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Carcinoids of unknown origin: Comparative analysis with foregut, midgut, and hindgut carcinoids
Carcinoids of unknown origin: Comparative analysis with foregut, midgut, and hindgut carcinoids Paul M. Kirshbom, MD, Aftab R. Kherani, BS, Mark W. Onaitis, MD, Jerome M. Feldman, MD, and Douglas S. Tyler, MD, Durham, NC
Background. Carcinoids are rare neuroendocrine tumors typically arising in the gastrointestinal tract. A significant percentage of these tumors present as metastatic disease of unknown primary site. The aim of this study was to better define the functional and clinical characteristics of carcinoids of unknown primary (CUP) site. Methods. This study examines the hormonal activity, clinical characteristics, and survival of 434 patients with carcinoids originating in the foregut, midgut, hindgut, or unknown location. The 143 patients with CUP were compared with the other groups with regard to presenting characteristics, diagnostic tests and therapeutic modalities used, hormonal activity, and survival. Results. The hormone levels (urinary 5-hydroxyindoleacetic acid and serotonin, serum and platelet serotonin) of CUP were not significantly different from midgut carcinoids with metastatic disease. Although survival with CUP was shorter than with carcinoids with identified primaries (10-year survivals of 22% vs 62%, 50%, and 48% for foregut, midgut, and hindgut, respectively), the survival curve for CUP was quite similar to that of patients with midgut carcinoids with distant disease (10-year survival of 22% vs 28%). Conclusions. CUP are similar to midgut carcinoids presenting with metastatic disease with regard to hormone production and survival. Like other carcinoids, CUP can be an indolent disease process with gradual progression over decades. (Surgery 1998;124:1063-70.) From the Departments of Surgery and Endocrinology, Duke University Medical Center, Durham, NC
CARCINOIDS ARE RELATIVELY RARE tumors that most commonly arise from neuroendocrine cells within the gastrointestinal tract.1-3 Because the biologic behavior of these tumors is related to their site of origin, a classification system was developed on the basis of the embryologic subdivisions of the gastrointestinal tract: foregut, midgut, and hindgut.4,5 Carcinoids originating from each of these embryologic sources exhibit different spectra of hormonal and clinical activity, with foregut and midgut carcinoids typically producing the highest levels of serotonin and the serotonin precursor 5hydroxytryptophan.6,7 Hormone release into the systemic circulation is felt to be responsible for the majority of the symptoms produced by metastatic carcinoids. These symptoms, collectively referred to as the carcinoid syndrome, include diarrhea, Presented at the 19th Annual Meeting of the American Association of Endoscopic Surgeons, Orlando, Fla, Apr 26-28, 1998. Reprint requests: Douglas S. Tyler, MD, Department of Surgery, PO Box 3118, Duke University Medical Center, Durham, NC 27710. Copyright © 1998 by Mosby, Inc. 0039-6060/98/$5.00 + 0 11/6/93105
flushing, abdominal pain, and, less frequently, valvular heart disease.8 The biochemical activity and natural history of carcinoids arising in different regions of the gastrointestinal tract have been discussed to varying degrees in the literature; however, relatively little attention has been paid to carcinoids that present as metastatic disease with no identifiable primary site. The largest reported series either exclude carcinoids of unknown origin or mention them only in passing.1,3,7 For example, Zeitels et al2 reported that 2 of the 101 patients in their series (2%) had metastatic carcinoid of unknown origin, whereas Modlin and Sandor3 categorized 50 of the 8305 cases (0.6%) in their National Cancer Institute database review as “site unspecified.” Neither study presented any specific data regarding these patients. Interestingly, there have been several reports that have defined the expected prognosis for patients with identified primary carcinoids in whom distant metastases develop. Midgut carcinoids with liver metastases, for example, have a 5year survival rate ranging from 35% to 79% depending on the degree of liver involvement and a variety of other factors. 3,7 However, the SURGERY 1063
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Table I. Distribution of carcinoid tumors by site of origin, gender, and age Site of origin
Patients
Foregut Stomach Duodenum Midgut Jejunum Ileum Cecum Hindgut Rectum Unknown Total
52 34 18 207 16 175 16 32 32 143 434
Gender (male/female) 28/24 14/20 14/4 127/80 9/7 106/69 12/4 22/10 22/10 87/57 264/171
prognosis of patients with carcinoids of unknown primary has not been clearly defined. The goals of this study were to analyze the hormonal activity and clinical course of a group of patients with carcinoids of unknown primary in an attempt to better define their prognosis and how it relates to other subgroups of patients with carcinoids of known primary. PATIENTS AND METHODS Patients. Between 1970 and 1997 more than 750 patients with carcinoid tumors were evaluated by 1 author (J. M. F.) at the Duke University Medical Center and the Durham Veterans Affairs Hospital. This study focuses on 143 patients with metastatic carcinoids of unknown primary. Groups selected for comparison included all patients with carcinoids originating from the stomach, duodenum, jejunum, ileum, cecum, and rectum. These patients were analyzed as foregut (stomach and duodenum), midgut (jejunum, ileum, and cecum), and hindgut (rectum) carcinoids with a total of 434 patients included in the study. The medical records of 226 patients randomly selected from this group were retrospectively reviewed to determine the diagnostic tests and treatment modalities used. The stage of disease at diagnosis was also documented, with regional disease defined as disease confined to regional lymph nodes or limited direct local spread. Distant disease was defined as the presence of liver or other distant organ metastases, peritoneal spread, or diffuse retroperitoneal involvement. Patients who initially had carcinoids of unknown primary whose primary site was subsequently diagnosed were crossed over to the appropriate primary group. Approximately 15% of patients initially diagnosed as having carcinoids of unknown primary subsequently had a primary site identified during their lifetimes. Follow-up data for all 434 patients were obtained from the medical records, patient interviews, or serial contacts by 1 author (J. M. F.).
