High-volume screening trials, including National Lung Screening Trial,[1] NELSON,[2] and Lung cancer Screening Intervention (LUSI)[3] trials, have demonstrated that the reduced lung cancer mortality is associated with lung cancer screening. Nevertheless, another question arises about the increasing percentage of lung cancer in young and female patients.[4–6] The outcome of lung cancer in young patients remains a controversy,[5–7] and little is known about lung cancer in young women. The incidental pulmonary nodule in young female patients is a headache even as encountering a pregnant plan. Combined concerns about the uncertain outcome of the suspicious lung cancer and radiation exposure on fetus during surveillance make it hard to decide where to go. Under this circumstance, there may be anxiety from female patients and certain overtreatment. Here, we reviewed the current evidences and proposed our clinical perspectives on the management of incidental pulmonary nodules in young women with pregnant intention.
Methods
We consecutively evaluated a series of female patients (no more than 40 years old) who underwent pulmonary surgery for nodules at our hospital between 2017 and 2020. Patients with pulmonary sequestration, bronchiectasis, or pneumothorax alone were excluded. The terms, including “female patient” or “women,” “lung cancer,” “pregnancy,” “hereditary,” “hormone,” “natural history of pulmonary nodule,” and “radiation exposure,” were searched in PubMed in March 2022. Comprehensive reviews of hereditary of lung cancer, effects of sexual hormone on lung cancer, natural history of pulmonary nodules, and computed tomography (CT) imaging with radiation exposure were performed. Two authors screened the literature and cross-checked the review.
Results
Real-world outcome of female patients (40 years old) with pulmonary nodule surgery
A total of 394 female patients (40 years old) who underwent surgery for pulmonary nodules between 2017 and 2020 were included. The pathological diagnoses based on surgical tissues are listed in Table 1. One patient had both primary adenocarcinoma and metastatic choriocarcinoma.
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Table 1: Pathological type of pulmonary nodules for female patients (≤40 years old)
According to the 8th edition Tumor-Nodule-Metastasis staging, 84% of cases confirmed as adenocarcinoma were classified as Stage IA and 15% of cases with adenocarcinoma were classified as Stage IB or higher stage. Forty-five of 125 (36%) patients with invasive adenocarcinoma had one or more risk factors for recurrence, including micropapillary or solid component, involvement of bronchus or pleura, pleural dissemination, lymphovascular invasion, spread through air space, and lymph node metastasis. Micropapillary component (22.4%), lymph node metastasis (18.4%), involvement of bronchus (16%) and visceral pleura (12%), and spread through air space (4%) were the top five risk factors.
No incidence of lung cancer in young women has ever been reported. In the real-world cohort, 66.50% of the targeted population with pulmonary nodule resection were diagnosed with primary non-small cell lung cancer (NSCLC) or precursor glandular lesions. Nearly 15% of cases with lung adenocarcinoma were classified as Stage it or more advanced stage. Nearly 36% of cases with invasive adenocarcinoma had one or more risk factors for recurrence. High-risk female population should be recognized and well managed.
Is lung cancer hereditary?
The history of lung cancer in a first-degree relative is generally a high risk for lung cancer. In 2012, an analysis from the International Lung Cancer Consortium revealed a 1.51-fold increase in the risk of lung cancer for a person with a first-degree lung cancer-affected relative after adjustment for smoking and other confounders.[8] Another study[9] in a twin cohort proved the heritability of lung cancer with 18% familiar risk, but lung cancer also had the highest shared environmental factors. Not only the history of lung cancer in a first-degree relative, but also the number of affected relatives including first-, second-, and third-degree relatives showed significant risk for lung cancer according to a complete family history study.[10] Nevertheless, a pooled meta-analysis[11] revealed that the familial risk of lung cancer was influenced by both genetic and nongenetic factors, including geographical regions, smoking status, sex, and age.
Theoretically, if pathogenic variants are present in the germline of an individual, their offspring can inherit the pathogenic mutations. However, little is known about definite pathogenic variants for lung cancer. Several rare germline variants with lung cancer-related genetic susceptibility include germline TP53 mutation (Li–Fraumeni syndrome)[12] and germline T790M variant.[13] Another study[14] of Chinese population indicated that pathogenic germline mutations fell most commonly in BRCA-2, followed by CHEK-2 and ATM; the TP53 and T790M did not show significant heritability, and the results also exhibited that the influence of germline mutations mimicked the effects of smoking and environmental factors, perhaps sharing the same pathway to DNA damage and repair. In 2016, a meta-analysis[15] illustrated that quitting smoking was highly beneficial to smokers for the decline of lung cancer risk regardless of their CHRNA-5 genetic status, which was associated with a high probability to develop lung cancer. What’s more, Jiang et al.[16] performed a comprehensive analysis quantifying the heritability and genetic correlation of six cancers, and the results demonstrated that different solid tumors, including lung cancer, shared common germline genetic influences; another finding about the genetic correlation between cancers and noncancer traits such as smoking, psychiatric disorders, and metabolic factors was also reported. Recently, results from a prospective cohort study[17] including 345,794 European ancestry participants revealed that both high genetic risk and smoking were independently associated with an increased risk of lung cancer; meanwhile, smoking cessation could provide protection against lung cancer regardless of genetic risk.
