In the recent decades, an increasing number of GGO lesions are detected, due to the popularity of LDCT as a lung cancer screening approach(Zhang, Jheon, et al., 2020). Histologically, GGO can be benign, pre-invasive or invasive adenocarcinoma(Zhang, Fu, et al., 2020). Lung adenocarcinoma manifesting as GGO is a special clinical subtype and is more prevalent in young female non-smokers who are not traditionally “high-risk” population. There is still no consensus on treatment or follow-up plans for young female patients with GGOs. Meanwhile, occupational pressure and potential childbearing plans make proper clinical management more challenging for clinicians. Therefore, we collected the follow-up CT images of four patients who went through pregnancy during the follow-up of GGOs. There was no significant change of the GGO in all four patients in a median follow-up duration of 45.5 (range: 17-86) months. In a comparison group of six patients, also no significant change was witnessed in all the nodules. We further analyzed a series of forty female patients who give birth within two years before surgical resection of GGOs to assess the possible impact of pregnancy and delivery. In this cohort, the majority of GGOs were pre-invasive lesions, and those with invasive adenocarcinomas were bigger in size and possess more solid component radiologically.
A major change induced by pregnancy is surging hormone levels. Estrogen has long been postulated as a contributor for lung cancer development and progression. Estrogen receptors (ER) are consistently found in lung cancer tissues and cell lines, especially adenocarcinoma, and mostly in the form of the ERβ(Huang et al., 2019; Rodriguez-Lara, Hernandez-Martinez, & Arrieta, 2018). Estrogen promoted lung cancer cell migration via the ERβ activation of the MEK/ERK signaling pathway. There are also evidences showing that estrogen interacts with the EGFR signaling pathways, promoting lung cancer cell metastasis through epithelial mesenchymal transition(Zhao et al., 2015). Estrogen can also stimulate lung cancer cell proliferation, death resistance and angiogenesis(Rodriguez-Lara et al., 2018). However, there were controversies in the relationship between the hormone replacement therapy (HRT) and lung cancer. Although most studies reported estrogen or HRT adversely affected the prognosis of lung cancer patients, some reported HRT decreased the risk and favorably affected the prognosis(Ayeni & Robinson, 2009; Chen et al., 2007; Farquhar, Marjoribanks, Lethaby, Suckling, & Lamberts, 2009; Hsu, Chu, & Kao, 2017; Schabath, Wu, Vassilopoulou-Sellin, Vaporciyan, & Spitz, 2004; Schwartz et al., 2007). Discrepancy may be due to the different usage of HRT(Siegfried & Stabile, 2014). Another mechanism in pregnancy that might affect tumor progression is immunoediting. The immune escape mechanisms at the base of tumor progression resembles the immune tolerance mechanisms occurring at the maternal–fetal interface(Bruno et al., 2020). The part cancer and pregnancy share include inflammation, immune cell tolerance, and angiogenesis. There are case-reports of patients giving birth at advanced staged lung cancer, leading to complications(Mitrou, Petrakis, Fotopoulos, Zarkavelis, & Pavlidis, 2016), including one with acute respiratory failure(Watanabe et al., 2019), which might be related to the mechanisms above.
There are a few clinical or pre-clinical studies on the relationships between pregnancy characteristics and malignancies, yet most on them focus on breast, endometrial, and ovarian cancers due to more pronounced hormonal etiology and higher incidence. For non-hormone-related tumors, prolactin has been reported to promote pancreatic tumorigenesis in vivo(Tandon et al., 2019). Also, in an active surveillance program for patients with low-risk papillary thyroid microcarcinomas (PMC) in Japan, nine women who became pregnant during active surveillance were compared with 27 nonpregnant women matched by age(Shindo et al., 2014). It was noted that PMC enlarged significantly more in pregnant patients compared with controls. Another review of literature demonstrated a negative impact of pregnancy on glioma with exacerbation of neurological symptoms(Zwinkels, Dörr, Kloet, Taphoorn, & Vecht, 2013).
Little research has been made about impact of pregnancy on the progression of GGO-featured adenocarcinoma. Young female adults are confronted with career pressure and potential childbirth plan. Incidentally spotted GGOs present as a major barrier in life trajectories of young women. In a randomized lung cancer screening trial conducted in Europe, 63% of GGO nodules disappeared after a 3-month follow-up(Heidinger et al., 2017). Those nodules that showed regression during follow-up were considered as benign lesions pathologically. Due to the fact that the majority of patients who gave birth within two years before surgery resection of GGOs turned out to be pre-invasive adenocarcinomas, reasonable assumption could be made that those GGOs were present before pregnancy. In addition, our result with the four patients who went through pregnancy during their follow-up showed no significant change in their nodules. Collectively, it could be indicated that pregnancy has little influence on the progress of GGO-featured adenocarcinoma. Clinicians may pay less attention to potential childbearing plans and focus more on the essence of the nodule. Rather than anxious about GGO lesions, young females could plan their birth-giving safely in the follow-up of GGOs.
This study had several limitations. First, only four patients were included. This is probably due to the fact that young women tend to delay childbearing or resort to surgical resection after incidental discovery of GGOs. Second, we only evaluated radiological results and the size change may be difficult to be calculated accurately based on a two-dimensional size measurement. 3D volumetric display could not be applied because not all patients underwent CT in our hospital. Therefore, research with more patients and the introduction of 3D volumetric display may further our conclusion.