Age at diagnosis (y) (median [range]) 59 (26-86) 60 (26-79) 54 (30-86) 59 (19-89) 58 (27-88) 59 (19-89) 60 (33-75) 61 (29-81) 61 (29-81) 59 (16-87) 59 (16-89)
Hormone levels. The majority of the patients (97%) had 24-hour urine specimens, blood samples, or both collected at the time of initial evaluation at Duke University Medical Center. The urine samples were stored at 3°C and assayed for 5hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) levels with use of spectrophotometric and radioenzymatic assays, respectively.9,10 Serotonin levels were also measured in the serum and platelets.10,11 After 1988 high-pressure liquid chromatography was used to measure all 5-HT levels.12 These data were prospectively collected and maintained in a database including patient demographics, site of tumor origin, and hormone levels at presentation. Statistics. Kruskal-Wallis 1-way analysis of variance (ANOVA) was used to compare groups with Dunn’s method applied for pairwise comparison. Kaplan-Meier analysis was used to evaluate survival from time of diagnosis to death. The Mantel-Cox log rank test was used to compare survival curves between groups. A P value <.05 was considered significant for all tests. The computer program Statistica for Windows version 5 (Statsoft, Tulsa, Okla) was used for all statistical calculations and survival curve generation. RESULTS Demographics. The patient demographics including carcinoid site of origin, gender, and age are summarized in Table I. As has been reported in multiple prior studies,2,3 the midgut carcinoids are far more common than are the foregut or hindgut carcinoids (207 vs 52 and 32, respectively). The gender distribution is also consistent with prior reports in that there is a male preponderance for all gastrointestinal sites except for gastric carcinoids, which occur more frequently in women. There is no significant difference in the age at diagnosis between groups. Carcinoids of unknown primary demonstrate gender and age distributions
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Surgery Volume 124, Number 6 Table II. Presenting symptoms Origin Foregut (n = 27) Midgut (n = 108) Hindgut (n = 8) Unknown (n = 83) Total (n = 226)
Pain
Diarrhea
Flushing
Obstructive symptoms
Cardiac valve disease
10 (37%) 69 (62%) 0 (0%) 50 (60%) 129 (57%)
2 (7%) 32 (30%) 0 (0%) 42 (51%) 75 (33%)
3 (11%) 34 (31%) 1 (13%) 30 (36%) 68 (30%)
5 (19%) 36 (33%) 0 (0%) 16 (19%) 57 (25%)
0 (0%) 3 (3%) 0 (0%) 9 (11%) 12 (5%)
Table III. Stage of carcinoid at diagnosis Origin
Localized
Regional
Distant
Foregut (n = 27) Midgut (n = 108) Hindgut (n = 8) Unknown (n = 83) Total (n = 226)
11 (41%) 25 (23%) 4 (50%) 0 (0%) 40 (18%)
6 (22%) 19 (18%) 0 (0%) 0 (0%) 25 (11%)
10 (37%) 61 (56%) 4 (50%) 81 (98%) 156 (69%)
Unknown stage 0 (0%) 3 (3%) 0 (0%) 2 (2%) 5 (2%)
Table IV. Diagnostic studies most commonly used Origin Foregut (n = 27) Midgut (n = 108) Hindgut (n = 8) Unknown (n = 83)
Test Esophagogastroduodenoscopy CT scan CT scan Upper GI contrast study Colonoscopy/flex sigmoidoscopy CT scan CT scan Barium enema
Performed 19 (70%) 14 (52%) 44 (41%) 29 (27%) 8 (100%) 4 (50%) 55 (66%) 19 (23%)
Positive results (%)* 95 71 95 48 88 50 95 11
CT, Computed tomography; GI, gastrointestinal. *Studies considered positive if they provided information concerning either primary tumor or metastatic disease.
that are not significantly different from those of the other groups. Clinical symptoms and staging. The most commonly noted symptoms at presentation included abdominal pain, flushing, diarrhea, and obstructive symptoms (nausea, vomiting, or frank intestinal obstruction). The incidence of these symptoms and cardiac valvular disease are summarized in Table II. As would be expected, the symptoms comprising the classic carcinoid syndrome, diarrhea, flushing, and valvular disease, occurred most commonly in the patients with carcinoids of unknown primary. Obstructive symptoms, on the other hand, occurred most commonly in patients with identified midgut carcinoids. Of the 226 patients for whom complete historic data were available, 156 (69%) had distant metastases (Table III). The incidence of distant metastatic disease in patients with foregut, midgut, and hindgut tumors was 37%, 56%, and 50%, respectively. Essentially, all the patients with carcinoids of unknown primary were first seen with distant
metastatic disease with the exception of 2 patients who were considered to have regional disease only. These 2 patients were found to have carcinoid tumor in mesenteric lymph nodes after bowel resection for other reasons. The primary tumors could not be identified in either of these patients, and on further work-up no evidence of distant metastatic disease could be found. Diagnosis and treatment. The 2 most commonly used diagnostic studies for each group are summarized in Table IV. Upper and lower endoscopy were the most common studies used to evaluate foregut and hindgut carcinoids, respectively. These studies were diagnostic in 95% and 88% of cases, respectively. The evaluation of midgut and unknown primary carcinoids was more varied with many different types of tests used over the course of this study. Liver/spleen scans were commonly used early in the study period, whereas CT scans and magnetic resonance imaging were more commonly used later. Iodine 131–labeled metaiodobenzylguanidine (MIBG) scans were used primarily for pre-
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Table V. Surgical procedures performed Intent Origin
Procedures
No.
Curative
Palliative
Foregut (n = 27)
Gastrectomy (partial or total) Gastric polypectomy Other Bowel resection Laparotomy for diagnosis Bypass procedure Partial hepatectomy Rectal polypectomy Low anterior resection Laparotomy for diagnosis Bowel resection Bypass procedure Laparoscopy for diagnosis Other
12 4 3 94 4 1 1 4 1 15 5 3 2 5
4 4 2 42 0 0 0 4 0 0 0 0 0 0
8 0 1 52 0 1 1 0 1 0 5 3 0 5
Midgut (n = 108)
Hindgut (n = 8) Unknown (n = 83)
Table VI. Hormonal levels of carcinoid patients Origin Foregut Midgut Hindgut Unknown Normal
Urine 5-HIAA (mg/24 h)
Urine 5-HT (µg/24 h)
4 ± 22 (47)* 21 ± 184 (199)* 3 ± 14 (29)* 34 ± 150 (137) 2-8
159 ± 4366 (43)* 182 ± 430 (184)* 98 ± 220 (22)* 326 ± 2815 (126) 50-220
Platelet 5-HT (pmol/mg protein) 626 ± 2239 (31)* 3220 ± 3003 (129) 307 ± 584 (13)* 3558 ± 6257 (111) 300-2200
Serum 5-HT (pmol/mL) 762 ± 2510 (36)* 4774 ± 5836 (156) 284 ± 1074 (23)* 5362 ± 6567 (125) 100-1500
Values are median ± SD (No.). *P < .05 vs unknown by ANOVA.
