untitled Multiple primary malignancies and lung cancer 193 Key words: primary malignancy, multiple, lung cancer Received 3 March 2008 Accepted 13 March 2008 Upsala J Med Sci 113 (2): 193–200, 2008 Multiple Primary Malignancies Involving Lung: An Analysis of 40 Cases Adnan Yilmaz, Muyesser Ertugrul, Leyla Yagci Tuncer, Ebru Sulu, Ebru Damadoglu Sureyyapasa Thoracic and Cardiovascular Diseases Teaching and Investigation Hospital-Istanbul Abstract 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 malig- nancies. 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 intes- tine 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 develop- ment 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 as- sociates (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 en- countered 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 194 Adnan Yilmaz et al. 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 devel- oping a second lung cancer in patients with non-small cell lung cancer is approxi- mately 1 % to 2 % per patient per year. For small cell lung cancer, it is approxi- mately 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 Dis- eases Training and Investigation Hospital, located in Istanbul. The clinical files of 1038 primary lung cancer patients diagnosed in our center in 2004 were retrospec- tively 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 originat- ing 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 pri- maries 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 sum- marized in table 1. Index tumour was located in larynx in 11 patients, in genitourinary system in 9 Multiple primary malignancies and lung cancer 195 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 re- jected 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. Fur- thermore, 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 Table 1. Distribution of multiple primary malignancies Patients n % with lung cancer reviewed 1038 100 with multiple primary malignancies 40 3.9 with double primary malignancies 37 3.6 with triple primary malignancies 3 0.3 with synchronous multiple primary malignancies 4 0.4 with metachronous multiple primary malignancies 36 3.5 196 Adnan Yilmaz et al. Table 2. Features of the patients with double primary malignancies Case No Age (years) Sex Index tumour Treatment of index tumour Interval Cell type of last tumour 1 60 M Colon Surgery 6 years Squamous 2 72 F Kidney Surgery 4 years Adeno 3 58 M Larynx Surgery 26 years Non-small 4 63 M Hodgkin RT* and CT** 5 years Squamous 5 49 M Pancreas Surgery and RT 5 years Non-small 6 68 M Larynx Surgery 2 years Adeno 7 54 M Larynx Surgery 18 months Squamous 8 66 F Breast Surgery and CT 5 months Adeno 9 72 M Colon Surgery 6 years Adeno 10 71 M Prostate CT 5 years Non-small 11 65 M Larynx Surgery 17 years Small cell 12 54 M Lung Surgery 30 months Squamous 13 62 F Uterus Surgery 10 months Non-small 14 61 M Lip Surgery 1 year Squamous 15 75 M Thyroid Surgery 9 years Squamous 16 40 F Breast Surgery 4 years Small cell 17 77 M Larynx Surgery 7 years Non-small 18 62 M Bladder Surgery 23 months Small cell 19 50 F Colon Surgery 11 years Adeno 20 69 M Skin Surgery 9 years Non-small 21 66 M Lung Surgery 8 months Squamous 22 51 M Larynx Surgery 4 years Squamous 23 49 M Small bowel Surgery 25 months Non-small 24 64 M Bladder Surgery 1 months Non-small 25 66 M Lung Surgery 20 months Adeno 26 77 M Testicular Surgery and RT 32 years Adeno 27 55 M Rectum Surgery 12 years Squamous 28 62 M Larynx Surgery 35 months Squamous 29 69 M Bladder Surgery 14 years Adeno 30 67 M Larynx Surgery 10 years Non-small 31 64 M Prostate CT 5 years Non-small 32 59 F Uterus CT 1 months Squamous 33 59 M Larynx RT and CT 1 months Non-small 34 56 M Muscle Surgery and CT 25 months Squamous 35 72 M Parotid Surgery 2 years Non-small 36 62 M Lip Surgery 13 years Squamous 37 60 M Larynx Surgery 17 months Squamous *RT: Radiotherapy **CT: Chemotherapy Multiple primary malignancies and lung cancer 197 malignancies. In the present series, the last tumour was lung cancer in all patients. Utsumi et al (12) reported that 37 of 313 primary lung cancer patients had a his- tory of previous malignancy. Hui et al (2) found that there were multiple primary malignancies in 2.1 % of the patients. In their series, apart from the 5 patients with simultaneous tumour, lung cancer was the index tumour in 8 patients and the sec- ond tumour was in 8 patients. It was reported that a total of 193 patients with mul- tiple primary cancers involving lung cancer were detected among 22,405 cancer patients. Of these 193 patients, 51 had lung cancer diagnosed before the occurrence of the other cancers and the remaining 142 had other cancers occurring ahead of the lung cancer (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, di- etary 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 sup- ported that there was a causal association between cigarette smoking and cancer of Table 3. Features of the patients with triple primary malignancies Case No Age (years) Sex Index tumour Treatment of index tumour Interval Second tumour Treatment of second tumour Interval Third tumour Cell type of last tumour 38 59 M Left cord vocal Surgery 42 months Right cord vocal Surgery 5 months Lung Adeno 39 77 M Larynx Surgery 18 years Penis Surgery and RT* 2 years Lung Squamous 40 58 M Thyroid Surgery 8 years Bone Surgery and CT** 6 years Lung Adeno * RT: Radiotherapy **CT: Chemotherapy 198 Adnan Yilmaz et al. the aerodigestive system, lungs, stomach, liver, kidney, uterine cervix, and bladder (19,20). Oral cavity, orohypopharynx and larynx were locations related to smok- ing 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. 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J Thorac Cardiovasc Surg 88: 502–10 Corresponding author: Associate Professor Adnan Yilmaz Maltepe Zumrutevler Atatürk Cad. Abant Apt. No: 30 Istanbul/Turkey Phone: + 90 216 3058324 Email:adnandr_63@yahoo.co.uk