Increased risk of lung cancer in patients with chondromatous hamartoma

J

THORAC CARDIOVASC SURG

80:217-220, 1980

Increased risk of lung cancer in patients with chondromatous hamartoma Fifty-two patients with chondromatous hamartoma of the lung (CHL) operated upon in one medical center in Israel during the years 1960 to 1975 were followed through the end of 1976 for occurrence of malignancy. In 51 patients. the operation followed the finding of a coin lesion in a routine chest x-ray film (32 cases) or an x-ray film taken due to symptoms related to the chest (19 cases). In one case. it followed a cytologic diagnosis of bronchogenic carcinoma. Four cases of carcinoma of the lung were observed in this group. three of them 2 to 10 years after the CHL was first observed; in the fourth the CHL was found during an operation for lung cancer. All four lung cancers were located in the same lobe as and in proximity to the CHL. Since hamartomas were randomly distributed among the lobes. this spatial association is highly significant (p = 0.0016). The risk of lung cancer in CHL patients was estimated to be 6.3 times higher than the age-sex-ethnic adjusted rate expected for the general Israeli population. No increased risk for malignancies of other sites was found.

Avraham Karasik, M.D., Michaela Modan, M.Sc., Chaim O. Jacob, M.D., and Yair Lieberman, M.D., Tel Hashomer, Israel

Several investigators have reported an association of chondromatous hamartoma of the lung (CHL) with malignant lung neoplasms and possible malignant degeneration of the benign tumor. HI A coincidence with extrapulmonary neoplasms was also mentioned. A recent article described four patients having a triad of CHL, extra-adrenal paraganglioma, and gastric leiomyosarcoma. The investigators suggested that this triad of uncommon tumors constitutes an etiologic syndrome as their coincidental occurrence is improbable. 4 The current study attempts to evaluate the association between CHL, lung cancer, and other neoplasms on the basis of their rates in the general population. Patients

The study consisted of 52 patients with CHL who underwent lung operations at the Chaim Sheba Medical Center, Tel Hashomer, during the period of 1960 to 1975. Three patients with non-chondromatous pulmonary hamartomas operated upon during the same period From the Departments of Thoracic Surgery and Clinical Epidemiology, Chaim Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Received for publication June 14, 1979. Accepted for publication Feb. 4, 1980. Address for reprints: Dr. Yair Lieberman, Department of Thoracic Surgery, Chaim Sheba Medical Center, Tel Hashomer, Israel.

were not included in this study. Cases were identified through the following sources: I. diagnostic listings of the medical record room; 2. listings in the pathology department; 3. operating room records. Because of changes in recording procedures in the hospital, sources (1) and (2) were utilized for the period 1960 to 1970 and sources (2) and (3) for the period 1971 to 1975. Follow-up

Information regarding subsequent development of malignancies was obtained from the alphabetical listings of the Central Cancer Registry. Vital status and cause of death were ascertained from the hospital records and from the Central Population Registry. The Israeli Cancer Registry has been shown to have at least a 95% ascertainment rate for all cancers. The files of both the Cancer Registry and the Population Registry are updated to the end of 1976. The expected number of lung cancer cases in the hamartoma patients was calculated according to the age-sex-ethnic specific rates in Israel." Results

The male-to-female ratio was 1: 1.1. The age span was 31 to 72 years with a mean of 53 years. There were 32 Jews of European origin, two of them born in Israel and the rest in Europe, eight were of non-European

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Table I. Clinical characteristics ofthe 52 patients with chondromatous hamartoma ofthe lung (CHL) operated upon in Tel Hashomer Hospital during the period 1961 to 1975 Clinical characteristic

No. of cases

Detection Routine chext x-ray film Symptoms related to chest Cytologic diagnosis of bronchogenic carcinoma Interval from detection to operation

32 19 I

o

:512 mo 13-24 mo >24 mo Type of operation for hamartoma Enucleation Wedge resection Lobectomy Pneumonectomy Diameter at operation Icm

1.5-3 ern 7cm Lobe of hamartoma Right Upper Middle Lower Lobe unknown Left Upper Lower Lobe unknown Side unknown

Comments

Found during operation for proved bronchogenic carcinoma

37 7

7

One case showed growth but no malignancy Three cases showed growth but no malignancy

48 I I

One CHL

+ lung

2

One CHL

+

carcinoma (See M. H. in Table II)

lung carcinoma (See D. B. in Table II)

2

47 2

Data from a series of 30 patients by Oldham et al. 2 *

II

5

6 9

6

2

4

8

5

II I

10

2

'Includes one endobronchial and one extralobar lesion.