Table VII. Hormone levels of unknown primary carcinoids and midgut carcinoids divided by stage Origin Midgut locoregional Midgut distant Unknown
Urine 5-HIAA (mg/24 h)
Urine 5-HT (µg/24 h)
8 ± 36 (43)* 54 ± 122 (60) 34 ± 150 (137)
139 ± 91 (38)* 306 ± 442 (59) 326 ± 2815 (126)
Platelet 5-HT (pmol/mg protein) 1460 ± 3028 (33)* 4975 ± 1966 (53) 3558 ± 6257 (111)
Serum 5-HT (pmol/mL) 2384 ± 3091 (34)* 6413 ± 6467 (52) 5362 ± 6567 (125)
Values are median ± SD (No.). *P < .05 vs unknown by ANOVA.
treatment screening and as follow-up studies rather than for initial diagnosis. Of the 226 patients reviewed in depth, 154 underwent surgical procedures involving their carcinoid tumors (Table V). The majority of these operations involved resection of the primary tumor as either a curative procedure or, in the face of disseminated disease, for palliation of symptoms. There were no attempts at curative resection in patients with carcinoids of unknown origin, although 2 patients did undergo multiple hepatic resections for palliation of carcinoid syndrome. Review of the chemotherapeutic regimens used over the course of the study period revealed such a heterogeneous collection of treatments as to defy
concise description. The majority of patients who had metastatic disease were treated with several different types of chemotherapy over the course of their disease. The most common combination of agents was 5-fluorouracil and streptozocin, which was used in 53 of the 112 patients whose chemotherapy treatment histories were available. An objective response was noted in 18 of 53 (34%) patients treated with this regimen, which is consistent with prior reports.13,14 Treatment with 131Ilabeled MIBG resulted in decreased tumor size or symptomatic improvement in 27 of 43 (63%) patients. Practically all patients with diarrhea or flushing received either cyproheptadine (Periactin) or octreotide (Sandostatin) at some point in their
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Fig 1. Survival curves for carcinoid patients divided by site of origin. P < .05 for all groups versus unknown primary.
course, with symptomatic improvement in the majority. Hormone levels. The levels of 5-HIAA and 5-HT in the urine and 5-HT in the serum and platelets are summarized in Table VI. The levels of all hormones were significantly lower in the foregut and hindgut carcinoids than in midgut and unknown primary carcinoids. This is likely a reflection both of the biologic activity of the tumors and the frequency of tumor metastasis. Given the similarities between the midgut carcinoids and the carcinoids of unknown origin, further analysis was focused on these 2 groups. The midgut carcinoids were subdivided into patients who had with locoregional disease (n = 44) and those with distant metastases (n = 61). The hormone levels of these groups were then compared with the unknown primaries; the results are shown in Table VII. There were no significant differences between the midgut carcinoids with distant disease and the carcinoids of unknown origin, whereas the levels of all hormones in both these groups were significantly higher than those of the midgut carcinoids with locoregional disease. Survival. Survival curves for all the patients included in the study divided by site of origin are displayed in Fig 1. The survival of patients with carcinoids of unknown primary is significantly lower than that of patients with carcinoids of known origin. Ten-year survivals for foregut, midgut, hindgut, and unknown primaries are 62%, 50%, 48%, and 22%, respectively.
The 226 patients whose medical records were reviewed were subdivided into those with local, regional, and distant metastatic disease at the time of diagnosis. The survival curves for these 3 groups, regardless of site of origin, are displayed in Fig 2. It is not surprising that patients with distant metastatic disease had a significantly worse prognosis, with a 10-year survival of 29% as opposed to 80% and 84% for local and regional disease, respectively. Because there was not a statistically significant difference in survival between local and regional disease over the time period of this study, these 2 groups were subsequently considered together as locoregional disease. Fig 3 demonstrates the difference in survival between the carcinoids of unknown primary and the midgut carcinoids divided into locoregional and distant disease. The 3 groups were significantly different from one another, with 10-year survivals of 82%, 28%, and 22% for midgut carcinoids limited to locoregional disease, midgut carcinoids with distant disease, and unknown primaries, respectively. Although statistically different, it can be clearly seen that patients with midgut carcinoids with metastatic disease have a survival curve that is essentially parallel to that of patients with carcinoids of unknown primary, with convergence in the 15- to 20-year range. DISCUSSION The term “karzinoide” was first coined by Oberndorfer15 in 1907 to describe a group of ileal
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Fig 2. Survival curves for carcinoid patients divided by stage. P < .05 for distant versus local and regional, not significant for local versus regional.
Fig 3. Survival of unknown primary carcinoids versus midgut carcinoids divided by stage. Midgut L/R, Midgut carcinoids with locoregional disease; midgut distant, midgut carcinoids presenting with distant metastatic disease. P < .05 for comparisons among all groups.