Vertical transmission of cancer cells to the placenta or the fetus has been reported in gestational lung cancer patients in advanced stage, with an incidence reaching 26%.[18] There is no report of this phenomena in early-stage lung cancer.
Taken together, unlike other genetic disorders (such as chromosomal disease and monogenic disease), the heritability of lung cancer for rare germline mutations was mixed with social and environmental factors, perhaps sharing the same mechanism with living habits to the development of lung cancer. Generally speaking, the probability of lung cancer passing from one generation to the next is extremely low, and changes in lifestyle and environment are potential to reduce some of the genetic predisposition.
Effects of hormone on lung cancer
The correlation between hormonal therapy and lung cancer has been reported by several studies, which indicated the certain effects of hormone on lung cancer, while the effects remained controversy. In 2006, Ganti et al.[19] conducted a retrospective review of women diagnosed with lung cancer at a community-based teaching hospital, demonstrating that overall survival was significantly higher in patients without hormone replacement therapy (HRT) compared with patients who received HRT, while the study also included small cell lung cancer and 36% of all cases had advanced-Stage (III B and IV) diseases. While another report from Katcoff et al.[20] according to Metropolitan Detroit Surveillance, Epidemiology, and End Results Registry suggested that HRT, especially estrogen plus progesterone, was associated with improved survival for NSCLC. Large-scale multicentric clinical trials, including Women’s Health Initiative clinical trial[21–23] and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial,[24,25] showed inconsistent results when compared with each other; even different conclusions were drawn per the same trial. Nevertheless, meta-analyses have revealed the protective roles of HRT in the incidence[26] and mortality[27] of lung cancer. Most participants in the HRT study were of postmenopausal.
Estrogen exerts biological effects by interacting with estrogen receptor (ER) α and β. The expression of ER α and ER β in lung cancer has been reported for a long time,[28,29] which also demonstrated a biological role through the signaling pathway. The expression of progesterone receptor (PR) has also been detected in lung cancer,[30–32] but no major differences were observed between men and women.[31]
Although many studies have demonstrated the presence of hormonal receptor expression in lung cancer, it remains unclear what the definite roles these biomarkers play in fact. In 2011, Sun et al.[32] reported that epidermal growth factor receptor (EGFR) mutation was independently associated with negative expression of PR. While a similar study[30] from M. D. Anderson Cancer Centre in 2019 found no correlation between PR expression and EGFR mutation status. No significant correlations between the expression of ER and PR were found, and the conclusion that PR expression had no prognostic value was also drawn by several other studies.[31,33]
The characteristic and prognostic value of ERs in NSCLC is inconsistent among different researches.[34] The study conducted by Raso et al.[30] revealed that cytoplasmic ER α expression was associated with worse recurrence-free survival for NSCLC, and ER α expression was correlated with EGFR mutation in adenocarcinoma. Rouquette et al.[31] thought that there was a positive link between ER and EGFR expression in lung cancer, but the expression of ER α was associated with improved disease-free survival. Not only ER α, but also ER β was found to be of important value in lung cancer. Wu et al.[35] declared for the first time the favorable prognostic factors of ER β in surgically resected Stage II and III NSCLC, while no ER α nuclear staining was detected. Toh et al.[33] showed that more EGFR mutations were seen in tumors with ER β positivity (60%) compared with those with negative expression (37.9%), and there was a tendency toward an inferior outcome for tumors with positive ER β expression.
In 2011, Nose et al.[36] elucidated the correlation between expression of ER β and the therapeutic effect of EGFR–tyrosine kinase inhibitors in lung adenocarcinoma, indicating that strong expression of ER β predicted a superior outcome for patients with lung adenocarcinoma after treatment with EGFR–tyrosine kinase inhibitors; it should be pointed out that the response rate amounted 22.7% in the weak expression group. Exception for cancer cells, ERs were also expressed on stromal and immune cells within the tumor microenvironment,[37] hinting at the potential role of ERs in the management of current cancer-related immunotherapy. In 2016, Hamilton et al.[38] used the ER antagonist fulvestrant to identify the capability of reducing mesenchymal features of human lung carcinoma cells, and finally indicated a potential role for estrogenic signaling in promoting tumor resistance to immune-mediated cytotoxicity in lung cancer; however, registered clinical trials of fulvestrant, including NCT00592007 and NCT00932152, have yielded no results.
