Multiple primary malignancies involving lung: an analysis of 40 cases.

We aimed to assess the incidence of multiple primary malignancies in primary lung cancer patients. We retrospectively evaluated the clinical files of 1038 primary lung cancer patients diagnosed in 2004. Forty patients (3.9 %) had multiple primary malignancies. There were 34 men (85 %) and 6 women (15 %). Their mean age was 62.4 ± 8.6 years. While 35 cases were smokers, 5 cases were nonsmokers. Tumour pathology of the lung was squamous cell carcinoma in 15 cases, adenocarcinoma in 10 cases, small cell carcinoma in 3 cases and non-small cell carcinoma in 12 cases. There were 2 primary tumours in 37 cases and 3 primary tumours in 3 cases. The first detected tumour was located in larynx in 11 cases, in genitourinary system in 9 cases, in intestine in 5 cases, in lung in 3 cases and in other organs in 12 cases. The mean interval between the first and the second tumour was 77 months with a range of 1 months to 32 years. This interval was shorter than 6 months in 4 cases. Treatment modality for the first detected tumour was surgery in 35 cases. The last primary tumour was treated with surgery in 12 cases. In conclusion, the development of multiple primary tumours is not a rare phenomenon. Patients with a malignancy should be followed for development of a second primary malignancy. The treatment of lung cancer in patients with a previous malignancy should be the same as for lung cancers presenting as the first cancer.


Introduction
Multiple primary malignancies are defined as the occurrence of two or more primary malignancies, where each cancer originates in a separate primary site and is neither an extension, recurrence or metastasis (1,2). In 1889 Billroth, quoted by Hui and associates (2), first described a patient in whom cancer of the stomach was found after the removal of an epithelioma of the external ear. In 1932 Warren and Gates identified 1259 verified cases of multiple malignancies either reported in the literature or encountered in their own postmortem examinations (3). While observations of multiple primary malignancies were previously considered isolated and exceptional cases, as a result of the improvement in the diagnostic tools, treatment modalities and supportive care, survival time for cancer patients has been prolonged and the number of multiple primary cancers has continued to grow (4). Up to 10 % of cancer patients have been reported to acquire multiple primary cancers of separate organ sites in the 10 years following the diagnosis of their first cancer (5).
Lung cancer is one of the most common cancers worldwide. The risk of developing a second lung cancer in patients with non-small cell lung cancer is approximately 1 % to 2 % per patient per year. For small cell lung cancer, it is approximately 6 % per patient per year (6). It was reported that 193 patients with multiple primary cancers involving lung cancer were found among 22,405 cancer cases (7). In this study, we aimed to assess the incidence of multiple primary malignancies in primary lung cancer patients.

Materials and methods
The present study was conducted at Sureyyapasa Thoracic and Cardiovascular Diseases Training and Investigation Hospital, located in Istanbul. The clinical files of 1038 primary lung cancer patients diagnosed in our center in 2004 were retrospectively evaluated to determine previous malignancies. Information recorded at the time of developing last primary cancer included patient characteristics, histology and anatomic localization of the primary cancers, interval between the first and the second primary malignancy, and treatment modalities.
Multiple primary malignancies were defined as multiple autonomously originating malignancies in an individual patient. Each tumour had to be clearly malignant histologically, each had to be geographically distinct, and the possibility that one tumour represented a metastasis had to be excluded (3). In cases of index tumour in lung, the criteria of Martini and Melamed (8) were used for the diagnosis of second primary cancer. All last tumours had been staged according to TNM staging system (9). The index tumour was defined as the first detected tumour. Synchronous primaries include any second malignancy occurring within 6 months of the diagnosis of the index tumour and metachronous primaries are diagnosed after 6 months.