tumors that were distinct from the more common intestinal carcinomas in that they followed a more benign clinical course. Although this initial clinical impression has proved correct, approximately 45% to 70% of patients with carcinoid tumors will have metastatic disease at the time of diagnosis.3,7 Despite this high incidence of metastatic disease,
these patients can expect prolonged survival, with 5-year survival in the 60% to 79% range reported for selected patients with midgut carcinoids and liver metastases.7,16 Although there has been considerable discussion in the literature concerning the biochemical and clinical behavior of carcinoid tumors, relative-
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ly little has been written concerning carcinoid tumors of unknown origin. It cannot be assumed that these patients will follow the clinical course of patients with metastatic carcinoids of known primary. Comparable clinical scenarios have been evaluated for both adenocarcinomas and melanomas of unknown primary. Adenocarcinomas of unknown primary, particularly those that are well differentiated, present a dismal prognosis with poor response to chemotherapy and median survival in the 4-month range.17 Although these tumors likely represent a heterogeneous group, this clinical course is worse than would be expected for the majority of gastrointestinal adenocarcinomas presenting with metastatic disease. The survival of melanomas of unknown origin, on the other hand, has been reported to be as good as or better than melanomas of similar stage with an identified primary.18,19 The data in this study suggest that carcinoids of unknown primary are biochemically and clinically similar to midgut carcinoids with distant metastatic disease. The hormone levels in Table VI clearly differentiate carcinoids of unknown primary and midgut carcinoids from foregut and hindgut carcinoids. The data presented in Table VII then demonstrate the ability of these hormone levels to differentiate between patients with distant metastatic disease and those with locoregional disease. With regard to survival, carcinoids of unknown primary clearly have a worse prognosis than do carcinoids of known primary if stage of disease is not taken into account. However, when these patients are compared with patients with midgut carcinoids with distant metastatic disease (Fig 3), the survival curves are essentially parallel. Midgut carcinoids with distant disease initially do better than unknown carcinoids, with approximately 24 months longer survival at any point above 50% survival; however, the curves trend toward convergence at approximately 8% to 10% survival in the 15- to 20-year range. One possible explanation for these data is that the majority of carcinoids of unknown primary, like the majority of carcinoids in general, are in fact midgut carcinoids. If this is the case, perhaps identified primary midgut carcinoids that present with metastatic disease are analogous to carcinoids of unknown primary with a 24-month lead time bias. Although many of the midgut carcinoids present when their primary tumor becomes symptomatic, the carcinoids of unknown primary do not present until their metastatic disease becomes symptomatic. It is the metastatic disease that ultimately determines long-term survival in the majority of
cases, but it may be a difference in the locoregional activity of the primary tumors in these 2 groups that causes them to present at different points in the course of disease. This hypothesis suggests that carcinoids of unknown origin are not inherently biologically more aggressive than are their identifiable cousins. As with all clinical studies, the patient population must be considered before the data can be extrapolated to other groups. The majority of these patients were referred to a tertiary care center for evaluation of their carcinoid tumors. Therefore these patients have a relatively higher incidence of distant metastatic disease (69%) than would the entire population of carcinoid patients (11% to 20%).3 It must also be recognized that this is by no means a natural history study because the majority of these patients underwent multiple courses of chemotherapy and surgeries as indicated. In conclusion, carcinoids of unknown origin are biochemically and clinically similar to midgut carcinoids with metastatic disease. As with other carcinoids, these patients can have a protracted and indolent course of disease progression with 10-year survival in the 22% range. REFERENCES 1. Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560-9. 2. Zeitels J, Naunheim K, Kaplan EL, II FS. Carcinoid tumors: a 37-year experience. Arch Surg 1982;117:732-7. 3. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997;79:813-29. 4. Williams ED, Sandler M. The classification of carcinoid tumours. Lancet 1963;1:238-9. 5. Stinner B, Kisker O, Zielke A, Rothmund M. Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum. World J Surg 1996;20:183-8. 6. Kema IP, Vries EGE, Schellings AMJ, Postmus PE, Muskiet FAJ. Improved diagnosis of carcinoid tumors by measurement of platelet serotonin. Clin Chem 1992;38:534-40. 7. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997;8:685-90. 8. Bax NDS, Woods HF, Batchelor A, Jennings M. Clinical manifestations of carcinoid disease. World J Surg 1996;20:142-6. 9. Udenfriend S, Titus E, Weissbach H. The identification of 5hydroxyindoleacetic acid in normal urine and a method for its assay. J Biol Chem 1955;216:499-505. 10. Hussain MN, Sole MJ. A simple specific radioenzymatic assay for picogram quantities of serotonin or acetyl serotonin in biological fluids or tissues. Anal Biochem 1981;111:105-10. 11. Feldman JM, Davis JA. Radioenzymatic assay of platelet serotonin, dopamine, and norepinephrine in subjects with normal and increased serotonin production. Clin Chim Acta 1981;9:275-83. 12. Taqari PC, Boullin DJ, Davies CL. Simplified determination of serotonin in plasma by liquid chromatography with electrochemical detection. Clin Chem 1984;30:131-5.
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13. Moertel CG. An odyssey in the land of small tumors. J Clin Oncol 1987;5:1503-22. 14. Kvols LK. Metastatic carcinoid tumors and the carcinoid syndrome. Am J Med 1986;81:49-54. 15. Oberndorfer S. Karzinoide tumoren des Dunndarms. Frankfurt Zeitschr Pathol 1907;1:426-32. 16. Makridis C, Ekbom A, Bring J, et al. Survival and daily physical activity in patients treated for advanced midgut carcinoid tumors. Surgery 1997;122:1075-82. 17. Greco FA, Hainsworth JD. The management of patients with adenocarcinoma and poorly differentiated carcinoma of unknown primary site. Semin Oncol 1989;16(Suppl 6):116-22. 18. Anbari KK, Schuchter LM, Bucky LP, et al. Melanoma of unknown primary site. Cancer 1997;79:1816-21. 19. Reintgen DS, McCarty KS, Woodard B, Cox E, Seigler HF. Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet 1983;156:335-40.
DISCUSSION Dr E. Christopher Ellison (Columbus, Ohio). On the basis of your experience, what diagnostic evalua-
Surgery December 1998 tion is needed in a patient with an unknown primary carcinoid before a palliative resection or biopsy is performed? Dr Kirshbom. Most patients in this series had extensive evaluation. Almost all of them had CT scans, and upper and lower endoscopy. Many also had MIBG scans. These studies identified the primaries in some patients, but they were negative in the 143 carcinoids of unknown primary that we are reporting. The question is whether finding a primary will make a significant difference for these patients. It probably won’t with regard to the longterm outcome. The question is how to deal with the metastatic disease to palliate the symptoms. There were various trials at our institution and elsewhere on the best way to treat metastases. Dr Ellison. Have you used somatostatin scintigraphy in this group of patients? Dr Kirshbom. Fairly infrequently in this group. There is a protocol ongoing at Duke that uses 131I-labeled MIGB for treating these patients.
