- Email: [email protected]
Carcinoid tumors of the lung and family history of cancer
J Clin Epidemiol Vol. 50, No. 6, pp. 705-709, Copyright 0 1997 Elsevier Science Inc.
0895s4356/97/$17.00 PII SO895-4356(97)00016-4
1997
ELSEVIER
Carcinoid Tumors of the Lung and Family History of Cancer Penny Perkins, ’ a*Ju hey-Jizum Lee,’ Bonnie L. Kemp,3 and James D. Cox’ ‘DEPARTMENTS OF RADIATION ONCOLOGY, ‘CLINICAL CANCER PREVENTION, AND ‘PATHOLOGY, UNIVERSITY OF TEXAS M.D. ANDERSON CANCER CENTER, HOUSTON, TEXAS
ABSTRACT.
Family history of cancer has been described among patients with lung neoplasms. Carcinoid tumors, originally thought to be slow growing and nonmetastatic, have not historically been included in these studies. In some instances these tumors have demonstrated aggressive metastatic potential. A medical record review of 86 patients with histopathologically confirmed carcinoid tumors of the lung, treated at the University of Texas M.D. Anderson Cancer Center between 1959 and 1994, was conducted to describe family history of cancer. Family history of cancer was recorded in 74 (86%) of the medical records and 32 (43%) reported tirstdegree relatives with cancer. Five-year survival for patients with affected relatives was 45% and 73% for patients without affected relatives (p = .23). A mong 67 patients without metastatic disease at diagnosis, the risk of distant metastasis by 5 years was 40% among patients with a positive family history of cancer compared to 6% of the patients without affected relatives (p = .03), (rate ratio 5.01). Th ese results suggest that genetic susceptibility may affect the metastatic potential of some carcinoid tumors. J CLIN EPIDEMIOL 50;6:705-709, 1997. 0 1997 Elsevier Science Inc.
KEY WORDS.
Carcinoid,
lung
cancer,
family
history,
metastasis
INTRODUCTION
METHODS
Historically, carcinoid tumors of the lung were considered to be slow growing and lack metastatic potential. However, clinical series (l-141 and population-based studies [15,16] have reported metastasizing tumors in some patients. The more aggressive behavior of some carcinoid tumors has been attributed to the presence of atypical histopathologic features [7,10,17-191. Although atypical carcinoid tumors have been associated with less favorable survival, these results have been inconsistent. Not all patients who experience a compromised clinical course have carcinoid tumors with atypical histopathologic features. A genetic etiology has been suggested for at least some carcinoid tumors since lung carcinoids can occur in the genetic disorder of multiple endocrine adenomatosis [20]. Studies of the family history of cancer among patients with adenocarcinoma, squamous cell, and small cell carcinoma suggest an association between lung cancer and a family history of cancer [21-241. The aim of this study was to describe the family history of cancer among first-degree relatives of patients with carcinoid tumors of the lung.
Newly diagnosed patients with histopathologically confirmed carcinoid tumors of the lung who were treated at the University of Texas M. D. Anderson Cancer Center (UTMDACC) from 1959 to 1994 were ascertained from the hospital tumor registry. Patients were excluded if prior treatment, other than surgery, was received prior to referral to UTMDACC. Medical records were reviewed for reported family history of cancer, which is routinely obtained during the initial history and physical examination at UTMDACC. Nursing admission forms and physician referral records also provided family history data. The histopathologic designations of typical and atypical carcinoid were obtained from a review of retrievable patient tumor tissue slides by a UTMDACC pathologist who was blinded to patient outcome. This evaluation was performed only on slides from the primary tumor. Classification as an atypical carcinoid required the presence, of ~4-5 mitotic figures per 10 high power fields or the presence of tumor necrosis. Focal loss of neuroendocrine pattern, or so-called “architectural disorder,” was not used as a criterion due to marked subjectivity in interpretation and lack of general consensus as to its true significance. Focal cytologic atypia was also excluded as a criterion. Data analyses included chi-square tests of homogeneity for patient and tumor characteristics, actuarial life table
‘Address for correspondence: Penny Perkins, Ph.D., M. D. Anderson Cancer Center, Department of Radiation Oncology, Box 97, 15 15 Holcomhe Blvd., Houston, TX 77030. Accepted for publication on 30 January 1997.
706
P. Perkins
analyses for survival probability estimates, odds ratio calculations for measures of association between family history and certain clinical features, and Cox proportional hazard regression models for rate ratio estimation. All analyses were generated using STATA statistical software [25]. RESULTS
Eighty-six patients who received primary treatment for carcinoid tumors of the lung at UTMDACC between 1959 and 1994 were identified. Among these patients, family history of cancer was recorded in 74 (86%) of the medical records. In two medical records, the relationship between the patient and the affected relative was not recorded, and in 10 medical records, family history was not documented. The term “family history” used in the following text refers to first-degree relatives only. Characteristics of the patients with and without family history documentation in their medical records are presented in Table 1. Both groups consisted of a higher proportion of white patients, age ~55, and no prior or concurrent malignancy. Statistical comparisons are not presented due to the small number of patients without family history documentation. Among the 74 patients with family history documentation in their medical records, 32 patients (43%) reported a positive family history of cancer. Median age of carcinoid tumor diagnosis was 59 years for both males and females. Seventy-five percent of the patients who were median age or older reported a positive family history of cancer compared to 25% of the patients less than the median age (p < .Ol).