ongin, and in 12 the ongm was unknown. Table I presents the clinical characteristics of the 52 patients in the study. Fifty-one of the 52 underwent thoracotomy following x-ray observation of a pulmonary lesion, which was subsequently diagnosed as CHL. In 32 of these the lesion was detected as a result of a routine chest roentgenogram. In the other 19, the x-ray study followed symptoms apparently related to the chest, such as cough or chest pain. The one additional patient was operated upon following cytologic diagnosis of bronchogenic carcinoma and the CHL was found embedded in the carcinoma. In 14 patients the pulmonary lesion was found and observed for at least 1 year prior to the operation. In four of these growth of tumor was noted during this period, but no malignancy was found at operation. The typical x-ray appearance of the CHL was a spherical well-delineated mass density in the lung. Calcification was noted only in three patients. All the hamartomas were located in the lung parenchyma. The

majority of the tumors measured at operation 1.5 to 3 ern in maximal diameter. Two patients had tumors larger than 7 em and two smaller than 1 cm. The hamartomas appeared in all the lobes with no preference for a specific lobe (Table I). Enucleation was performed in 48 patients, pneumonectomy in two, and wedge resection and segmental resection in one patient each. There were no operative deaths nor major postoperative complications. Six cases of malignancy were found among our patients. Four patients had a malignant neoplasm of the lung in the same lobe as the CHL (Table II). In two of these the hamartoma was found on a routine chest x-ray film with no symptoms and was enucleated. There was an interval of 2 and 8 years between the operation for the hamartoma and the diagnosis of the carcinoma. The third patient was operated upon for a new growing mass density in the left lung, found on a chest x-ray film taken for follow-up of a static coin lesion that had been

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Chondromatous hamartoma of lung

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Table II. Hamartoma patients with pulmonary malignancies Pa-

tient

Sex

Age at diagnosis of hamartoma* (yr)

Way of detection hamartoma

Lobe of hamartoma and carcinoma

Routinet Routinet Unknown Carcinoma§

RLL RUL LLL RLL

T. G.

M

42

M.A. M. H.

F F

67

69

D. B.

M

64

Interval to diagnosis of malignancy (yr) 8 2 IO:j: 0

Type of malignancy

Type of operation of hamartoma

Oat cell carcinoma Histology unknown Undifferentiated carcinoma Undifferentiated carcinoma

Enucleation Enucleation Lobectomy Pneumonectomy

• All except patient M. H. were operated upon within the minimal possible delay after diagnosis of a pulmonary lesion had been established. tRoutine chest x-ray film not associated with chest symptoms. :j:Both tumors were found during the same thoractomy. 10 years after the initial x-ray observation of a pulmonary lesion. The operation was performed when the follow-up indicated a new lesion which increased in size during follow-up. § The operation was performed after a cytologic diagnosis of carcinoma and the hamartoma was a coincidental finding.

known for at least 10 years. At operation the old coin lesion was found to be a CHL, and the new growth was diagnosed as an undifferentiated carcinoma. In these three cases the information available in the records does not enable us to state whether the carcinoma developed in the exact same area within the lobe from which the hamartoma previously had been removed. Nevertheless, the records do indicate that the carcinoma was very close to the CHL. The fourth lung cancer patient underwent thoracotomy following a cytologic diagnosis of carcinoma, and the CHL was found embedded within the carcinoma. Three of the tumors were undifferentiated carcinomas; information concerning the histologic type of the fourth could not be retrieved. Re-examination of the histopathological preparations of the hamartomas in these cases did not reveal any unusual characteristics. Three consisted of pure cartilaginous tissue and the fourth had in addition a minor mesothelial component. The expected number of lung cancer cases in our CHL group according to the rates in the general population was 0.66. The observed rate of lung cancer in the CHL group was thus 6.3 times higher than the expected rate. This difference was highly significant (p < 0.01). Two additional patients in the group had an extrapulmonary malignancy-one had an adenocarcinoma of the pancreas and the other, an adenocarcinoma of the colon. The rate of extrapulmonary malignancies did not differ from the expected rates. The most striking observation was the occurrence of the lung carcinoma in the same lobe as the CHL in all four patients. Since CHL is randomly distributed in all five pulmonary lobes (Table I), the probability that this could happen by chance is 0.0016. Discussion The term hamartoma was coined by Albrecht" in 1904 for tumor composed of tissues normally present