Background. Carcinoids are rare neuroendocrine tumors typically arising in the gastrointestinal tract. A significant percentage of these tumors present as metastatic disease of unknown primary site. The aim of this study was to better define the functional and clinical characteristics of carcinoids of unknown primary (CUP) site. Methods. This study examines the hormonal activity, clinical characteristics, and survival of 434 patients with carcinoids originating in the foregut, midgut, hindgut, or unknown location. The 143 patients with CUP were compared with the other groups with regard to presenting characteristics, diagnostic tests and therapeutic modalities used, hormonal activity, and survival. Results. The hormone levels (urinary 5-hydroxyindoleacetic acid and serotonin, serum and platelet serotonin) of CUP were not significantly different from midgut carcinoids with metastatic disease. Although survival with CUP was shorter than with carcinoids with identified primaries (10-year survivals of 22% vs 62%, 50%, and 48% for foregut, midgut, and hindgut, respectively), the survival curve for CUP was quite similar to that of patients with midgut carcinoids with distant disease (10-year survival of 22% vs 28%). Conclusions. CUP are similar to midgut carcinoids presenting with metastatic disease with regard to hormone production and survival. Like other carcinoids, CUP can be an indolent disease process with gradual progression over decades. (Surgery 1998;124:1063-70.) From the Departments of Surgery and Endocrinology, Duke University Medical Center, Durham, NC
CARCINOIDS ARE RELATIVELY RARE tumors that most commonly arise from neuroendocrine cells within the gastrointestinal tract.1-3 Because the biologic behavior of these tumors is related to their site of origin, a classification system was developed on the basis of the embryologic subdivisions of the gastrointestinal tract: foregut, midgut, and hindgut.4,5 Carcinoids originating from each of these embryologic sources exhibit different spectra of hormonal and clinical activity, with foregut and midgut carcinoids typically producing the highest levels of serotonin and the serotonin precursor 5hydroxytryptophan.6,7 Hormone release into the systemic circulation is felt to be responsible for the majority of the symptoms produced by metastatic carcinoids. These symptoms, collectively referred to as the carcinoid syndrome, include diarrhea, Presented at the 19th Annual Meeting of the American Association of Endoscopic Surgeons, Orlando, Fla, Apr 26-28, 1998. Reprint requests: Douglas S. Tyler, MD, Department of Surgery, PO Box 3118, Duke University Medical Center, Durham, NC 27710. Copyright © 1998 by Mosby, Inc. 0039-6060/98/$5.00 + 0 11/6/93105
flushing, abdominal pain, and, less frequently, valvular heart disease.8 The biochemical activity and natural history of carcinoids arising in different regions of the gastrointestinal tract have been discussed to varying degrees in the literature; however, relatively little attention has been paid to carcinoids that present as metastatic disease with no identifiable primary site. The largest reported series either exclude carcinoids of unknown origin or mention them only in passing.1,3,7 For example, Zeitels et al2 reported that 2 of the 101 patients in their series (2%) had metastatic carcinoid of unknown origin, whereas Modlin and Sandor3 categorized 50 of the 8305 cases (0.6%) in their National Cancer Institute database review as “site unspecified.” Neither study presented any specific data regarding these patients. Interestingly, there have been several reports that have defined the expected prognosis for patients with identified primary carcinoids in whom distant metastases develop. Midgut carcinoids with liver metastases, for example, have a 5year survival rate ranging from 35% to 79% depending on the degree of liver involvement and a variety of other factors. 3,7 However, the SURGERY 1063
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Table I. Distribution of carcinoid tumors by site of origin, gender, and age Site of origin
Patients
Foregut Stomach Duodenum Midgut Jejunum Ileum Cecum Hindgut Rectum Unknown Total
52 34 18 207 16 175 16 32 32 143 434
Gender (male/female) 28/24 14/20 14/4 127/80 9/7 106/69 12/4 22/10 22/10 87/57 264/171
prognosis of patients with carcinoids of unknown primary has not been clearly defined. The goals of this study were to analyze the hormonal activity and clinical course of a group of patients with carcinoids of unknown primary in an attempt to better define their prognosis and how it relates to other subgroups of patients with carcinoids of known primary. PATIENTS AND METHODS Patients. Between 1970 and 1997 more than 750 patients with carcinoid tumors were evaluated by 1 author (J. M. F.) at the Duke University Medical Center and the Durham Veterans Affairs Hospital. This study focuses on 143 patients with metastatic carcinoids of unknown primary. Groups selected for comparison included all patients with carcinoids originating from the stomach, duodenum, jejunum, ileum, cecum, and rectum. These patients were analyzed as foregut (stomach and duodenum), midgut (jejunum, ileum, and cecum), and hindgut (rectum) carcinoids with a total of 434 patients included in the study. The medical records of 226 patients randomly selected from this group were retrospectively reviewed to determine the diagnostic tests and treatment modalities used. The stage of disease at diagnosis was also documented, with regional disease defined as disease confined to regional lymph nodes or limited direct local spread. Distant disease was defined as the presence of liver or other distant organ metastases, peritoneal spread, or diffuse retroperitoneal involvement. Patients who initially had carcinoids of unknown primary whose primary site was subsequently diagnosed were crossed over to the appropriate primary group. Approximately 15% of patients initially diagnosed as having carcinoids of unknown primary subsequently had a primary site identified during their lifetimes. Follow-up data for all 434 patients were obtained from the medical records, patient interviews, or serial contacts by 1 author (J. M. F.).