TABLE of the
1. Characteristics lung
of patients Family history documentation
Characteristic Age group <55 255 Gender Male Female Ethnicity White Hispanic Black Prior/concurrent malignancy Yes No Diagnosis date Prior to 1988 1989 to 1994
(n = 74)
with
carcinoid
tumors
No family history documentation (n = 12)
32 (43%) 42 (57%)
3 (25%) 9 (75%)
36 (49%) 38 (51%)
3 (25%) 9 (75%)
65 (88%) 7 (9%) 2 (3%)
7 (58%) 3 (25%) 2 (17%)
19 (26%) 55 (74%)
4 (33%) 8 (67%)
35 (47%) 39 (53%)
9 (75%) 3 (25%)
TABLE cinoid
2. Family history of cancer tumors of the lung
Family
among Number families
history
First-degree relatives w/cancer No Yes One Two or more Fathers and mothers with cancer No affected parents Father only Mother only Father and mother Proband families with cancer (n = 32)” Digestive Lung Genito-urinary Breast Skin Brain Head and neck Other “Each
family
patients
may have
multiple
with
et al.
car-
of %
42 32 21 11
(57) (43)
49
(66)
11
(15)
(28) (15)
(12)
9
(7)
(38) (22)
12
(22) (19)
7 6
(16) (13) (9)
4 7 cancer
sites
reported.
The overall difference between males and females reporting a positive family history of cancer, 47% and 39% respectively, was not statistically significant. However, more females (n = 8) than males (n = 3) reported multiple relatives with cancer, (p = .03). Family relationships and cancer sites are presented in Table 2. Twenty patients (27%) reported either a father or mother with cancer and five patients (7%) reported both affected parents. The most frequently reported cancer sites in families involved the digestive system, followed by lung, genito-urinary, and breast. A positive family history of cancer was not significantly associated with prior and/or current malignancies (odds ratio 1.67, p = .39) or atypical histopathology (odds ratio 1.10, p = .89). Mean and median years of follow-up for the 74 patients with carcinoid tumors of the lung was 4.10 and 1.95 years, respectively, ranging from .02 years to 20.39 years. Mean and median follow-up was similar for patients with and without a family history of cancer. Five-year survival was 73% for patients with a negative family history of cancer, compared to 45% for patients with a positive family history (log rank test, p = .23). The univariate
Cox
regression
analysis
rate
ratio
was
1.73
(p =
.23).
Analyses to examine development of metastasis after diagnosis excluded seven patients who presented with metastasis. Among the 67 patients without metastatic disease at diagnosis, the risk of distant metastases by 5 years was 40% among
patients
with
a family
history
of cancer
compared
to
Lung Carcinoid
TABLE
carcinoid cancer
3.
Five-year distant metastasis among patients with tumors of the lung by reported family history of Family
Distant
Positive (%)
metastasis
Overall (n = 67) Patients without nodal involvement (n = 47) Patients with typical histopathology (n = 42) Patients without prior malignancy (n = 50) Patient with smoking history (n = 42) Patients receiving surgery alone (n = 55) Patients younger than median age” Patients older or equal to median age“ “Median
707
and Family History
age (58.17)
history Negative W)
Log rank pvalue
40
6
.03
28
0
.Ol
24
0
.04
49
4
.Ol
58
5
.02
23
0
.02
71
4
.Ol
24
9
.53
is based on n = 67.