Consequently, estrogen, progesterone, and their receptors perhaps have certain regular values during tumorigenesis; the rational use of the target may be able to neutralize some of the clinical side effects in selected patients. However, there is no significant decisive effect on the progression of lung cancer, even for the fluctuations of hormone levels during pregnancy. Recently, a retrospective study[39] demonstrated that pregnancy may have little influence on ground-glass opacities suspected for lung adenocarcinoma.
Natural history of pulmonary nodules
A pulmonary nodule appears as a rounded or irregular, well or poorly defined opacity, measuring up to 3 cm in diameter.[40] Considering the confusing and interchangeable use of the terms, the Fleischner Society recommended that “pure ground-glass nodule (GGN)” was preferred as more precise than “ground-glass opacity (GGO),” a combination of both ground-glass and solid components was referred to as “part-solid GGN,” whereas the term “subsolid” nodules included both pure and part-solid GGNs.[41]
Studies have shown the association between radiological and pathological findings for pulmonary nodules.[42–44] As early as in 2003, Ohde et al.[45] conducted a retrospective investigation of high-resolution CT finding and pathological results, which classified the presence of lymph vascular invasion and lymph node metastasis into invasive disease, and proposed that the consolidation to the maximum tumor diameter (C/T) ratio of ≤0.5 was an effective predictor for noninvasive adenocarcinoma ≤3 cm. In 2011, a multicentric prospective study (JCOG 0201) illustrated that a pathologically noninvasive cancer could be predicted by a C/T ratio of ≤ 0.25 in tumors ≤2 cm with a specificity of 98.7%.[44]
Otherwise, the volume doubling time (VDT) was identified as an index of growth rate of primary lung carcinoma as early as in 1963 and varied in tumors with different pathological subtypes.[46] The relation between VDT and survival has also been documented by several studies.[47–49] The study conducted by Arai et al.[49] in 1994 included both NSCLC and small cell carcinoma and stratified the growing speed based on doubling times, in which a doubling time of more than 252.4 days was identified as “slow growing.” The tumor sizes were measured according to chest X-ray in the researches above.
In 2000, Hasegawa et al.[50] reported the growth rates of 61 small lung cancers, and VDTs were calculated per CT images. The mean VDTs were 813, 457, and 149 days for GGOs, GGOs with a solid component, and solid nodules, respectively. In 2011, Oda et al.[51] illustrated that the mean VDTs for atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, and adenocarcinoma were 859.2 ± 428.9, 421.2 ± 228.4, and 202.1 ± 84.3 days, respectively. Song et al.[52] conducted an evaluation of growth rates of subsolid nodules with the use of VDT and mass doubling time (MDT) and disclosed that the median MDT was 1556.1 days (range 642.5–3564.5 days) for pure GGNs, 1199.9 days (range 838.6–2578.7 days) for part-solid GGNs with solid components of ≤5 mm, and 627.7 days (range 340.0–921.2 days) for part-solid GGNs with solid components of >5 mm, and the VDTs showed the same tendency as MDTs. In 2020, Qi[53] investigated the nature of persistent pure GGNs with deep learning-assisted nodule segmentation, illustrating that the median VDT of 52 pure GGNs was 1448 days and the median MDT was 1332 days. The mean time to growth in volume was 854 ± 675 days. The various VDTs for different pulmonary nodules are listed in Table 2.
Table 2: Volume doubling time for different pulmonary nodules
In 2016, Kakinuma et al.[55] reported the evolution of pulmonary subsolid nodules from a prospective multicentric study, in which pure GGNs and heterogeneous GGNs (solid component only in lung windows) did not exhibit the solid component growth of ≥2 mm during the first 2 years of follow-up, while part-solid nodules (solid component both in lung and mediastinal window) showed solid component growth of ≥2 mm at 6 months after the start of follow-up. The mean intervals of development into part-solid nodules for pure and heterogeneous GGNs were 3.8 ± 2.0 and 2.1 ± 2.3 years, respectively. In 2017, Sato et al.[56] investigated the natural course of multiple GGNs, of which 32% of the included patients experienced GGN progression at 36 months, thus suggesting that the optimal observation period for multiple GGNs was 36 months.
The typical CT images of GGNs with different GGO components during surveillance are shown in [Figure 1a-h]. All the GGNs exhibited were pathologically confirmed as invasive adenocarcinomas ultimately without lymph node metastasis, but the solid one [Figure 1g and h] had two risk factors for recurrence (solid component and spread through air space).