Age at diagnosis (y) (median [range]) 59 (26-86) 60 (26-79) 54 (30-86) 59 (19-89) 58 (27-88) 59 (19-89) 60 (33-75) 61 (29-81) 61 (29-81) 59 (16-87) 59 (16-89)
Hormone levels. The majority of the patients (97%) had 24-hour urine specimens, blood samples, or both collected at the time of initial evaluation at Duke University Medical Center. The urine samples were stored at 3°C and assayed for 5hydroxyindoleacetic acid (5-HIAA) and serotonin (5-HT) levels with use of spectrophotometric and radioenzymatic assays, respectively.9,10 Serotonin levels were also measured in the serum and platelets.10,11 After 1988 high-pressure liquid chromatography was used to measure all 5-HT levels.12 These data were prospectively collected and maintained in a database including patient demographics, site of tumor origin, and hormone levels at presentation. Statistics. Kruskal-Wallis 1-way analysis of variance (ANOVA) was used to compare groups with Dunn’s method applied for pairwise comparison. Kaplan-Meier analysis was used to evaluate survival from time of diagnosis to death. The Mantel-Cox log rank test was used to compare survival curves between groups. A P value <.05 was considered significant for all tests. The computer program Statistica for Windows version 5 (Statsoft, Tulsa, Okla) was used for all statistical calculations and survival curve generation. RESULTS Demographics. The patient demographics including carcinoid site of origin, gender, and age are summarized in Table I. As has been reported in multiple prior studies,2,3 the midgut carcinoids are far more common than are the foregut or hindgut carcinoids (207 vs 52 and 32, respectively). The gender distribution is also consistent with prior reports in that there is a male preponderance for all gastrointestinal sites except for gastric carcinoids, which occur more frequently in women. There is no significant difference in the age at diagnosis between groups. Carcinoids of unknown primary demonstrate gender and age distributions
Kirshbom et al 1065
Surgery Volume 124, Number 6 Table II. Presenting symptoms Origin Foregut (n = 27) Midgut (n = 108) Hindgut (n = 8) Unknown (n = 83) Total (n = 226)
Pain
Diarrhea
Flushing
Obstructive symptoms
Cardiac valve disease
10 (37%) 69 (62%) 0 (0%) 50 (60%) 129 (57%)
2 (7%) 32 (30%) 0 (0%) 42 (51%) 75 (33%)
3 (11%) 34 (31%) 1 (13%) 30 (36%) 68 (30%)
5 (19%) 36 (33%) 0 (0%) 16 (19%) 57 (25%)
0 (0%) 3 (3%) 0 (0%) 9 (11%) 12 (5%)
Table III. Stage of carcinoid at diagnosis Origin
Localized
Regional
Distant
Foregut (n = 27) Midgut (n = 108) Hindgut (n = 8) Unknown (n = 83) Total (n = 226)
11 (41%) 25 (23%) 4 (50%) 0 (0%) 40 (18%)
6 (22%) 19 (18%) 0 (0%) 0 (0%) 25 (11%)
10 (37%) 61 (56%) 4 (50%) 81 (98%) 156 (69%)
Unknown stage 0 (0%) 3 (3%) 0 (0%) 2 (2%) 5 (2%)
Table IV. Diagnostic studies most commonly used Origin Foregut (n = 27) Midgut (n = 108) Hindgut (n = 8) Unknown (n = 83)
Test Esophagogastroduodenoscopy CT scan CT scan Upper GI contrast study Colonoscopy/flex sigmoidoscopy CT scan CT scan Barium enema
Performed 19 (70%) 14 (52%) 44 (41%) 29 (27%) 8 (100%) 4 (50%) 55 (66%) 19 (23%)
Positive results (%)* 95 71 95 48 88 50 95 11
CT, Computed tomography; GI, gastrointestinal. *Studies considered positive if they provided information concerning either primary tumor or metastatic disease.
that are not significantly different from those of the other groups. Clinical symptoms and staging. The most commonly noted symptoms at presentation included abdominal pain, flushing, diarrhea, and obstructive symptoms (nausea, vomiting, or frank intestinal obstruction). The incidence of these symptoms and cardiac valvular disease are summarized in Table II. As would be expected, the symptoms comprising the classic carcinoid syndrome, diarrhea, flushing, and valvular disease, occurred most commonly in the patients with carcinoids of unknown primary. Obstructive symptoms, on the other hand, occurred most commonly in patients with identified midgut carcinoids. Of the 226 patients for whom complete historic data were available, 156 (69%) had distant metastases (Table III). The incidence of distant metastatic disease in patients with foregut, midgut, and hindgut tumors was 37%, 56%, and 50%, respectively. Essentially, all the patients with carcinoids of unknown primary were first seen with distant
metastatic disease with the exception of 2 patients who were considered to have regional disease only. These 2 patients were found to have carcinoid tumor in mesenteric lymph nodes after bowel resection for other reasons. The primary tumors could not be identified in either of these patients, and on further work-up no evidence of distant metastatic disease could be found. Diagnosis and treatment. The 2 most commonly used diagnostic studies for each group are summarized in Table IV. Upper and lower endoscopy were the most common studies used to evaluate foregut and hindgut carcinoids, respectively. These studies were diagnostic in 95% and 88% of cases, respectively. The evaluation of midgut and unknown primary carcinoids was more varied with many different types of tests used over the course of this study. Liver/spleen scans were commonly used early in the study period, whereas CT scans and magnetic resonance imaging were more commonly used later. Iodine 131–labeled metaiodobenzylguanidine (MIBG) scans were used primarily for pre-
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Table V. Surgical procedures performed Intent Origin
Procedures
No.
Curative
Palliative
Foregut (n = 27)
Gastrectomy (partial or total) Gastric polypectomy Other Bowel resection Laparotomy for diagnosis Bypass procedure Partial hepatectomy Rectal polypectomy Low anterior resection Laparotomy for diagnosis Bowel resection Bypass procedure Laparoscopy for diagnosis Other
12 4 3 94 4 1 1 4 1 15 5 3 2 5
4 4 2 42 0 0 0 4 0 0 0 0 0 0
8 0 1 52 0 1 1 0 1 0 5 3 0 5
Midgut (n = 108)
Hindgut (n = 8) Unknown (n = 83)
Table VI. Hormonal levels of carcinoid patients Origin Foregut Midgut Hindgut Unknown Normal
Urine 5-HIAA (mg/24 h)
Urine 5-HT (µg/24 h)
4 ± 22 (47)* 21 ± 184 (199)* 3 ± 14 (29)* 34 ± 150 (137) 2-8
159 ± 4366 (43)* 182 ± 430 (184)* 98 ± 220 (22)* 326 ± 2815 (126) 50-220
Platelet 5-HT (pmol/mg protein) 626 ± 2239 (31)* 3220 ± 3003 (129) 307 ± 584 (13)* 3558 ± 6257 (111) 300-2200
Serum 5-HT (pmol/mL) 762 ± 2510 (36)* 4774 ± 5836 (156) 284 ± 1074 (23)* 5362 ± 6567 (125) 100-1500
Values are median ± SD (No.). *P < .05 vs unknown by ANOVA.