6% among patients with a negative family history (0 = .03) (Table 3). The rate of distant metastasis within 5 years was 5-fold higher among patients with a positive family history of cancer compared to those with no affected relatives (rate ratio 5.01, P < .05). Also presented in Table 3 are the results of univariate life table analyses which examined 5-year distant metastasis by patient characteristics and family history of cancer. Results demonstrated that, among patients with no nodal involvement, typical tumor histopathology, positive smoking history, treatment by surgery only, or age less than the median, the risk of distant metastasis by 5 years was significantly greater among patients who had a positive family history of cancer. Among patients older than the median age, 5-year distant metastatic risk by family history was not significant, although 24% of the patients with a positive family history of cancer experienced metastasis compared to 9% of the patients with no affected relatives. The number of patients with nodal involvement, atypical tumor histopathology, and nonsmokers was too small to make meaningful comparisons of 5-year distant metastasis by family history. DISCUSSION This is the first descriptive study of the family history of cancer among patients with carcinoid tumors of the lung; comparisons with the literature are limited to family history studies among patients with other lung cancer histology. UTMDACC patients with carcinoid tumors of the lung reported 43% of their families as having a relative with cancer. This was lower than the 58% reported by researchers at Roswell Park Cancer Institute in New York among the
patients in their clinical series [23]. However, patient probands in their study were diagnosed with adeno, large cell, small cell, or squamous cell cancer of the lung. In our study, older patients reported a positive family history of cancer more often than younger patients which was similar to the results of a study conducted by Sellers et al. [21] in southern Louisiana. It is reasonable to assume that, with increased years of life, by chance alone, older patients are more likely to have a positive family history of cancer. Some studies suggest that familial clustering of cancer is independent of the proband’s age at diagnosis [26,27]. Among the patients in our clinical series, 22% reported at least one relative with lung cancer. This was similar to the 26% reported by a population-based study conducted among residents in the Texas Gulf Coast region [22], which included the geographic area where UTMDACC is also located. Our results and those from the entire Gulf Coast region were somewhat lower than a population-based study conducted in Louisiana where the proportion of families with lung cancer was 29% [21]. The proportion of fathers and mothers with cancer in our study, 22% and 19%, respectively, was comparable with the population-based Texas Gulf Coast study, 19% and 21%. Similar proportions were reported by the Saskatchewan Cancer Center in Canada [28], 23% with affected fathers and 21% with affected mothers. The 5-year survival difference between patients in our series with a positive family history of cancer and a negative family history was not statistically significant. Researchers from Duke University Medical Center also reported that family history was not a predictor for survival in their study [29]. In our clinical series, 73% of the patients with no family history of cancer survived 5 years compared to 45% of the patients with a positive family history of cancer. Although this difference was not statistically significant, the magnitude of the difference suggested further exploration into the possible effects of family history in this patient population. Risk of 5-year distant metastasis was examined among patients with and without a family history of cancer. The proportion of patients with distant metastasis was significantly higher among patients with a positive family history of cancer. This finding was further supported by subgroup univariate analyses performed among patients with no nodal involvement, typical tumor histopathology, no prior or concurrent malignancy, positive smoking histories, and surgical treatment only. Younger patients (less than median age) with a positive family history of cancer were also more likely to experience distant metastases by 5 years than those without affected relatives. This pattern was also found among the older age group (greater or equal to median age), however the difference was not statistically significant. Although we used family history as an indicator of genetic predisposition, we were aware that the increased probability of older patients having relatives with cancer would dilute
P. Perkins et al.
708
the effect of family history as an indicator of genetic predisposition in the older age group. As a result, in our study, family history was not a significant indicator of 5-year distant metastasis in the older age group. The major limitation of our study was that although patient admissions for carcinoid tumors were reviewed as far back as 1944 and the first case was diagnosed in 1959, the number of patients was not large enough to perform bivariate stratified analyses of interest. Because most of the patients had a positive smoking history, did not have prior or concurrent malignancies, were diagnosed with local disease, had typical carcinoid tumors, or received surgical treatment alone, we were limited to examining the effect of family history among these subgroups. However, our univariate analyses among these subgroups, presented in Table 3, consistently demonstrated that patients with a positive family history of cancer were more likely to experience 5-year distant metastasis than patients without a family history of cancer. The aim of this study was to describe the family history of cancer among first-degree relatives of patients with newly diagnosed carcinoid tumors of the lung, based on the data obtained from patient medical records. Although our study was based on reported family history among first-degree relatives, UTMDACC medical records provided family history data for other relatives as well. Family history of cancer was recorded in 93% of the medical records of patients registering at UTMDACC after 1988. In conclusion, the results of our study suggest that patients with carcinoid tumors of the lung and a positive family history of cancer among first-degree relatives (index of genetic susceptibility) were more likely to experience distant metastasis within 5 years than those without a positive family history of cancer. Limiting the analyses to patients with typical tumor histopathology, historically considered to behave benignly, the metastatic differential remained. We were not able to calculate 5-year distant metastasis among patients with atypical tumor histopathology, due to the small number of patients in this analytic group. The question arises as to the reasons for the differences in metastatic potential. Our analyses were limited by the small size of our patient series and sometimes unavailable patient data over the 35-year period. Larger patient series are indicated that would allow extensive evaluations of tumor histopathology, oncogenes, and suppressor genes to examine the metastatic potential of carcinoid tumors.
3.
4.
5.
6.
7.
8.
9. 10.
11. 12.
13.
14.
15. 16.
17.
18.
19.
20.
2 1. This research
was supported
by the Fair Foundation. 22.
