Sex-specificity in Surgical Stages of Lung Cancer in Young Adults

1. INTRODUCTION

Lung cancer is mainly a neoplasm of the elderly, with a peak of incidence between the sixth and seventh decades of life, only 5 to 10% of non-small cell lung cancer (NSCLC) are diagnosed in individuals younger than 50 years of age [1]. Lung cancer is the leading cause of mortality worldwide among men and the second most common cancer among women [2, 3]. In Tunisia, both incidence and mortality from lung cancer continue to increase sharply and constitute a serious threat to public health. International data demonstrate increased rates of lung cancer in women, while the incidence in men continues to fall [3]. However, previous studies have reported converging lung cancer rates between sexes [4].

This single-center study was designed to define the characteristics of lung cancer in surgical stages and its incidence rates in young women versus young men in 45-year-old or younger in our population. Our overview will help to expand our understanding of this subgroup of lung cancer and provide good prevention and improved prognosis.

2. MATERIALS AND METHODS

3. RESULTS

4. DISCUSSION

Research on lung cancer in the young population is attracting considerable attention with rapid increases in the morbidity and mortality attributable to lung cancer [2]. Studies suggest that lung cancer in younger patients has distinct characteristics, particularly with respect to patient gender, smoking status, and tumor morphology [4]. Not only are the types of lung cancer different between men and women, the general risk of developing this disease appears to vary between the sexes. Aside from sex, most cases of lung cancer occur in patients in the sixth and seventh decades of life, but research from Europe and Asia (Japan and China) have demonstrated a trend of increasing incidence of lung cancer in young adults [2].

The aim of the study was to evaluate sex differences among young patients under the age of 45 years operated for lung cancer regarding risk factors, histological type, treatment modalities, adverse events, and survival.

Among all kinds of cancers, lung cancer remains the leading type in both incidence and mortality, with 2.1 million new cases and 1.8 million deaths in 2018 [5-7]. According to a study conducted in China, 2019,around 1.4% of lung cancer occurs in people under 35 years [2]. The definition of young adults with regard to lung cancer is uncertain and generally ranges from 40-50 years [2]. One of the studies in the UK reported that young adults (18–39 years) accounted for 0.5% of non-small cell lung cancer from 2004–2011 [8, 9], and another in the USA detected an incidence rate of 1.16% in a young population (18–40 years) [10]. One of the ways in which lung cancer differs in young people related to the gender is that young women are affected more by the disease than young men [11]. In contrast, the ratio seen in the larger population of people with cancer is 57.8% male to 45.9% female [12]. This finding is consistent with our study showing that younger patients with NSCLC are more likely to be male (66% males and 34% females).

The predominant type is the NSCLC which accounts for 85% of all cases [13]. Adenocarcinoma is the most common subtype that we find in young and even older patients. The distinction of cancer type is important in the clinic, not only for staging but also for treatment and prognosis. Initially, a difference between sexes in the incidence of lung cancer histological types was reported. Females are more likely to develop adenocarcinoma rather than squamous cell carcinoma or large cell lung cancer [6, 14]. Adenocarcinoma accounted for more than 50% of female cases in 2010 [15]. In contrast, in males, squamous cell carcinoma is the most common histologic subtype [6]. Analysis of the histologic data in our study indicated that the largest histological type in females was typical carcinoid tumor (n=13, 54%), and in males was adenocarcinoma (n= 25, 53%).

The case-control study by Brownson et al. examined the relationship between smoking and lung cancer by gender and histologic type. The result showed that the relative risk associated with ever-smoking, and the level of smoking was consistently higher in women than men for all lung cancer combined (ever-smoking odds ratios: 12.7 for females and 9.1 for males) [6]. Harris et al. concluded through a case-control study that women are more at risk than men for a given level of smoking (relative risk = 1.7) [6, 16]. Another cohort study in Iceland showed that the risk of lung cancer was more higher among female smokers than male smokers [6, 17].

While roles of sex hormones in other types of cancers affecting females or males have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen hormone and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent pulmonary carcinogenesis [15]. The elevation of estrogen circulating levels in women together with the reduction of DNA repair capabilities, cause women more vulnerable to the cancer-causing effect of tobacco [18]. Researchers have shown that Anti-estrogen treatment strategies can decrease tumor size, growth, and cell proliferation which may contribute to improved patient outcomes [19]. Regarding progesterone, this hormone is involved in cell proliferation and lung disease emerging evidence has revealed an active role in lung carcinogenesis. Some studies have revealed that progesterone receptors are present commonly in non-tumor lung tissues compared with cancer tissue [20]. The role of male sex hormones in lung cancer has also been reported in the literature. The androgen receptor, which is expressed mostly in pneumocytes and lung epithelium of male patients, is known to be an active player in lung cancer pathogenesis [21]. The role of hormone replacement therapy used in postmenopausal women was presented in Table 6.

Studies have shown that increasing the resection rates for lung cancer improves cancer survival. The literature contains conflicting data about the prognosis of young patients with lung cancer. In 2010, on analysing the SEER database (Surveillance, Epidemiology, and End Results), Subramamian et al. [10] found that younger age was clearly associated with reduced mortality rate due to NSCLC. On the contrary, in a case-control study by Bryant et al [26], patients younger than 45 years showed a 5-year overall survival of 51%, statistically worse than the 5-year overall survival of 62% in patients older than 45 years (p = 0.04). This is true, that younger adults are typically healthier with few morbidities and receive more complete and aggressive treatment that could explain better survival [1, 2]. However, at the same time, they underestimate symptoms and thus delay medical visits. To sum up, this difference could be related to the delay in diagnosis and treatment, but also to the different genetic and molecularcharacteristics of lung cancer in young patients, especially those who were never smokers.

The second aspect we investigated is thedifference between female and male patients with lung cancer is the prognosis which may differ. A recent Spanish nationwide prospective cohort study showed that the perioperative profile is better in women than in men (less often current or ex-smokers, had better lung functions and fewer comorbidities) [27, 28]. This study also showed that lower FEV1 is associated with increased cardiovascular and all-cause mortality [27, 28]. These findings imply that women are overall better candidates for surgical treatments [28] which could be related to a long-term survival as well. Women, in a Norwegian population-based study, were an independent favorable prognostic factor regardless of stage, age, type of operation, or histology [29]. In another study, in surgically treated early-stage (I and II) lung cancer, patients, age, gender, tumor size, and type of surgery are the important predictors of survival [30].

Our results showed that the female gender was associated with more favorable short- and long-term outcomes after surgery for lung cancer. Male sex was significant in predicting postoperative complications (p <0.05). In Kaplan-Meier analyses, the median survival rate was about 7 years in the women group and 5 years in the men group.

Our study has several limitations. First, it was a single-center retrospective investigation. Further, a relatively small proportion of our patients underwent genetic assessment. In the future, a large-scale and deeper investigation of this topic will be initiated and prospective studies will be required, to clarify the biological and genetic variance of lung cancer in younger males and females.

CONCLUSION

Lung cancer in younger patients is a distinct entity that predominantly presents as adenocarcinoma, with late-stage at onset, and a higher frequency of gene alteration, relative to older patients. Much recent research has shown a trend of increasing the incidence of lung cancer in young adults. It remains unknown, how sex influences this cancer risk, treatment decisions, and outcomes. However,evidence of specific differences in presentation, smoking risk, and mutational burden supports the need to better leveragethese gender-associated differences to improve further detection, diagnosis, and systemic regimens to advance theoverall care strategy for young people with lung cancer.

REFERENCES