Table VII. Hormone levels of unknown primary carcinoids and midgut carcinoids divided by stage Origin Midgut locoregional Midgut distant Unknown
Urine 5-HIAA (mg/24 h)
Urine 5-HT (µg/24 h)
8 ± 36 (43)* 54 ± 122 (60) 34 ± 150 (137)
139 ± 91 (38)* 306 ± 442 (59) 326 ± 2815 (126)
Platelet 5-HT (pmol/mg protein) 1460 ± 3028 (33)* 4975 ± 1966 (53) 3558 ± 6257 (111)
Serum 5-HT (pmol/mL) 2384 ± 3091 (34)* 6413 ± 6467 (52) 5362 ± 6567 (125)
Values are median ± SD (No.). *P < .05 vs unknown by ANOVA.
treatment screening and as follow-up studies rather than for initial diagnosis. Of the 226 patients reviewed in depth, 154 underwent surgical procedures involving their carcinoid tumors (Table V). The majority of these operations involved resection of the primary tumor as either a curative procedure or, in the face of disseminated disease, for palliation of symptoms. There were no attempts at curative resection in patients with carcinoids of unknown origin, although 2 patients did undergo multiple hepatic resections for palliation of carcinoid syndrome. Review of the chemotherapeutic regimens used over the course of the study period revealed such a heterogeneous collection of treatments as to defy
concise description. The majority of patients who had metastatic disease were treated with several different types of chemotherapy over the course of their disease. The most common combination of agents was 5-fluorouracil and streptozocin, which was used in 53 of the 112 patients whose chemotherapy treatment histories were available. An objective response was noted in 18 of 53 (34%) patients treated with this regimen, which is consistent with prior reports.13,14 Treatment with 131Ilabeled MIBG resulted in decreased tumor size or symptomatic improvement in 27 of 43 (63%) patients. Practically all patients with diarrhea or flushing received either cyproheptadine (Periactin) or octreotide (Sandostatin) at some point in their
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Fig 1. Survival curves for carcinoid patients divided by site of origin. P < .05 for all groups versus unknown primary.
course, with symptomatic improvement in the majority. Hormone levels. The levels of 5-HIAA and 5-HT in the urine and 5-HT in the serum and platelets are summarized in Table VI. The levels of all hormones were significantly lower in the foregut and hindgut carcinoids than in midgut and unknown primary carcinoids. This is likely a reflection both of the biologic activity of the tumors and the frequency of tumor metastasis. Given the similarities between the midgut carcinoids and the carcinoids of unknown origin, further analysis was focused on these 2 groups. The midgut carcinoids were subdivided into patients who had with locoregional disease (n = 44) and those with distant metastases (n = 61). The hormone levels of these groups were then compared with the unknown primaries; the results are shown in Table VII. There were no significant differences between the midgut carcinoids with distant disease and the carcinoids of unknown origin, whereas the levels of all hormones in both these groups were significantly higher than those of the midgut carcinoids with locoregional disease. Survival. Survival curves for all the patients included in the study divided by site of origin are displayed in Fig 1. The survival of patients with carcinoids of unknown primary is significantly lower than that of patients with carcinoids of known origin. Ten-year survivals for foregut, midgut, hindgut, and unknown primaries are 62%, 50%, 48%, and 22%, respectively.
The 226 patients whose medical records were reviewed were subdivided into those with local, regional, and distant metastatic disease at the time of diagnosis. The survival curves for these 3 groups, regardless of site of origin, are displayed in Fig 2. It is not surprising that patients with distant metastatic disease had a significantly worse prognosis, with a 10-year survival of 29% as opposed to 80% and 84% for local and regional disease, respectively. Because there was not a statistically significant difference in survival between local and regional disease over the time period of this study, these 2 groups were subsequently considered together as locoregional disease. Fig 3 demonstrates the difference in survival between the carcinoids of unknown primary and the midgut carcinoids divided into locoregional and distant disease. The 3 groups were significantly different from one another, with 10-year survivals of 82%, 28%, and 22% for midgut carcinoids limited to locoregional disease, midgut carcinoids with distant disease, and unknown primaries, respectively. Although statistically different, it can be clearly seen that patients with midgut carcinoids with metastatic disease have a survival curve that is essentially parallel to that of patients with carcinoids of unknown primary, with convergence in the 15- to 20-year range. DISCUSSION The term “karzinoide” was first coined by Oberndorfer15 in 1907 to describe a group of ileal
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Fig 2. Survival curves for carcinoid patients divided by stage. P < .05 for distant versus local and regional, not significant for local versus regional.
Fig 3. Survival of unknown primary carcinoids versus midgut carcinoids divided by stage. Midgut L/R, Midgut carcinoids with locoregional disease; midgut distant, midgut carcinoids presenting with distant metastatic disease. P < .05 for comparisons among all groups.
