Familial Occurrence of Carcinoid Tumors and Association with Other Malignant Neoplasms1

Vol. 8, 715–719, August 1999 Cancer Epidemiology, Biomarkers & Prevention 715

Dusica Babovic-Vuksanovic, Costas L. Constantinou, tomies (3). The most frequent sites for carcinoid tumors are the Joseph Rubin, Charles M. Rowland, Daniel J. Schaid, gastrointestinal tract (73–85%) and the bronchopulmonary sys- and Pamela S. Karnes2 tem (10–28.7%). Carcinoids are occasionally found in the Departments of Medical Genetics [D. B-V., P. S. K.] and Medical Oncology larynx, thymus, kidney, ovary, prostate, and skin (4, 5). Ade- [C. L. C., J. R.] and Section of Biostatistics [C. M. R., D. J. S.], Mayo Clinic nocarcinomas and carcinoids are the most common malignan- and Mayo Foundation, Rochester, Minnesota 55905 cies in the small intestine in adults (6, 7). In children, they rank second behind lymphoma among alimentary tract malignancies (8). Carcinoids appear to have increased in incidence during the Abstract past 20 years (5). Carcinoid tumors are generally thought to be sporadic, Carcinoid tumors were originally thought to possess a very except for a small proportion that occur as a part of low metastatic potential. In recent years, their natural history multiple endocrine neoplasia syndromes. Data regarding and malignant potential have become better understood (9). In the familial occurrence of carcinoid as well as its ϳ40% of patients, metastases are already evident at the time of potential association with other neoplasms are limited. A diagnosis. The overall 5-year survival rate of all carcinoid chart review was conducted on patients indexed for tumors, regardless of site, is ϳ50% (5). The epidemiology of malignant carcinoid tumor of the gastrointestinal tract carcinoid tumors is still poorly understood because of the rarity seen at the Mayo Clinic between 1988 and 1996. A survey of large population-based studies (10). of family history of malignancies and personal history of Except for a small proportion of carcinoids, which occur other tumors was mailed to all eligible patients. Data for as a part of MEN3 syndromes, carcinoid tumors are generally 245 patients were analyzed. Observed rates of carcinoids considered to be sporadic. However, a number of patients have and other malignancies were compared with Surveillance, been seen at the Mayo Clinic who had at least one first-degree Epidemiology, and End Results data. Estimates of the relative with isolated carcinoids, without evidence of other cumulative probability for first-degree relatives MEN-associated findings. This suggests that some carcinoids developing a carcinoid tumor were calculated. Nine may be familial, but no data are available on the percentage of (3.7%) patients with carcinoid tumor had at least one patients with a family history of carcinoid. In addition, the first-degree relative with the same malignancy. The rate literature is contradictory as to whether patients with carcinoid of carcinoid tumor in first-degree relatives of probands tumor within the gastrointestinal tract have an increased inci- was higher (P < 0.0001) than expected based on the dence of other malignancies (2, 4, 11–15). Surveillance, Epidemiology, and End Results population The purpose of this study was to determine the proportion data. Cumulative probability in a first-degree relative for of familial cases among patients with carcinoid tumor, calculate developing a carcinoid was calculated to be 1.5% at age the risk of developing carcinoids for relatives of probands, and 80. There was an increased risk for developing a determine the prevalence of other malignant tumors among carcinoid tumor among first-degree relatives of patients patients with carcinoids. with carcinoid. Neither patients with carcinoid nor their first-degree relatives had an increased incidence of other Materials and Methods malignancies. A chart review was conducted on all patients indexed for malignant carcinoid tumor in the gastrointestinal tract at Mayo Introduction Clinic between 1988 and 1996. Carcinoids are neuroendocrine tumors, the cells of which are The presence of carcinoid tumor was documented by pa- capable of secreting vasoactive substances such as serotonin, thology from either a surgical biopsy performed at Mayo Clinic histamine, and bradykinin. These are relatively slow-growing or outside excised material. Patients of both sexes, ages 20–70 tumors and, the majority of patients harboring gastrointestinal years, were included in the study. The exclusion criteria in- carcinoids are asymptomatic (1). Carcinoids of the small intes- cluded previous diagnosis of MEN 1 or MEN 2 or presence of tine are found in ϳ1 of 150 patients at autopsy (2), and MEN-associated endocrine tumors (medullary thyroid carci- carcinoids of the appendix are found in ϳ1 of 300 appendec- noma and parathyroid, pancreatic, and suprarenal tumors). Two hundred forty-five eligible Mayo patients were identified based on the above criteria, as documented in their clinical records, of which 67 were deceased. A survey of the Received 10/19/98; revised 5/3/99; accepted 6/8/99. The costs of publication of this article were defrayed in part by the payment of family history of carcinoid tumors and personal history of other page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This project was supported by Mayo Foundation Grant 478-97. 2 To whom requests for reprints should be addressed, at the Department of 3 The abbreviations used are: MEN, multiple endocrine neoplasia; SEER, Sur- Medical Genetics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. veillance, Epidemiology, and End Results; CI, confidence interval.