References 1. Akiba T, K, et al. study of 2. Bertelsen Jacobsen
23. Naruke T, Kondo H, Goya T, Tsuchiya R, Suemasu Carcinoid tumor of the lung: Clinicopathological 32 cases. Jpn J Clin Oncol 1992; 22: 92-95. S, Aasted A, Lund C, Badsberg E, Christoffersen I, M, et al. Bronchial carcinoid tumors: A clinicopath-
24.
ologic study of 82 cases. Stand J Thor Cardiovasc Surg 1985; 19: 105-111. El-Naggar AK, Ballance W, Karim FW, Ordonez NG, McLemore D, Giacco GG, et al. Typical and atypical bronchopulmonary carcinoids: A clinicopathologic and flow cytometric study. Am J Clin Path01 1991; 95: 828-834. Goldstraw P, Lamb D, McCormack RJM, Walbaum PR. The malignancy of bronchial adenoma. J Thor Card Surg 1976; 72(2): 309-314. Grote TH, Macon WR, Davis B, Greco FA, Johnson DH. Atypical carcinoid of the lung: A distinct clinicopathologic entity. Chest 1988; 93(2): 370-374. Hallgrimsson JG, Jonsson T, Johannsson JH. Bronchopulmonary carcinoids in Iceland 1955-1984. Stand J Thor Cardiovast 1989; 23: 275-278. Hasleton PS, Gomm VB, Thatcher N. Pulmonary carcinoid tumours: A clinico-pathological study of 35 cases. Br J Cancer 1986; 54: 963-967. Martini N, Zaman MB, Bains MS, Burt ME, McCormack PM, Rusch VW, et al. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994; 107: l-7. McCaughan BC, Martini N, Bains MS. Bronchial carcinoids. J Thorac Cardiovasc Surg 1985; 89: 8-17. Mills SE, Cooper PH, Walker AN, Kron IL. Atypical carcinoid tumor of the lung: A clinicopathologic study of 17 cases. Am J Surg Path01 1982; 6: 643-654. Okike N, Bematz PE, Woolner LB. Carcinoid tumors of the lung. Ann Thor Surg 1976; 22(3): 270-277. Torre M, Barberis M, Barbieri B, Bonacina E, Belloni P. Typical and atypical bronchial carcinoids. Respiratory Medicine 1989; 83: 305-308. Turnbull AD, Huvos AG, Goodner JT, Beattie EJ. The malignant potential of bronchial adenoma. Ann Thor Surg 1972; 14(5): 453-462. Conley YD, Cafoncelli AR, Khan JH, Khan MZ, Aburahma AF, Boland JP. Bronchial carcinoid tumor: Experience over 20 years. American Surgeon 1992; 58: 670-672. Godwin JD. Carcinoid tumors. Cancer 1975; 36: 560-569. Greenberg RS, Baumgarten DA, Clark WS, Isacson P, McKeen K. Prognostic factors for gastrointestinal and bronchopulmonary carcinoid tumors. Cancer 1987; 60: 24762483. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972; 64: 413421. Goodner JT, Berg JW, Watson WL. The nonbenign nature of bronchial carcinoids and cylindromas. Cancer 1961; 14(3): 539-546. Johnson LA, Lavin P, Moertel CG, Weiland L, Dayal Y, Doos WG, et al. Carcinoids: The association of histologic growth pattern and survival. Cancer 1983; 51: 882-889. Godwin JD, Brown CC. Comparative epidemiology of carcinoid and oat-cell tumors of the lung. Cancer 1977; 40: 16711673. Sellers TA, Elston RC, Atwood LD, Rothschild H. Lung cancer histologic type and family history of cancer. Cancer 1992; 69: 86-91. Shaw GL, Falk RT, Pickle LW, Mason TJ, Buffler PA. Lung cancer risk associated with cancer in relatives. J Clin Epidemiol 1991; 44: 429-437. Ambrosone CB, Rao U, Michalek AM, Cummings MK, Met&n CJ. Lung cancer histologic types and family history of cancer. Cancer 1993; 72: 1192-1198. Ogawa H, Kato I, Tominage S. Family history of cancer among cancer patients. Jpn J Cancer Res (Gann) 1985; 76: 113-118.
Lung
25.
Carcinoid
and Family
History
Stata Corporation. Stata Statistical Software. Release 4.0. College Station, TX. 1995. 26. Schneider NR, Chaganti SR, German J, Chaganti RSK. Familial predisposition to cancer and age at onset of disease in randomly selected cancer patients. Am J Hum Genet 1983; 35: 454-467. 27. Weiss KM, Chakraborty R, Smouse PE, Buchanan AV, Strong LC. Familial aggregation of cancer in Laredo, Texas: A gener-
709
ally low-risk Mexican-American population. Genetic Epidemiol 1986; 3: 121-143. 28. McDuffie HH. Clustering of cancer in families of patients with primary lung cancer. J Clin Epidemiol 1991; 44( 1): 69-76. 29. Harpole DH, Feldman JM, Buchanan S, Young WG, Wolfe WG. Bronchial carcinoid tumors: A retrospective analysis of 126 patients. Ann Thorac Surg 1992; 54: 50-55.
