Epidemiologic and Histopathologic Feature of Lung Cancer in Central Iran (2012-2018)

Background: Lung cancer is one of the common causes of death worldwide. Although the incidence rate of lung cancer in Western countries is decreasing, it presents a growing trend in developed countries. Since there is no accurate enough information about the epidemiological and Histopathologic features of lung cancer in central Iran, Isfahan, we were motivated to conduct this research. Materials and Methods: This was a descriptive, cross-sectional study carried out in central Iran, Isfahan. All demographic, histopathological and clinical data of the lung cancer patients registered in MACSA, a referral charity-based cancer center in central Iran, was analyzed within 2012-2018 using SPSS v.22 software. Results: Altogether 260 patients with lung cancer were included in this study from 6127 cancer patients registered within 2012-2018 (4.2%). Out of them, 66.2% were men, and 18.8 % of the patients were alive at the time of the study. The mean age of the patients at diagnosis was 61.56 (SD=14.11, range: 9-93). Altogether, 63.1% of patients had metastasis of whom 57.6% were in stage IV at diagnosis. The Frequency of different types of lung cancer was 36.9% adenocarcinomas, 14.2% squamous cell Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 8 April 2020 doi:10.20944/preprints202004.0112.v1 © 2020 by the author(s). Distributed under a Creative Commons CC BY license. carcinoma, 9.6% bronchogenic carcinoma and 8.1% small cell lung cancer, respectively. Altogether, 128 cases were smokers with an average 35.45 ± 14 packyears. Only in 36.2% of the patients, the diagnostic and therapeutic biomarkers had been checked, and CK7 was positive in 88.9% of the cases in which the biomarker had been checked. Conclusion: Despite to similar Iranian studies, the most common histopathologic type of lung cancer among the patients was adenocarcinoma that it may be attributed to the lower consumption of smoking in our population and their different genetic context. Molecular biomarkers had been checked in a small portion of the patients. More education of the clinicians along with the development of cancer molecular testing may lead to promote the personalized-based approach. Key word: lung cancer, Epidemiology, Histopathology, Central Iran, Isfahan

Lung cancer is usually divided into two groups: small cell lung cancer (SCLC) and nonsmall cell lung cancer (NSCLC). NSCLCs accounts for about 85% of all lung cancers and are classified into squamous cell carcinoma (SCC), adenocarcinoma (AC), and large cell carcinoma (9). The epidemiology of lung cancer is changing in many parts of the world, as we enter the 21st century. The incidence trend of lung cancer is not promising, however, it moves from developed to less developed countries (10). However, the relationship between smoking and various types of histological findings of lung cancer is not similar, so there is a significant relationship between smoking and the occurrence of SCLC and SCC, but its association with adenocarcinoma is lower (11).
There are Limited epidemiologic studies on lung cancer in Iran. Some studies show that the incidence of lung cancer may be increased by changes in the smoking pattern. The incidence of lung cancer in the North West and West provinces of Iran has been estimated higher than other regions (12). Since there is no accurate enough information about the epidemiological and Histopathologic feature of the lung cancer in central Iran, Isfahan, we were motivated to conduct this research.

Materials and Methods
This was a descriptive, cross-sectional study carried out in Ala cancer control and prevention center (MACSA), a charity-based institute for supportive and palliative care of cancer in central Iran, Isfahan. All the patients registered in MACSA have an electronic database including clinical and para-clinical information. In this study, demographic, histopathological and clinicopathological information of all patients with lung cancer admitted to MACSA was obtained from 2012 to 2018. Demographic variables included age at diagnosis, age at death, gender, and location of living. Moreover, some cancer-related risk factors such as smoking (cigarette, opium or Hookah), alcohol addiction, and chronic contact with chemical substance were also included.
Histopathological variables including pathologic feature, metastasis state, the tumor stage, type and size, and the tumor biomarkers were also assessed. Moreover, clinicopathological factors containing the first main symptom, past medical history, the family history of cancer and the type of treatment were included. The collected data was analyzed to determine the statistical information and correlations by SPSS v.22 software.

Results
Altogether among 6127 cancer patients registered in MACSA within 2012-2018, 260 patients with lung cancer (4.2%) were included in this study. Out of this population, 172 (66.2%) were men, and 49 (18.8 %) patients were alive at the time of the study. The male to female ratio is 1.95. Overall, 242 patients (93.1%) were urban residents, and the others (6.9%) were rural. The average age of the patients at diagnosis was 60.30 (SD=14. 31,, and at the time of death 62.59 (SD=13.71). Moreover, the mean period time from diagnosis to death was 13.36 (SD=12.31) months.
Out of total lung cancer patients, 135 cases (51.9%) had a positive family history of cancer of whom 92 (68.1%) cases have at-least a first-degree relative with cancer. The most common malignancies among the affected family members were in lung (32,23.7%), breast (17, 12.6%) and stomach (17,12.6%), respectively. (Table 1) Altogether, 164 (63.1%) and 150 (57.6%) patients had metastasis at the time of study and diagnosis, respectively ( Table 2). The common sites of metastasis were bone (73, 44.5%), brain (60, 36.6%) and liver (31,18 The exposure rate of the patients with some of the environmental factors investigated in this study listed in Table 4. According to our study, 125 (72.6%) of men and 3 (3.4%) of women were active cigarette smoker.