Table 1 Location of primary carcinoid tumor within the gastrointestinal tract Table 2 Location of carcinoid tumor in first-degree relatives of index patientsa Tumor site No. of patients (%) 95% Location of No. No. Risk Ileum 129 (52.6) confidence P carcinoid tumor observed expected ratio Jejunum 43 (17.5) interval Duodenum 4 (1.6) Ͻ Appendix 33 (13.5) Any location 10 1.437 6.957 3.336–12.901 0.0001 Ͻ Colon 12 (4.9) Small intestine 5 0.385 12.975 4.217–30.232 0.0001 Rectum 24 (9.8) Colon 2 0.130 15.365 1.859–55.313 0.008 Total 245 (100.0) a In three relatives, the location of carcinoid tumor within the gastrointestinal tract was unknown. Expected values are based on rates calculated from the SEER Public Use Data CD-ROM. Histology codes 8240–8241 were used to access carcinoid tumors in the SEER database. Rates were based on data from 1990– 4 malignancies was mailed to all eligible patients. The question- 1995. naire requested information on the patient’s current age, age of diagnosis of carcinoid tumor, prior or present diagnosis of other malignant tumors, and age at diagnosis. The questionnaire also Table 1. The small bowel was the most common site (176 inquired about the family history, including total number and patients; 71.8%), followed by the colon (36 patients; 14.6%) ages of all living and deceased first-degree relatives, the pres- and appendix (33 patients; 13.4%). In 31 (12.6%) patients, ence of carcinoid tumor or other malignancy in first-degree carcinoid was discovered as an incidental finding during sur- relatives, and their ages at diagnosis. One repeat mailing fol- gery performed for another reason. In 179 (73%) patients, the lowed nonresponse. For patients who agreed to participate in tumor showed signs of local invasion or distant metastases at the study, additional information that was pertinent to the the time of diagnosis. personal and family history of malignant tumors was obtained by telephone in all cases when there was a discrepancy between Occurrence of Carcinoid Tumors in First-Degree Relatives information provided in the questionnaire and information of Probands. Nine (3.7%) patients with carcinoid tumor had at found in the medical record. For patients who were deceased at least one first-degree relative (parent, sibling, or child) with the the time of data collection, the information was extracted from same malignancy. None of the index patients were related to their Mayo medical charts only. These results were analyzed each other. One patient had two affected relatives. There were separately. a total of 1772 first-degree relatives of probands, and information about their age was available for 1498. The mean age of Statistical Methods. Estimates of the cumulative probability first-degree relatives at the time of data collection was 52.5 Ϯ for first-degree relatives being diagnosed with a carcinoid tu- 21.5 years (range, 1–98 years). Carcinoid tumor was present in mor were calculated using the method of Kaplan and Meier 10 (0.68%). The presence of carcinoid tumor in relatives was (16). Expected rates of cancers other than carcinoids are based based on information in patient charts and questionnaires and on the SEER age- and sex-specific incidence rates for the time confirmed by review of medical records of the relatives of four period from 1990–1994 (17). Expected rates for carcinoid probands (which includes five relatives). The presence of car- tumors were based on the SEER age- and sex-specific incidence 4 cinoid tumor in the relative was confirmed in two other cases by rates for the time period from 1990 to 1995. Observed inci- a telephone interview with the proband, who had definite dence rates were calculated by dividing the total number of knowledge of the diagnosis, location of tumor, and symptoms observed events by the total person years (sum of the individual consistent with carcinoid syndrome (flushing and diarrhea) in follow-up times in years) at risk. Standard morbidity ratios the affected relative. Unfortunately, we were unable to obtain were calculated by dividing the observed rates by the expected definite confirmation of carcinoid in three relatives, due to rate adjusted for age and sex (the sum of the products of each change of the proband’s address or death. age- and sex-specific SEER rate multiplied by the study pop- Five (50%) of the affected relatives had a carcinoid in the ulation total person years at risk within the corresponding age small bowel, and two (20%) had a carcinoid in the colon. and sex category). Confidence intervals for the rate ratios were Information about the location of the carcinoid tumor was based on the assumption that the observed number of events unavailable in three cases. The observed number of carcinoid has a Poisson distribution and the number of person years is tumors in first-degree relatives was significantly higher (P Ͻ fixed (18). 0.0001) than expected, based on the SEER data (Table 2). Among first-degree relatives in our series, the incidence Results rate for carcinoid tumors, age-adjusted to the 1970 United Probands with Carcinoid Tumor. Two hundred forty-five States white population was 12.5 per 100,000 person-years patients (22 males and 123 females) were included in our (95% CI, 0.6–24.9) for males and 15.7 per 100,000 person- analysis. Information was collected from medical charts and years (95% CI, 2.8–28.5) for females. The cumulative proba- questionnaires for 178 probands. For an additional 67 patients bility of developing carcinoid tumor for a first-degree relative who were deceased, data were obtained from medical records. at age 80 was calculated to be 1.5% (Table 3). The mean age of patients at the time of data collection was Associated Tumors in Patients with Carcinoid Tumor. In 58.2 Ϯ 11.46 years. The mean age at diagnosis of carcinoid 66 of 245 (26.9%) of patients with carcinoid tumor, a second tumor was 52.7 Ϯ 10.7 years (range, 17–70 years). The distri- tumor other than carcinoid was identified. A total of 81 tumors bution of tumors within the gastrointestinal tract is presented in were reported, 53 of which were malignant (Table 4). One tumor in addition to carcinoid was present in 51 patients, two additional tumors were present in 13 patients, and four additional tumors were present in one patient. Observed incidence 4 Surveillance, Epidemiology, and End Results (SEER) Program Public Use CD-ROM (1973–1995), National Cancer Institute, DCPC, Surveillance Program, rates are presented on the Table 5. The incidence of colorectal Cancer Statistics Branch, released April 1998. adenocarcinoma, adjusted for the sex and age of patients, was