0895s4356/97/$17.00 PII SO895-4356(97)00016-4
1997
ELSEVIER
Carcinoid Tumors of the Lung and Family History of Cancer Penny Perkins, ’ a*Ju hey-Jizum Lee,’ Bonnie L. Kemp,3 and James D. Cox’ ‘DEPARTMENTS OF RADIATION ONCOLOGY, ‘CLINICAL CANCER PREVENTION, AND ‘PATHOLOGY, UNIVERSITY OF TEXAS M.D. ANDERSON CANCER CENTER, HOUSTON, TEXAS
ABSTRACT.
Family history of cancer has been described among patients with lung neoplasms. Carcinoid tumors, originally thought to be slow growing and nonmetastatic, have not historically been included in these studies. In some instances these tumors have demonstrated aggressive metastatic potential. A medical record review of 86 patients with histopathologically confirmed carcinoid tumors of the lung, treated at the University of Texas M.D. Anderson Cancer Center between 1959 and 1994, was conducted to describe family history of cancer. Family history of cancer was recorded in 74 (86%) of the medical records and 32 (43%) reported tirstdegree relatives with cancer. Five-year survival for patients with affected relatives was 45% and 73% for patients without affected relatives (p = .23). A mong 67 patients without metastatic disease at diagnosis, the risk of distant metastasis by 5 years was 40% among patients with a positive family history of cancer compared to 6% of the patients without affected relatives (p = .03), (rate ratio 5.01). Th ese results suggest that genetic susceptibility may affect the metastatic potential of some carcinoid tumors. J CLIN EPIDEMIOL 50;6:705-709, 1997. 0 1997 Elsevier Science Inc.
KEY WORDS.
Carcinoid,
lung
cancer,
family
history,
metastasis
INTRODUCTION
METHODS
Historically, carcinoid tumors of the lung were considered to be slow growing and lack metastatic potential. However, clinical series (l-141 and population-based studies [15,16] have reported metastasizing tumors in some patients. The more aggressive behavior of some carcinoid tumors has been attributed to the presence of atypical histopathologic features [7,10,17-191. Although atypical carcinoid tumors have been associated with less favorable survival, these results have been inconsistent. Not all patients who experience a compromised clinical course have carcinoid tumors with atypical histopathologic features. A genetic etiology has been suggested for at least some carcinoid tumors since lung carcinoids can occur in the genetic disorder of multiple endocrine adenomatosis [20]. Studies of the family history of cancer among patients with adenocarcinoma, squamous cell, and small cell carcinoma suggest an association between lung cancer and a family history of cancer [21-241. The aim of this study was to describe the family history of cancer among first-degree relatives of patients with carcinoid tumors of the lung.
Newly diagnosed patients with histopathologically confirmed carcinoid tumors of the lung who were treated at the University of Texas M. D. Anderson Cancer Center (UTMDACC) from 1959 to 1994 were ascertained from the hospital tumor registry. Patients were excluded if prior treatment, other than surgery, was received prior to referral to UTMDACC. Medical records were reviewed for reported family history of cancer, which is routinely obtained during the initial history and physical examination at UTMDACC. Nursing admission forms and physician referral records also provided family history data. The histopathologic designations of typical and atypical carcinoid were obtained from a review of retrievable patient tumor tissue slides by a UTMDACC pathologist who was blinded to patient outcome. This evaluation was performed only on slides from the primary tumor. Classification as an atypical carcinoid required the presence, of ~4-5 mitotic figures per 10 high power fields or the presence of tumor necrosis. Focal loss of neuroendocrine pattern, or so-called “architectural disorder,” was not used as a criterion due to marked subjectivity in interpretation and lack of general consensus as to its true significance. Focal cytologic atypia was also excluded as a criterion. Data analyses included chi-square tests of homogeneity for patient and tumor characteristics, actuarial life table
‘Address for correspondence: Penny Perkins, Ph.D., M. D. Anderson Cancer Center, Department of Radiation Oncology, Box 97, 15 15 Holcomhe Blvd., Houston, TX 77030. Accepted for publication on 30 January 1997.
706
P. Perkins
analyses for survival probability estimates, odds ratio calculations for measures of association between family history and certain clinical features, and Cox proportional hazard regression models for rate ratio estimation. All analyses were generated using STATA statistical software [25]. RESULTS
Eighty-six patients who received primary treatment for carcinoid tumors of the lung at UTMDACC between 1959 and 1994 were identified. Among these patients, family history of cancer was recorded in 74 (86%) of the medical records. In two medical records, the relationship between the patient and the affected relative was not recorded, and in 10 medical records, family history was not documented. The term “family history” used in the following text refers to first-degree relatives only. Characteristics of the patients with and without family history documentation in their medical records are presented in Table 1. Both groups consisted of a higher proportion of white patients, age ~55, and no prior or concurrent malignancy. Statistical comparisons are not presented due to the small number of patients without family history documentation. Among the 74 patients with family history documentation in their medical records, 32 patients (43%) reported a positive family history of cancer. Median age of carcinoid tumor diagnosis was 59 years for both males and females. Seventy-five percent of the patients who were median age or older reported a positive family history of cancer compared to 25% of the patients less than the median age (p < .Ol).