Epidemiology
Although the incidence rate of lung cancer in Western countries is decreasing, it presents a growing trend in developed countries (13). According to the some previous studies, it seems the incidence rate of lung cancer in Iran is lower than Western countries (6). The national reports have showed that the prevalence of lung cancer is ranked as seventh or eighth among men and above the tenth among women, while on the global scale, it is the first in men and fourth in women (14). This retrospective study was conducted on the 260 patients with lung cancer out of 6127 cancer patients registered in MACSA within 2012-2018. The aim of this study was to investigate the epidemiological and histoclinicopathological features among the lung cancer patients in central Iran.
According to the previous studies in Iran, male to female ratio has been reported 2.85 (12), 3.22 (15) and 5.09 (16), while in our study it was 1.95. In other countries like Spain and India the ratio was 8.1 (17) and 4.1 (18) respectively. The lower male to female ratio with the lung cancer compared with other countries can be due to difference in environmental exposures of Iranian women, also, some probable genetics variations.
Further investigations based on the risk assessment are highly recommended for this population.
In our study, the mean age of the patients at the time of study was 61.5 (SD=14).

Histopathological features
Overall, 63.1% of the patients had metastasis at the time of study of which 57.6% had presented metastasis at diagnosis. Common metastatic sites were bone, brain, and liver.
According to one study in India (26), the rate of lung cancer metastasis was 32.5%. In the study at Tehran(15) 67.3% of patients had metastasis in which the sites included contralateral lung, bone, liver, brain. According to table 2, 57.6% patients were diagnosed in stage 4 and 21.5% in stage 3. In the studies at Tehran(15), 85.3% were in stages 3 to 4, in other study at Tehran (22), 48.5% were in Stage 4, and in the study at Sari( north of Iran) (27), 85.1% of patients were in stage 4.
In most cases of lung cancer, the disease is diagnosed in advanced stages (28). Based on this information the screening program in Iran should be paid more attention to early detection of lung cancers and making biological clues for different sites of metastasis.
According to the pathological reports ( According to other studies, smoking is associated with a higher proportion of SCC. The lower prevalence of SCC in our study may be due to the lower consumption of cigarettes in the population than other populations studied in Iran. There was, also, a significant difference in the histopathologic type of lung cancer (p<0.001) between sexes in this study, similar to other Iranian studies (15,16,23).
Due to the limitations of our study (inaccessibility to the other risk factors and comprehensive molecular study), we could not conclude any other items.

Clinical aspects
According to the results, the most common early symptoms of lung cancer among the patients were cough and dyspnea. In the Qazvin study (16), 76.5% patients had cough as an early symptom but in the Ardebil study (20) the most common symptom was hemoptysis (32.7%). This controversy in studies needs more comprehensive data to make an accurate decision about the early symptoms of lung cancer in Iranian patients.
Altogether, 67.3% patients had a history of chemotherapy and 38.1% had a history of radiation therapy. In one study at Sari (north of Iran) (27), 57% of the patients had tolerated chemotherapy. These results may be correlated to the stage of diagnosis in our patients. Curative chemotherapy and radiotherapy are more acceptable for the patients who are not in the advanced stage.

Conclusion
This study was performed on 260 patients with lung cancer who had been referred to MACSA-Isfahan within 2012-2018. The prevalence of disease was significantly more in men and in urban patients.
There was a significant difference between the mean age of women and men with lung cancer. Most of the patients had metastasis at the time of referral and bones were the most common site of metastasis. There was a significant relationship between sex and smoking. The most common histopathologic feature of lung cancer among the patients was adenocarcinoma, probably due to the lower consumption of smoking in our population. In some patients, the diagnostic and therapeutic biomarkers had been checked, and CK7 was positive in most of the cases in which the biomarker was checked. Given the limitations of this study regarding the accessibility of the patients' data and sample size, more investigations are recommended to reveal a more accurate epidemiologic and clinicohistopathologic feature of the disease and its risk factors in central Iran.       *the diagnostic biomarkers. **the prognostic biomarkers. ***the predictive biomarkers. (29,33,36,37)