Table 3 Cumulative risk of developing carcinoid tumor for first-degree Table 4 Other tumors in patients with carcinoid relatives of probanda Malignant tumors Cumulative Estimated Tumor site Age (yr) No. at risk 95% CI (%) no. of events probability (%) Tumor type No. of patients 0 0 1498 Breast Adenocarcinoma 10 50 3 821 0.3 0.0–0.6 Uterus Sarcoma 1 65 6 506 0.8 0.1–1.4 Squamous carcinoma (cervix) 3 a 80 9 178 1.5 0.5–3.0 Skin Carcinoma 9 Melanoma 1 a Data are based on exclusion of 15% of relatives for whom there was no Colorectal Adenocarcinoma 10 information on age. Anus Squamous cell carcinoma 1 Lung Carcinomab 2 Prostate Adenocarcinoma 3 Kidney Adenocarcinoma 1 significantly higher than expected. After patients for whom data Ovary Adenocarcinoma 3 were collected only through chart review were excluded, the Thyroid Adenocarcinoma 2 incidence of colorectal adenocarcinoma was only moderately Intestine Lymphoma 1 elevated. Of 10 patients who had both carcinoid tumor and Bladder Carcinomab 3 colorectal carcinoma, seven presented with symptoms related to Testis Carcinomab 1 colon cancer and the carcinoid tumor was detected as a coin- Pleura Mesothelioma 1 b cidental finding. Excluding these patients, the incidence of Peritoneum Carcinoma 1 colorectal carcinoma was not significantly higher than ex- Total 53 pected. a Basal cell carcinoma in four, squamous cell carcinoma in one patient, and unspecified carcinoma in four patients. Other Malignant Tumors in Relatives of Proband with b In the absence of more specific histology, these tumors were classified as Carcinoid Tumor. One hundred twenty-nine of 245 patients “carcinoma.” with carcinoid (54.88%) reported a history of malignancy in a first-degree relative. The most commonly observed tumors in relatives are shown in Table 6. The incidence of gastric carcinoma was significantly increased, whereas the incidence of gastrointestinal tract in patients with colonic carcinoid because prostate and lung cancer was lower than expected among rel- of a high rate of other gastrointestinal malignant neoplasms. atives of patients with carcinoid. Some reports in the more recent literature describe concurrent carcinoid and intestinal adenocarcinoma (22, 23). However, a large population-based study of a 1029 patients with carcinoids Discussion failed to confirm a general excess cancer risk in patients with In the gastrointestinal tract, carcinoid tumors are most com- carcinoid tumors (14, 15). Because of contradictory literature monly found in the small bowel (28.7%), appendix (18.9%), data, it is important to clarify these concerns since they may and rectum (12.6%; Ref. 3). One report suggested a high have a significant impact on patient management and progno- prevalence of rectal carcinoids (55%), compared to other gas- sis. In our series, 66 of 245 patients had a second tumor other trointestinal carcinoids (19). Small intestinal and colonic car- than carcinoid. When compared with SEER data adjusted for cinoids have higher metastatic potential than do tumors in other age and sex, there was a significant increase in the number of locations (20), with a higher percentage of nonlocalized lesions colorectal cancers. A slightly smaller but still significant dif- (71.2% for small intestinal and 70.7% for colonic), as opposed ference was present after exclusion of data based solely on the to the overall percentage of nonlocalized lesions for all carci- chart review (deceased patients). This probably represents noids (45.3%; Ref. 5). In our series, there was a higher prev- higher mortality of patients with coexisting colorectal cancer. alence of small intestinal carcinoids (71.8%) and relatively However, after exclusion of patients in whom carcinoids were small number of appendiceal (13.5%) and rectal (9.8%) carci- detected as an incidental finding, the incidence of colorectal noids. Furthermore, 73% of our patients had a nonlocalized cancer among patients with carcinoid tumor was not higher than lesion at the time of diagnosis. The observed number of met- expected. Considering the relative indolence of carcinoid tu- astatic carcinoids and the increased incidence of ileal carcinoids mors, it is not clear whether or not all these patients would be as compared with population based-data are probably a reflec- diagnosed with carcinoid tumor during their lifetime, in the tion of the referral bias of our institution. absence of a more aggressive tumor, such as colorectal cancer. Several studies indicate that patients with carcinoid tumors Thus, our data do not support the association of carcinoids with are at increased risk for developing another primary malignancy other tumors or increased tumor susceptibility in patients with (2, 11, 12). Chen et al. (13) postulated that small intestinal carcinoid. adenocarcinoma and carcinoid may have common endogenous In our series, a large number of patients with carcinoid or environmental risk factors. Kothari and Mangla (11) found were reported to have a first-degree relative with a malignant that 36% of patients with ileal carcinoid had an associated tumor (129 of 245). The distribution of these tumors was malignancy. Brown and Smith (12) reported a patient with extensive, without a particular predilection. When compared malignant carcinoid tumor of the ileum who subsequently de- with SEER data, the incidence of colorectal cancer was as veloped four other tumors, two malignant (one being colon expected and the number of lung cancers was somewhat lower adenocarcinoma) and two benign. These authors suggested a than expected in age- and sex-matched population, but there 17–53% incidence of second primary malignancy in patients was an increased number of “stomach” cancers. We did not with carcinoids, based on a review of the literature from 1949 observe a similar increase in gastric cancer among our primary to 1970. Ballantyne et al. (21) found metachronous gastroin- patients with carcinoid. A probable explanation for this appar- testinal malignant neoplasm in 6 of 54 patients with carcinoid ent increase in “gastric” cancers is that patients frequently of the colon. They recommended surveillance of the entire identify as stomach cancer a variety of intraabdominal malig-