TABLE of the
1. Characteristics lung
of patients Family history documentation
Characteristic Age group <55 255 Gender Male Female Ethnicity White Hispanic Black Prior/concurrent malignancy Yes No Diagnosis date Prior to 1988 1989 to 1994
(n = 74)
with
carcinoid
tumors
No family history documentation (n = 12)
32 (43%) 42 (57%)
3 (25%) 9 (75%)
36 (49%) 38 (51%)
3 (25%) 9 (75%)
65 (88%) 7 (9%) 2 (3%)
7 (58%) 3 (25%) 2 (17%)
19 (26%) 55 (74%)
4 (33%) 8 (67%)
35 (47%) 39 (53%)
9 (75%) 3 (25%)
TABLE cinoid
2. Family history of cancer tumors of the lung
Family
among Number families
history
First-degree relatives w/cancer No Yes One Two or more Fathers and mothers with cancer No affected parents Father only Mother only Father and mother Proband families with cancer (n = 32)” Digestive Lung Genito-urinary Breast Skin Brain Head and neck Other “Each
family
patients
may have
multiple
with
et al.
car-
of %
42 32 21 11
(57) (43)
49
(66)
11
(15)
(28) (15)
(12)
9
(7)
(38) (22)
12
(22) (19)
7 6
(16) (13) (9)
4 7 cancer
sites
reported.
The overall difference between males and females reporting a positive family history of cancer, 47% and 39% respectively, was not statistically significant. However, more females (n = 8) than males (n = 3) reported multiple relatives with cancer, (p = .03). Family relationships and cancer sites are presented in Table 2. Twenty patients (27%) reported either a father or mother with cancer and five patients (7%) reported both affected parents. The most frequently reported cancer sites in families involved the digestive system, followed by lung, genito-urinary, and breast. A positive family history of cancer was not significantly associated with prior and/or current malignancies (odds ratio 1.67, p = .39) or atypical histopathology (odds ratio 1.10, p = .89). Mean and median years of follow-up for the 74 patients with carcinoid tumors of the lung was 4.10 and 1.95 years, respectively, ranging from .02 years to 20.39 years. Mean and median follow-up was similar for patients with and without a family history of cancer. Five-year survival was 73% for patients with a negative family history of cancer, compared to 45% for patients with a positive family history (log rank test, p = .23). The univariate
Cox
regression
analysis
rate
ratio
was
1.73
(p =
.23).
Analyses to examine development of metastasis after diagnosis excluded seven patients who presented with metastasis. Among the 67 patients without metastatic disease at diagnosis, the risk of distant metastases by 5 years was 40% among
patients
with
a family
history
of cancer
compared
to
Lung Carcinoid
TABLE
carcinoid cancer
3.
Five-year distant metastasis among patients with tumors of the lung by reported family history of Family
Distant
Positive (%)
metastasis
Overall (n = 67) Patients without nodal involvement (n = 47) Patients with typical histopathology (n = 42) Patients without prior malignancy (n = 50) Patient with smoking history (n = 42) Patients receiving surgery alone (n = 55) Patients younger than median age” Patients older or equal to median age“ “Median
707
and Family History
age (58.17)
history Negative W)
Log rank pvalue
40
6
.03
28
0
.Ol
24
0
.04
49
4
.Ol
58
5
.02
23
0
.02
71
4
.Ol
24
9
.53
is based on n = 67.