tumors that were distinct from the more common intestinal carcinomas in that they followed a more benign clinical course. Although this initial clinical impression has proved correct, approximately 45% to 70% of patients with carcinoid tumors will have metastatic disease at the time of diagnosis.3,7 Despite this high incidence of metastatic disease,
these patients can expect prolonged survival, with 5-year survival in the 60% to 79% range reported for selected patients with midgut carcinoids and liver metastases.7,16 Although there has been considerable discussion in the literature concerning the biochemical and clinical behavior of carcinoid tumors, relative-
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ly little has been written concerning carcinoid tumors of unknown origin. It cannot be assumed that these patients will follow the clinical course of patients with metastatic carcinoids of known primary. Comparable clinical scenarios have been evaluated for both adenocarcinomas and melanomas of unknown primary. Adenocarcinomas of unknown primary, particularly those that are well differentiated, present a dismal prognosis with poor response to chemotherapy and median survival in the 4-month range.17 Although these tumors likely represent a heterogeneous group, this clinical course is worse than would be expected for the majority of gastrointestinal adenocarcinomas presenting with metastatic disease. The survival of melanomas of unknown origin, on the other hand, has been reported to be as good as or better than melanomas of similar stage with an identified primary.18,19 The data in this study suggest that carcinoids of unknown primary are biochemically and clinically similar to midgut carcinoids with distant metastatic disease. The hormone levels in Table VI clearly differentiate carcinoids of unknown primary and midgut carcinoids from foregut and hindgut carcinoids. The data presented in Table VII then demonstrate the ability of these hormone levels to differentiate between patients with distant metastatic disease and those with locoregional disease. With regard to survival, carcinoids of unknown primary clearly have a worse prognosis than do carcinoids of known primary if stage of disease is not taken into account. However, when these patients are compared with patients with midgut carcinoids with distant metastatic disease (Fig 3), the survival curves are essentially parallel. Midgut carcinoids with distant disease initially do better than unknown carcinoids, with approximately 24 months longer survival at any point above 50% survival; however, the curves trend toward convergence at approximately 8% to 10% survival in the 15- to 20-year range. One possible explanation for these data is that the majority of carcinoids of unknown primary, like the majority of carcinoids in general, are in fact midgut carcinoids. If this is the case, perhaps identified primary midgut carcinoids that present with metastatic disease are analogous to carcinoids of unknown primary with a 24-month lead time bias. Although many of the midgut carcinoids present when their primary tumor becomes symptomatic, the carcinoids of unknown primary do not present until their metastatic disease becomes symptomatic. It is the metastatic disease that ultimately determines long-term survival in the majority of
cases, but it may be a difference in the locoregional activity of the primary tumors in these 2 groups that causes them to present at different points in the course of disease. This hypothesis suggests that carcinoids of unknown origin are not inherently biologically more aggressive than are their identifiable cousins. As with all clinical studies, the patient population must be considered before the data can be extrapolated to other groups. The majority of these patients were referred to a tertiary care center for evaluation of their carcinoid tumors. Therefore these patients have a relatively higher incidence of distant metastatic disease (69%) than would the entire population of carcinoid patients (11% to 20%).3 It must also be recognized that this is by no means a natural history study because the majority of these patients underwent multiple courses of chemotherapy and surgeries as indicated. In conclusion, carcinoids of unknown origin are biochemically and clinically similar to midgut carcinoids with metastatic disease. As with other carcinoids, these patients can have a protracted and indolent course of disease progression with 10-year survival in the 22% range. REFERENCES 1. Godwin JD. Carcinoid tumors: an analysis of 2837 cases. Cancer 1975;36:560-9. 2. Zeitels J, Naunheim K, Kaplan EL, II FS. Carcinoid tumors: a 37-year experience. Arch Surg 1982;117:732-7. 3. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997;79:813-29. 4. Williams ED, Sandler M. The classification of carcinoid tumours. Lancet 1963;1:238-9. 5. Stinner B, Kisker O, Zielke A, Rothmund M. Surgical management for carcinoid tumors of small bowel, appendix, colon, and rectum. World J Surg 1996;20:183-8. 6. Kema IP, Vries EGE, Schellings AMJ, Postmus PE, Muskiet FAJ. Improved diagnosis of carcinoid tumors by measurement of platelet serotonin. Clin Chem 1992;38:534-40. 7. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 1997;8:685-90. 8. Bax NDS, Woods HF, Batchelor A, Jennings M. Clinical manifestations of carcinoid disease. World J Surg 1996;20:142-6. 9. Udenfriend S, Titus E, Weissbach H. The identification of 5hydroxyindoleacetic acid in normal urine and a method for its assay. J Biol Chem 1955;216:499-505. 10. Hussain MN, Sole MJ. A simple specific radioenzymatic assay for picogram quantities of serotonin or acetyl serotonin in biological fluids or tissues. Anal Biochem 1981;111:105-10. 11. Feldman JM, Davis JA. Radioenzymatic assay of platelet serotonin, dopamine, and norepinephrine in subjects with normal and increased serotonin production. Clin Chim Acta 1981;9:275-83. 12. Taqari PC, Boullin DJ, Davies CL. Simplified determination of serotonin in plasma by liquid chromatography with electrochemical detection. Clin Chem 1984;30:131-5.
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13. Moertel CG. An odyssey in the land of small tumors. J Clin Oncol 1987;5:1503-22. 14. Kvols LK. Metastatic carcinoid tumors and the carcinoid syndrome. Am J Med 1986;81:49-54. 15. Oberndorfer S. Karzinoide tumoren des Dunndarms. Frankfurt Zeitschr Pathol 1907;1:426-32. 16. Makridis C, Ekbom A, Bring J, et al. Survival and daily physical activity in patients treated for advanced midgut carcinoid tumors. Surgery 1997;122:1075-82. 17. Greco FA, Hainsworth JD. The management of patients with adenocarcinoma and poorly differentiated carcinoma of unknown primary site. Semin Oncol 1989;16(Suppl 6):116-22. 18. Anbari KK, Schuchter LM, Bucky LP, et al. Melanoma of unknown primary site. Cancer 1997;79:1816-21. 19. Reintgen DS, McCarty KS, Woodard B, Cox E, Seigler HF. Metastatic malignant melanoma with an unknown primary. Surg Gynecol Obstet 1983;156:335-40.
DISCUSSION Dr E. Christopher Ellison (Columbus, Ohio). On the basis of your experience, what diagnostic evalua-
Surgery December 1998 tion is needed in a patient with an unknown primary carcinoid before a palliative resection or biopsy is performed? Dr Kirshbom. Most patients in this series had extensive evaluation. Almost all of them had CT scans, and upper and lower endoscopy. Many also had MIBG scans. These studies identified the primaries in some patients, but they were negative in the 143 carcinoids of unknown primary that we are reporting. The question is whether finding a primary will make a significant difference for these patients. It probably won’t with regard to the longterm outcome. The question is how to deal with the metastatic disease to palliate the symptoms. There were various trials at our institution and elsewhere on the best way to treat metastases. Dr Ellison. Have you used somatostatin scintigraphy in this group of patients? Dr Kirshbom. Fairly infrequently in this group. There is a protocol ongoing at Duke that uses 131I-labeled MIGB for treating these patients.