within a given organ, but lacking normal organization. The origin and cause of CHL are in debate. Three etiologic theories have been suggested" 7. 8; (1) congenital malformation due to displaced bronchial embryonic rest; (2) benign acquired tumor; (3.) response to an inflammatory process. In a series of 7,972 autopsies a frequency of 0.25% of pulmonary hamartomas was found." The nature and stimulus for the growth of this tumor have become even more intriguing in light of numerous reports of CHL that supposed Iy underwent malignant change- :l or the coexistence of this growth with carcinoma of the lung.": 8 The possibility of a connection between CHL and extrapulmonary malignancies has also been raised.': 4 The question whether CHL patients have an increased risk for lung cancer or other malignancies, however, has not been analyzed quantitatively. In our group of 52 patients, four cases of lung cancer were found, three of which appeared years after the hamartoma was detected. The risk of this tumor developing was significantly increased-6.3 times higher than in the general Israeli population. The increased risk was specific to lung cancer as compared to malignancies of other sites. The question arises whether this increased risk represents a spurious association. A potential source of bias could be a high percentage of smokers in the hamartoma group, leading to a high incidence among lung cancer patients. Such a high percentage of smokers would occur if the higher rate of chest symptoms among smokers would result in an increased detection of hamartoma. In contradiction, in at least two of our four lung cancer patients, the hamartoma was detected during a routine chest x-ray film, not associated with chest symptoms. However, even if such a bias does exist, it would not explain the finding that in all four lung cancer cases the malignancy appeared in the same lobe as the hamartoma and very close to it. In one case,

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the hamartoma was even embedded within the carcinoma. The likelihood that this phenomenon is due to chance is extremely small (p = 0.0016), whereas independent location of the two tumors would be expected if their association was spurious. The two tumors seem to be in close proximity in most cases reported in the literature, if not all. :1. r. H Our data do not enable us to conclude whether the hamartoma itself degenerates into a malignancy or whether both tumors have common risk factors. Nevertheless, the spatial association of the two tumors seems to support the first possibility. A higher risk for lung cancer at the site of a fibrosing process of the lung has been reported in a number of lung conditions. 10-12 It has been claimed that 5% to 25% of all lung cancer are associated with scars. 12 Compression of unaffected lung tissue and its supplying bronchi by an adjacent hamartoma has been suggested. I:! It is not unlikely that our findings present another example of the so-called scar carcinomas. Persons who have had pulmonary tuberculosis have a higher risk of developing lung cancer-the best recognized scar carcinoma-than does to general population in Israel, and this risk is of the same magnitude as in the CHL patients in our series. 14 Of more pragmatic interest is the question raised by this study as to whether the concept of conservative resection of CHL should be altered. The possibility of employing at least segmental resection should be considered. The helpful remarks of Drs. Gerald Baum and Baruch Modan and the pathological re-evaluation by Dr. Golda Selzer are appreciated. REFERENCES Shah JP, Choudhry KU, Huvos AG, Martini N, Beattie EJ: Hamartomas of the lung. Surg Gynecol Obstet 136:406-408, 1973

Thoracic and Cardiovascular Surgery

2 Oldham HN, Young WG, Sealy We: Hamartoma of the lung. J THoRAc CARDIOVASC SURG 53:735-742, 1967 3 Hayward RH, Carabasi RJ: Malignant hamartoma of the lung. Fact or fiction? J THoRAc CARDIOVASC SURG 53:457-466, 1967 4 Carney JA, Sheps SG, Go VLW, Gordon H: The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 296: 1517-1518, 1977 5 Cancer Incidence in Five Continents, J Waterhouse, C Muir, P Correa, J Powell, eds., IARC Scientific Publications No. 15, Lyon, France, 1976, International Agency for Research on Cancer 6 Albrecht E: Ueber Hamartoma. Verh Dtsch Pathol Ges 7:153,1904 7 Weinberger M, Kakos GS, Kilman JW: The adult form of pulmonary hamartoma. A reappraisal. Ann Thorac Surg 15:67-72, 1973 8 Morgan WKC, Andrews CE: Bronchogenic carcinoma, Textbook of Pulmonary Diseases, ed 2, G Baum, ed., Boston, 1974, Little, Brown & Company, pp. 755-787 9 McDonald JR, Harrington SW. Clagett OT: Hamartoma (often called chondroma) of the lung. J THoRAc SURG 14:128-143,1945 10 Kleinerman J: Industrial pulmonary diseases. Silicosis, asbestosis and talc pneumoconiosis, Textbook of Pulmonary Diseases, ed 2, G Baum, ed., Boston, 1974, Little, Brown & Company, pp. 489-507, 1974 11 Kleinerman J: Industrial pulmonary diseases: Coalworkers ' pneumoconiosis, bergliosis and miscellaneous causes, Textbook of Pulmonary Diseases, ed 2, G Baum, ed., Boston, 1974, Little, Brown & Company, pp. 509524 12 Haupt R: Narbenkrebs der Lunge. Abhandlungen Moderner Medizin 4, Leipzig, 1972, J. A. Barth 13 Spencer H: Hamartoma, blastoma and teratoma of the lung, Pathology of the Lung, ed 3, Oxford, 1977, Pergamon Press Inc., p. 980 14 Steinitz R: Pulmonary tuberculosis and carcinoma of the lung. Am Rev Respir Dis 92:758-766, 1965