Table 5 The incidence of malignant tumors among probands with carcinoida

Location and type of tumor No. observed No. expected Risk ratio 95% confidence interval P Colorectal adenocarcinoma 10 [6] 3.0 [2.3] 3.299 [2.660] 1.582–6.071 0.001 [0.975–5.786] [0.08] 2 [1]b 2.9 [2.2]b 0.682 [0.452]b 0.082–2.454 0.445 [0.011–2.509]b [0.345]b Breast carcinoma 10 [8] 5.9 [4.4] 1.701 [1.836] 0.815–3.129 0.08 [0.793–3.615] [0.08] Lung carcinoma 2 [1] 4.6 [3.4] 0.440 [0.297] 0.053–1.582 0.16 [0.008–1.648] [0.15] Uterine (corpus) cancer 1 [0] 2.1 [1.5] 0.49 [0.0] 0.012–2.70 0.38 [0–2.45] [0.22] Kidney cancer 1 [1] 0.8 [0.6] 1.2 [1.7] 0.03–6.69 0.55 [0.04–9.18] 0.45 Ovarian carcinoma 3 [3] 1.6 [1.2] 1.9 [2.6] 0.38–5.40 0.22 [0.53–7.44] 0.12 Thyroid carcinoma 2 [2] 0.7 [0.5] 2.8 [3.9] 0.34–10.22 0.16 [0.47–13.96] 0.09 Bladder carcinoma 3 [2] 1.2 [0.8] 2.6 [2.4] 0.54–7.6 0.12 [0.29–8.5] 0.19 Testicular carcinoma 1 [0] 0.8 [0.6] 1.2 [0] 0.03–6.83 0.55 [0–6.26] 0.55 Prostate carcinoma 3 [3] 3.8 [2.8] 0.787 [1.055] 0.163–2.296 0.47 [0.218–3.077] [0.53] Gastric carcinoma 0 [0] 0.5 [0.4] 0.61 [0.67] a Numbers in brackets are numbers after exclusion of data based on the chart review only. Rates are not shown for cervical cancer, skin cancer, and peritoneal/pleural tumors, for which data on histology were not available. b Numbers represent data after exclusion of patients in whom carcinoid was discovered as a coincidental finding during surgery for colorectal cancer.