Results
Of the 1038 patients with primary lung cancer, 40 (3.9 %) patients had multiple primary malignancies. There were 34 men (85 %) and 6 women (15 %). Their mean age at the time of diagnosis of the last tumour was 62.4 ± 8.6 years. While 35 cases were smokers, 5 cases were nonsmokers. The incidence of the patients with multiple primary malignancies was 4.8 % (35/724) among smokers and was 7.7 % (5/65) among nonsmokers (p>0.05). Four patients had history of alcohol and 6 patients had positive family history of malignancy. Thirty-seven patients (3.6 %) had double primary malignancies and 3 (0.3 %) had triple primary malignancies. The first and the second tumours were synchronous in 4 patients. Results are summarized in table 1.
Index tumour was located in larynx in 11 patients, in genitourinary system in 9 patients, in intestine in 5 patients, in lung in 3 cases and in other organs in 12 cases. While the index primary tumour was treated with surgery in 35 patients, treatment modality was radiotherapy and/or chemotherapy in 5 patients. The mean interval between the first and the second tumour was 77 months with a range of 1 months to 32 years. This interval was shorter than 6 months in 4 cases. The interval between the second and the third tumour in three patients with the triple tumours were 5, 24 and 72 months (table 2 and table 3). The last primary tumour was lung cancer in all patients. Tumour type of the lung was squamous cell carcinoma in 15 cases, adenocarcinoma in 10 cases, small cell carcinoma in 3 cases and non-small cell carcinoma in 12 cases. Among patients with non-small cell carcinoma, the stage was 6 stage IA, 7 stage IB, 3 stage IIB, 3 stage IIIA, 12 stage IIIB, and 6 stage IV. All patients with stage IA were treated with surgical resection. While 4 patients with stage IB were treated with surgery, 1 patient rejected surgery. There were 2 medically inoperable patients in this group. While 1 patient with stage IIB was subjected to surgical resection, 2 patients rejected surgery. Among patients with stage IIIA, 1 patient was treated with surgery. One patient rejected surgical treatment. Because the other had multiple N2 disease, he was treated with radiotherapy. There were 6 patients with stage IV in this series. They were given chemotherapy.

Discussion
The incidence of multiple primary malignancies has increased in recent decades (7,10). The American Cancer Society, quoted by Mydlo and associates (11), has reported that one out of 5 Americans will develop cancer in his or her lifetime. Furthermore, there is one out of three chances of developing a synchronous, antecedent or subsequent tumour in these patients' lifetime. According to two previous reports, the incidence of multiple primary malignancies has ranged from 0.4 % to 11.8 % (2,12). This incidence was 2.4 % in Buiatti's report (13), was 2.5 % in Cheng's series (14) and was 11 % in Brock's study (15). In our series, 3.9 % of the patients with primary lung cancer had multiple primary   (7). Index tumour was lung cancer in three patients in our series. In this series, the most frequent index tumour was larynx carcinoma, followed by malignancy of genitourinary and digestive systems. Laryngeal index tumours have the highest percentage of pulmonary second primaries (16,17). Jones et al (14) reported that 47 per cent of 110 laryngeal index tumours have second primaries in lung. There were 37 lung cancer patients with a history of previous malignancy in a previous report. The previous malignancies included 13 gastric cancers and 6 colorectal cancers (12). According to a previous report, the mean interval between the first and the second tumour was 6 years and 8 months with a range of 2-20 years. The interval between the second and the third tumour in 2 patients with the triple tumours were 2 and 6 months (2). In our series, the mean interval between the first and the second tumour was 77 months with a range of 1 month to 32 years. The interval between the second and the third tumour in 3 patients with the triple tumours were 5, 24 and 72 months. The development of multiple primary malignancies may be associated with several factors such as genetic factors, hormones, environmental carcinogens, dietary factors, previous therapy, alcohol and smoking (7,11,12,14,18). Liu et al (10) pointed out that smoker patients had a significantly higher risk for the development of multiple primary malignancies involving lung cancer. Two previous reports supported that there was a causal association between cigarette smoking and cancer of  lungs, stomach, liver, kidney, uterine cervix, and bladder (19,20). Oral cavity, orohypopharynx and larynx were locations related to smoking and alcohol (18). In our study, most of the index tumours were tumours related to smoking. It was showed that risk of lung cancer was significantly increased in patients treated for Hodgkin's lymphoma and breast cancer (21,22). The risk of developing a second lung cancer in patients who survived resection of a non-small cell lung cancer is approximately 1 % to 2 % per patient per year (6). It is known that genetic factors play an important role in the development of multiple primary malignancies (11,12,15,23). In our series, there were 35 smoker patients. Four of 35 patients also drunk alcohol. Six patients had a family history of malignancy. One of 6 patients was nonsmoker. Among nonsmoker patients, one patient received chemotherapy for breast cancer and one patient was treated with radiotherapy for uterine cancer. Treatment of lung cancer in patients with previous malignancies should be the same as for lung cancer presenting as the first cancer (12). Surgery should always be the treatment of choice in these patients if the tumour is operable (24,25). We considered surgical treatment in 20 patients. Because the patients rejected surgery or they were medically inoperable in 8 cases, resection was performed in only 12 patients.
In conclusion, the development of multiple primary tumours is not a rare phenomenon. Patients with a malignancy should be followed for development of a second primary malignancy. Treatment of lung cancer in patients with a previous malignancy should be the same as for lung cancer presenting as the first cancer.