6% among patients with a negative family history (0 = .03) (Table 3). The rate of distant metastasis within 5 years was 5-fold higher among patients with a positive family history of cancer compared to those with no affected relatives (rate ratio 5.01, P < .05). Also presented in Table 3 are the results of univariate life table analyses which examined 5-year distant metastasis by patient characteristics and family history of cancer. Results demonstrated that, among patients with no nodal involvement, typical tumor histopathology, positive smoking history, treatment by surgery only, or age less than the median, the risk of distant metastasis by 5 years was significantly greater among patients who had a positive family history of cancer. Among patients older than the median age, 5-year distant metastatic risk by family history was not significant, although 24% of the patients with a positive family history of cancer experienced metastasis compared to 9% of the patients with no affected relatives. The number of patients with nodal involvement, atypical tumor histopathology, and nonsmokers was too small to make meaningful comparisons of 5-year distant metastasis by family history. DISCUSSION This is the first descriptive study of the family history of cancer among patients with carcinoid tumors of the lung; comparisons with the literature are limited to family history studies among patients with other lung cancer histology. UTMDACC patients with carcinoid tumors of the lung reported 43% of their families as having a relative with cancer. This was lower than the 58% reported by researchers at Roswell Park Cancer Institute in New York among the
patients in their clinical series [23]. However, patient probands in their study were diagnosed with adeno, large cell, small cell, or squamous cell cancer of the lung. In our study, older patients reported a positive family history of cancer more often than younger patients which was similar to the results of a study conducted by Sellers et al. [21] in southern Louisiana. It is reasonable to assume that, with increased years of life, by chance alone, older patients are more likely to have a positive family history of cancer. Some studies suggest that familial clustering of cancer is independent of the proband’s age at diagnosis [26,27]. Among the patients in our clinical series, 22% reported at least one relative with lung cancer. This was similar to the 26% reported by a population-based study conducted among residents in the Texas Gulf Coast region [22], which included the geographic area where UTMDACC is also located. Our results and those from the entire Gulf Coast region were somewhat lower than a population-based study conducted in Louisiana where the proportion of families with lung cancer was 29% [21]. The proportion of fathers and mothers with cancer in our study, 22% and 19%, respectively, was comparable with the population-based Texas Gulf Coast study, 19% and 21%. Similar proportions were reported by the Saskatchewan Cancer Center in Canada [28], 23% with affected fathers and 21% with affected mothers. The 5-year survival difference between patients in our series with a positive family history of cancer and a negative family history was not statistically significant. Researchers from Duke University Medical Center also reported that family history was not a predictor for survival in their study [29]. In our clinical series, 73% of the patients with no family history of cancer survived 5 years compared to 45% of the patients with a positive family history of cancer. Although this difference was not statistically significant, the magnitude of the difference suggested further exploration into the possible effects of family history in this patient population. Risk of 5-year distant metastasis was examined among patients with and without a family history of cancer. The proportion of patients with distant metastasis was significantly higher among patients with a positive family history of cancer. This finding was further supported by subgroup univariate analyses performed among patients with no nodal involvement, typical tumor histopathology, no prior or concurrent malignancy, positive smoking histories, and surgical treatment only. Younger patients (less than median age) with a positive family history of cancer were also more likely to experience distant metastases by 5 years than those without affected relatives. This pattern was also found among the older age group (greater or equal to median age), however the difference was not statistically significant. Although we used family history as an indicator of genetic predisposition, we were aware that the increased probability of older patients having relatives with cancer would dilute
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the effect of family history as an indicator of genetic predisposition in the older age group. As a result, in our study, family history was not a significant indicator of 5-year distant metastasis in the older age group. The major limitation of our study was that although patient admissions for carcinoid tumors were reviewed as far back as 1944 and the first case was diagnosed in 1959, the number of patients was not large enough to perform bivariate stratified analyses of interest. Because most of the patients had a positive smoking history, did not have prior or concurrent malignancies, were diagnosed with local disease, had typical carcinoid tumors, or received surgical treatment alone, we were limited to examining the effect of family history among these subgroups. However, our univariate analyses among these subgroups, presented in Table 3, consistently demonstrated that patients with a positive family history of cancer were more likely to experience 5-year distant metastasis than patients without a family history of cancer. The aim of this study was to describe the family history of cancer among first-degree relatives of patients with newly diagnosed carcinoid tumors of the lung, based on the data obtained from patient medical records. Although our study was based on reported family history among first-degree relatives, UTMDACC medical records provided family history data for other relatives as well. Family history of cancer was recorded in 93% of the medical records of patients registering at UTMDACC after 1988. In conclusion, the results of our study suggest that patients with carcinoid tumors of the lung and a positive family history of cancer among first-degree relatives (index of genetic susceptibility) were more likely to experience distant metastasis within 5 years than those without a positive family history of cancer. Limiting the analyses to patients with typical tumor histopathology, historically considered to behave benignly, the metastatic differential remained. We were not able to calculate 5-year distant metastasis among patients with atypical tumor histopathology, due to the small number of patients in this analytic group. The question arises as to the reasons for the differences in metastatic potential. Our analyses were limited by the small size of our patient series and sometimes unavailable patient data over the 35-year period. Larger patient series are indicated that would allow extensive evaluations of tumor histopathology, oncogenes, and suppressor genes to examine the metastatic potential of carcinoid tumors.
