructive,4 as would capsule endoscopy and/or double balloon enteroscopy.4 Also, an echocardiogram is warranted to determine cardiac involvement, as it occurs in almost 50% of patients.
There have been few clinical trials on which to base therapy, and because there is great variability in clinical presentation, treatment approaches must be tailored for each individual. That stated, there is general agreement that for those with carcinoid syndrome (flushing, diarrhea, bronchospasm, etc.), treatment with somatostatin analogs is a first priority. Once these symptoms are controlled, treatment directed at the tumor, per se, may be undertaken.
Somatostatin analogs, including octreotide and lanreotide, are generally effective in controlling tumor-related symptoms in about 50%-80% of patients.5 Such treatment should be undertaken before any debulking procedure to prevent "carcinoid crisis." For example, continuous-infusion octreotide, at a dose of 50 mg/hour, starting 12 hours before surgery and continuing a minimum of 48 hours post-operatively, has been recommended.6 Long-acting octreotide is currently available, and newer analogs, such as SOM-230, are currently under evaluation for patients who are refractory to octreotide.
With regard to anti-tumor approaches, surgery remains the greatest chance for extending life. However, as mentioned, most patients present with metastatic disease, and curative approaches are infrequent. For patients such as the current case, an exploratory laparotomy might be required to find the primary lesion. In addition to excision of the primary lesion, lymphadenectomy should be undertaken, as well as cholecystectomy in anticipation of future use of somatostatin analogs and hepatic arterial embolization. For patients with one or two approachable hepatic lesions, and a presurgical evaluation which indicates no extrahepatic tumor deposits, surgical resection of the metastatic deposits may provide improved survival.7
Hepatic metastases also may be approached successfully by interventional radiologists using trans-catheter arterial embolization (TAE) or chemoembolization (TACE).8 Such approaches have resulted in objective tumor response rates in up to 86% of cases.8-10 Similarly, radiofrequency ablation (RFA) has a role in the management of liver involvement, particularly if the lesions are few in number and between 3 and 5 cm in diameter.11 In fact, RFA has been used successfully in patients in whom TAE has failed.12
Systemic treatment with chemotherapy, including agents such as 5FU, streptozotocin, thalidomide, temozolomide, and doxorubicin has been variably tried, but response rates are generally low, in the 15% range in most studies. Interferon, angiogenesis, and tyrosine-kinase inhibitors may offer improved response rates, and these alone or in combination are under investigation.
With this as a background, my recommended approach for the current patient would be to treat initially with octreotide. Once symptoms have abated, I would recheck the 5HIAA urinary level and then proceed to surgery. It is likely, although not definite, that the primary lesion will be found in the jeujunum or ileum and, if so, it should be excised to the extent possible, and the surgical specimen should include as many nodes as possible. If exploration (including lymph node histopathology) indicates no other extra-hepatic sites, the lesions in the liver could be addressed by a second surgery or either TAE or RFA. Postoperatively, 5HIAA should be followed, but expectation would be that survival would be 5 years or more.
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