Correspondence
Carcinoid Tumors
N Engl J Med 1999; 341:453-455August 5, 1999
- Article
To the Editor:
In the article by Kulke and Mayer (March 18 issue),1 it is stated with respect to the biochemical diagnosis of carcinoid tumors that measurement of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine collection may be useful in confirming the diagnosis. We would like to draw attention to the measurement of other biogenic amines — such as serotonin, catecholamines, and histamine and its metabolites — in the platelets, plasma, and urine of patients with carcinoid tumors.
By using high-performance liquid chromatography and gas chromatography–mass spectrometry, we have characterized carcinoid tumors in more than 100 patients. The platelet serotonin level has a higher sensitivity for the detection of carcinoid tumors and is more consistently elevated than is urinary 5-HIAA, particularly in tumors that are characterized by a low rate of serotonin production (e.g., foregut carcinoids and those in patients with residual disease).2 In cases characterized by a high rate of secretion of serotonin, the platelet serotonin level reaches a maximum, whereas urinary 5-HIAA does not, indicating that the platelet compartment is saturable. In contrast to urinary 5-HIAA, platelet serotonin is not influenced by the consumption of a serotonin-rich diet.3 Although measurement of urinary 5-HIAA is useful in the follow-up of carcinoid tumors with a high serotonin-secretion rate, platelet serotonin should be preferred to make the primary diagnosis.
Furthermore, analysis of catecholamines and their metabolites showed consistent elevation not only of dopamine, as suggested by Kulke and Mayer, but also of noradrenaline and adrenaline metabolites in more than 30 percent of midgut carcinoids. This explains certain side effects, such as arrhythmia and perioperative carcinoid crisis, in patients for whom somatostatin premedication is indicated. Although urinary levels of histamine metabolites were less consistently elevated, increased histamine production in carcinoids was found to be the cause of specific symptoms, such as angioedema, which could be treated specifically.4 Overall, we conclude that, apart from measurement of urinary 5-HIAA, determination of other frequently produced biogenic amines not only enables more sensitive detection but also can indicate more specific measures in particular patients.
4 ReferencesIdo P. Kema, Ph.D.
Pax H.B. Willemse, M.D., Ph.D.
Elisabeth G.E. de Vries, M.D., Ph.D.
University Hospital Groningen, 9700 RB Groningen, the Netherlands1
Kulke MH ,Mayer RJ . Carcinoid tumors. N Engl J Med 1999;340:858-868
Full Text | Web of Science | Medline2
Kema IP ,de Vries EG ,Slooff MJ ,Biesma B ,Muskiet FA . Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors. Clin Chem 1994;40:86-95
Web of Science | Medline3
Kema IP ,Schellings AM ,Meiborg G ,Hoppenbrouwers CJ ,Muskiet FA . Influence of a serotonin- and dopamine-rich diet on platelet serotonin content and urinary excretion of biogenic amines and their metabolites. Clin Chem 1992;38:1730-1736
Web of Science | Medline4
Wymenga AN ,de Monchy JG ,de Vries EG . The carcinoid syndrome and angioedema. Ann Intern Med 1995;123:636-636
Web of Science | Medline
To the Editor:
The review by Kulke and Mayer nicely summarizes current knowledge about carcinoid tumors. However, one aspect is neglected: the role of metaiodobenzylguanidine (MIBG). MIBG is a derivative of bretylium and guanethidine. Radioiodinated MIBG ([131I]MIBG) is widely used for diagnostic imaging as well as for targeted radiotherapy. MIBG is transported across the plasma membrane and stored in neurosecretory granules.1 Scintigraphy with a tracer dose of [131I]MIBG reveals tumor deposits in up to 84 percent of patients with metastatic carcinoids. Treatment with a higher dose of [131I]MIBG (7.4 GBq [200 mCi]) to deliver internal radiation is widely used with success for various neuroendocrine tumors, such as neuroblastoma and pheochromocytoma. An impressive palliative effect has been reported for metastatic carcinoid tumors: two cycles resulted in a long-lasting (median, nine months) symptomatic response in 60 percent of 30 patients.2 For patients in poor condition or with a negative [131I]MIBG scan, we administered the unlabeled MIBG compound in pharmacologic doses. Such an excess of MIBG most likely interferes with the storage and subsequent release of serotonin. The beneficial effect observed with this simple regimen on an outpatient basis was similar to that with [131I]MIBG therapy, except that the effect was of shorter duration (i.e., four to five months).
2 ReferencesBabs G. Taal, M.D., Ph.D.
Cornelis Hoefnagel, M.D., Ph.D.
Marja Rutgers, Ph.D.
Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands1
Taal BG ,Hoefnagel CA ,Valdes Olmos RA ,Boot H . Combined diagnostic imaging with 131I-metaiodobenzylguanidine and 111In-penetreotide in carcinoid tumours. Eur J Cancer 1996;32:1924-1932
CrossRef | Web of Science2
Taal BG ,Hoefnagel CA ,Valdes Olmos RA ,Boot H ,Beijnen JH . Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors. J Clin Oncol 1996;14:1829-1838
Web of Science | Medline
To the Editor:
The article on carcinoid tumors by Kulke and Mayer contains no information about an important group of these tumors — those arising in the ovary. The carcinoid syndrome has been reported in 29 to 33 percent of cases of primary ovarian carcinoid tumors.1,2 The carcinoid syndrome associated with ovarian tumors occurs in the absence of hepatic metastasis, presumably because the vasoactive substances that cause the symptoms enter the systemic circulation by way of the ovarian veins without first passing through the liver. Carcinoid heart disease from an ovarian carcinoid has also been reported.3 Many ovarian carcinoids arise within dermoid cysts.4 Women with symptoms suggestive of the carcinoid syndrome should have a thorough evaluation of their ovaries by pelvic examination and, if needed, by imaging studies. Fortunately, most ovarian carcinoids are limited to the ovary when diagnosed, and the prognosis after surgical removal is good.1,2,4
4 ReferencesMack Barham, M.D.
3418 Medical Park Dr., Monroe, LA 712031
Davis KP ,Hartmann LK ,Keeney GL ,Shapiro H . Primary ovarian carcinoid tumors. Gynecol Oncol 1996;61:259-265
CrossRef | Web of Science | Medline2
Robboy SJ ,Norris HJ ,Scully RE . Insular carcinoid primary in the ovary: a clinicopathologic analysis of 48 cases. Cancer 1975;36:404-418
CrossRef | Web of Science | Medline3
Stephan E ,de Wit J . Carcinoid heart disease from primary carcinoid tumor of the ovary: haemodynamic and cine coronary angiocardiographic study after operation. Br Heart J 1974;36:613-616
CrossRef | Web of Science | Medline4
Robboy SJ ,Scully RE . Strumal carcinoid of the ovary: an analysis of 50 cases of a distinctive tumor composed of thyroid tissue and carcinoid. Cancer 1980;46:2019-2034
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Taal and colleagues point out that treatment with MIBG has resulted in subjective improvement in patients with metastatic carcinoid tumor. Unfortunately, objective responses with MIBG therapy are rare. Indeed, in the trial described by Taal et al., only two patients treated with radiolabeled MIBG had a decrease in 5-HIAA excretion, and no patients had radiologic regression of disease.1 Another factor limiting the widespread use of this treatment is the variability in uptake by the tumor among patients and even among different tumor sites within the same patient.2
Kema and colleagues found that among patients with carcinoid tumors, platelet serotonin levels are more often elevated than are urinary 5-HIAA levels.3 We would recommend further studies to establish the specificity of this assay before advocating its use in the diagnosis of carcinoid tumors. We agree with the authors that the secretion of catecholamines and histamine may account for some of the symptoms of the carcinoid syndrome. Aside from rare cases in which treatment with antihistamines may be of benefit, however, it is unclear that routine measurement of these substances would substantially change the clinical care of patients with the carcinoid syndrome.
We thank Barham for his description of ovarian carcinoids. Although ovarian carcinoids are rare, accounting for only 0.5 percent of all carcinoid tumors in one study,4 we agree with Barham that the possibility of an ovarian carcinoid should not be overlooked in the appropriate clinical setting.
4 ReferencesMatthew H. Kulke, M.D.
Robert J. Mayer, M.D.
Dana–Farber Cancer Institute, Boston, MA 021151
Taal BG ,Hoefnagel CA ,Valdes Olmos RA ,Boot H ,Beijnen JH . Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors. J Clin Oncol 1996;14:1829-1838
Web of Science | Medline2
Troncone L ,Rufini V . 131I-MIBG therapy of neural crest tumours. Anticancer Res 1997;17:1823-1831
Web of Science | Medline3
Kema IP ,de Vries EG ,Slooff MJ ,Biesma B ,Muskiet FA . Serotonin, catecholamines, histamine, and their metabolites in urine, platelets, and tumor tissue of patients with carcinoid tumors. Clin Chem 1994;40:86-95
Web of Science | Medline4
Modlin IM ,Sandor A . An analysis of 8305 cases of carcinoid tumors. Cancer 1997;79:813-829
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Wilhelmina H. A. Jong, Marianne H. L. I. Wilkens, Elisabeth G. E. Vries, Ido P. Kema. (2010) Automated mass spectrometric analysis of urinary and plasma serotonin. Analytical and Bioanalytical Chemistry 396:7, 2609-2616
CrossRef