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2 1. This research
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References 1. Akiba T, K, et al. study of 2. Bertelsen Jacobsen
23. Naruke T, Kondo H, Goya T, Tsuchiya R, Suemasu Carcinoid tumor of the lung: Clinicopathological 32 cases. Jpn J Clin Oncol 1992; 22: 92-95. S, Aasted A, Lund C, Badsberg E, Christoffersen I, M, et al. Bronchial carcinoid tumors: A clinicopath-
24.
ologic study of 82 cases. Stand J Thor Cardiovasc Surg 1985; 19: 105-111. El-Naggar AK, Ballance W, Karim FW, Ordonez NG, McLemore D, Giacco GG, et al. Typical and atypical bronchopulmonary carcinoids: A clinicopathologic and flow cytometric study. Am J Clin Path01 1991; 95: 828-834. Goldstraw P, Lamb D, McCormack RJM, Walbaum PR. The malignancy of bronchial adenoma. J Thor Card Surg 1976; 72(2): 309-314. Grote TH, Macon WR, Davis B, Greco FA, Johnson DH. Atypical carcinoid of the lung: A distinct clinicopathologic entity. Chest 1988; 93(2): 370-374. Hallgrimsson JG, Jonsson T, Johannsson JH. Bronchopulmonary carcinoids in Iceland 1955-1984. Stand J Thor Cardiovast 1989; 23: 275-278. Hasleton PS, Gomm VB, Thatcher N. Pulmonary carcinoid tumours: A clinico-pathological study of 35 cases. Br J Cancer 1986; 54: 963-967. Martini N, Zaman MB, Bains MS, Burt ME, McCormack PM, Rusch VW, et al. Treatment and prognosis in bronchial carcinoids involving regional lymph nodes. J Thorac Cardiovasc Surg 1994; 107: l-7. McCaughan BC, Martini N, Bains MS. Bronchial carcinoids. J Thorac Cardiovasc Surg 1985; 89: 8-17. Mills SE, Cooper PH, Walker AN, Kron IL. Atypical carcinoid tumor of the lung: A clinicopathologic study of 17 cases. Am J Surg Path01 1982; 6: 643-654. Okike N, Bematz PE, Woolner LB. Carcinoid tumors of the lung. Ann Thor Surg 1976; 22(3): 270-277. Torre M, Barberis M, Barbieri B, Bonacina E, Belloni P. Typical and atypical bronchial carcinoids. Respiratory Medicine 1989; 83: 305-308. Turnbull AD, Huvos AG, Goodner JT, Beattie EJ. The malignant potential of bronchial adenoma. Ann Thor Surg 1972; 14(5): 453-462. Conley YD, Cafoncelli AR, Khan JH, Khan MZ, Aburahma AF, Boland JP. Bronchial carcinoid tumor: Experience over 20 years. American Surgeon 1992; 58: 670-672. Godwin JD. Carcinoid tumors. Cancer 1975; 36: 560-569. Greenberg RS, Baumgarten DA, Clark WS, Isacson P, McKeen K. Prognostic factors for gastrointestinal and bronchopulmonary carcinoid tumors. Cancer 1987; 60: 24762483. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972; 64: 413421. Goodner JT, Berg JW, Watson WL. The nonbenign nature of bronchial carcinoids and cylindromas. Cancer 1961; 14(3): 539-546. Johnson LA, Lavin P, Moertel CG, Weiland L, Dayal Y, Doos WG, et al. Carcinoids: The association of histologic growth pattern and survival. Cancer 1983; 51: 882-889. Godwin JD, Brown CC. Comparative epidemiology of carcinoid and oat-cell tumors of the lung. Cancer 1977; 40: 16711673. Sellers TA, Elston RC, Atwood LD, Rothschild H. Lung cancer histologic type and family history of cancer. Cancer 1992; 69: 86-91. Shaw GL, Falk RT, Pickle LW, Mason TJ, Buffler PA. Lung cancer risk associated with cancer in relatives. J Clin Epidemiol 1991; 44: 429-437. Ambrosone CB, Rao U, Michalek AM, Cummings MK, Met&n CJ. Lung cancer histologic types and family history of cancer. Cancer 1993; 72: 1192-1198. Ogawa H, Kato I, Tominage S. Family history of cancer among cancer patients. Jpn J Cancer Res (Gann) 1985; 76: 113-118.
Lung
25.
Carcinoid
and Family
History
Stata Corporation. Stata Statistical Software. Release 4.0. College Station, TX. 1995. 26. Schneider NR, Chaganti SR, German J, Chaganti RSK. Familial predisposition to cancer and age at onset of disease in randomly selected cancer patients. Am J Hum Genet 1983; 35: 454-467. 27. Weiss KM, Chakraborty R, Smouse PE, Buchanan AV, Strong LC. Familial aggregation of cancer in Laredo, Texas: A gener-
709
ally low-risk Mexican-American population. Genetic Epidemiol 1986; 3: 121-143. 28. McDuffie HH. Clustering of cancer in families of patients with primary lung cancer. J Clin Epidemiol 1991; 44( 1): 69-76. 29. Harpole DH, Feldman JM, Buchanan S, Young WG, Wolfe WG. Bronchial carcinoid tumors: A retrospective analysis of 126 patients. Ann Thorac Surg 1992; 54: 50-55.