Table 6 The incidence of malignant tumors among first-degree relativesa

Type of cancer No. observed No. expected Risk ratio 95% confidence interval P Colon/rectum 28 [24] 28.5 [22.0] 0.982 [1.092] 0.652–1.419 0.51 [0.699–1.624] [0.36] Breast 31 [29] 38.4 [30.2] 0.805 [0.960] 0.547–1.143 0.13 [0.643–1.379] [0.46] Lung 25 [19] 37.0 [28.5] 0.675 [0.666] 0.437–0.997 0.02 [0.401–1.039] [0.04] Prostate 18 [16] 42.5 [32.0] 0.424 [0.499] 0.251–0.670 Ͻ0.0001 [0.285–0.822] [0.001] Stomach 16 [13] 4.6 [3.6] 3.461 [3.643] 1.977–5.620 Ͻ0.0001 [1.933–6.235] [0.0001] a Numbers in brackets are after exclusion of data based on the chart review only. Data are based on exclusion of 15% of relatives for whom no information on age was known.

nancies. The reported incidence of prostate cancer among the series had at least one affected first-degree relative. The calcu- relatives was lower than expected. This probably reflects dif- lated incidence rates for carcinoid tumors among first degree ferent sensitivities in diagnostic modalities for prostate cancer relatives were 12.5 per 100,000 person-years for males and 15.7 as a function of time. Overall, our data do not support an per 100,000 person-years for females, adjusted to the 1970 increased general tumor susceptibility in relatives of patients United States white population. This is much higher than the with carcinoid, but there is a slightly increased risk for carci- age-adjusted incidence rates for carcinoid tumors (all sites, noid in first-degree relatives. including extraintestinal locations) reported by Modlin and Carcinoids are neuroendocrine neoplasms, which are en- Sandor (5), which were 1.20 and 1.28 per 100,000 population countered either sporadically or as part of a familial syndrome, per year for white males and females, respectively. Carcinoid most notably, MEN 1, and occasionally in MEN 2. When tumors in small bowel (P Ͻ 0.0001), colon (P ϭ 0.008), and associated with these familial syndromes, carcinoids are more total number of gastrointestinal carcinoids (P Ͻ 0.0001) in likely to develop in the foregut, especially in the thymus and first-degree relatives showed a similar increase over expected lung. It is estimated that only ϳ4% of patients with carcinoids rates based on SEER data from 1990–1995. also have other endocrine tumors (24), and these are inherited The MEN 1 gene on chromosome 11q13 probably func- in an autosomal dominant fashion. The majority of carcinoid tions as a tumor suppressor gene. Recently, it has been shown tumors are thought to be sporadic, with only anecdotal reports that a majority (78%) of sporadic carcinoids display loss of in the older literature describing familial occurrences (25–27). heterozygosity for markers around the MEN 1 region, thus Our results show that familial occurrence of carcinoid in some suggesting involvement of this gene in pathogenesis (28). Sim- cases is more than incidental. Nine (3.7%) patients from our ilar findings were noted in studies of sporadic parathyroid

tumors, when a somatic MEN 1 mutation contributed to tumor- 13. Chen, C. C., Neugut, A. I., and Rotterdam, H. Risk factors for adenocarci- igenesis in a substantial number of tumors (30%; Ref. 29). noma and malignant carcinoids of the small intestine: preliminary findings. Similar to familial hyperparathyroidism (30), it is possible that Cancer Epidemiol. Biomark. Prev., 3: 205–207, 1994. 14. Westergaard, T., Frisch, M., and Melbye, M. Carcinoid tumors in Denmark specific mutations within the MEN 1 or some other gene pro- 1978–1989 and the risk of subsequent cancers. A population-based study. Cancer duces familial carcinoid without expression of other endocrine (Phila.), 76: 106–109, 1995. tumors. Additional molecular studies are necessary to explore 15. Westergaard, T., Frisch, M., and Melbye, M. Carcinoid tumors in Denmark this possibility. 1978–1989 and the risk of development of new cancers (in Danish). 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Dusica Babovic-Vuksanovic, Costas L. Constantinou, Joseph Rubin, et al.

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