Figure 1: Typical CT images of different GGNs. (a and b) A pure GGN has been monitored annually for more than 7 years. (c and d) A part-solid GGN with GGO >50% has been under surveillance for 5 years. (e and f) A part-solid GGN with GGO of nearly 50% has been observed for 3 years. (g and h) A solid GGN (solid component could be detected in mediastinal window) showed obvious growth with 5 months. CT: Computed tomography, GGN: Ground glass nodule, GGO: Ground glass opacity
For a long time, National Comprehensive Cancer Network clinical practice guidelines in oncology[57] identified a doubling time of ≥400 days as one of the indications for sublobar resection of pulmonary nodules for their little invasiveness. In the NELSON trial,[2] pulmonary nodules with a volume >500 mm3 or a VDT <400 days were identified as positive screening cases. The same VDT category was also applied in LUSI trial[3] for nodule stratification. Nevertheless, as reported by Song et al.,[52] Qi et al.,[58] and Kakinuma et al.,[55] the VDT did not show statistical difference among different subtypes of adenocarcinomas. MDT may be more sensitive for the evaluation of growth rate of pulmonary nodules according to synthesized understanding from Song et al.[52] and Qi et al.,[58] which needs to be further confirmed.
Rational surveillance for conservative management of subsolid GGNs until signs of growth has proved the safety for patients.[56,59] The C/T ratio, VDT, MDT, or volume of nodules assesses the growth rates and risks of pulmonary nodules from different perspectives. How to detect the high-risk population with pulmonary nodules and avoid overtreatment using the current tools should be the key point.
Chest computed tomography with radiation exposure in pregnancy
How different imaging modalities contribute to fetal radiation dose and what the influences of different radiation doses on fetus might be the two primary questions, regarding imaging with radiation exposure in pregnancy.
It is difficult to measure the fetal dose in reality. The estimated fetal dose from a single chest CT acquisition is 0.01–0.66 mGy according to different reports.[60–62] In 2013, Osei and Darko[63] reported their results from a multinational study investigating the fetal doses after diagnostic radiology procedures with the use of FetDose software, (Grand River Regional Cancer Center, Kitchener, Ontario, Canada) in which three cases of chest CT examination showed fetal absorbed dose of 0.02 mGy/examination, and the risk of childhood cancer and risk of hereditary disease were 1 in 500,000 and 1 in 10,000,000, respectively, which were lower than the natural incidences. In 2021, Saeed[64] used the anatomical models to mimic pregnant patients receiving CT scan and then calculated the fetal doses with the aid of software; the calculated fetal doses for chest CT were 0.26–0.77 mGy. In fact, fetal dose should be estimated based on the actual technique parameters and the fetal condition.
Observational results[65–67] from nuclear accidents, animal studies, or radioactive therapy event revealed the consequences of radiation exposure to fetus, including pregnancy loss, congenital malformation, developmental retardation, and carcinogenesis. Exception for carcinogenesis as the stochastic effect, the other three phenomena are deterministic or threshold effects.[67] According to what Kumar and De Jesus summarized,[68] the radiational threshold of fetal malformation under 16 gestational week is about 100–200 mGy, the threshold is 500–700 mGy after 16th gestational week; a physical growth restriction is positively associated with increasing radiation dose, significantly above 1 Gy; the risk of mental retardation emerged as a linear function of dose exposed, with a threshold of 120 mGy at 8–15 week and 210 mGy at 16–25 week. Obviously, the gestational age and threshold of radiation exposure are the decisive factors for the exposure-related consequences.
In 1952, Russell proposed that radiation exposure for medical purposes should be limited to 14 days preceding ovulation, which was changed to a 10-day option by the International Commission on Radiological Protection considering the variation of menstrual cycles.[69,70] In 2007, Patel et al.[71] summarized the radiation-induced effects in different gestational ages, which was endorsed by the American College of Radiology and American College of Obstetricians and Gynaecologists’ Committee, thus guiding the diagnostic imaging during pregnancy and lactation.[62] Of particular concern, the estimated threshold dose before implantation (0–2 week after conception) is 50–100 mGy, while the effect is characterized by failure to implant or no significant effect (i.e. ”all or none”); the gestational period of 8–15 week is of high risk because of the rapid neuronal development, and the corresponding threshold dose for severe mental retardation is 60–310 mGy.
The use of iodinated contrast media in pregnant or lactating women is another concern. Upon previous evidences on animals and human, the European Society of Urogenital Radiology declared that the iodinated contrast media may be given to pregnant women if the radiographic examination is essential in exceptional circumstances, but the thyroid function should be monitored in the neonate during the 1st week and there should be no interruption for breastfeeding during lactation; which was consistent with what was advocated by the American College of Obstetricians and Gynaecologists’ Committee[62] and has been stayed unchanged in the latest version updated in 2019;[72] but for radioactive iodine, the committee banned the use of iodin 131 during pregnancy for the long half-life and the influence on fetal thyroid, and technetium 99 m was recommended as the alternative.
As suggested by several guidelines,[62,71] the estimated radiation exposure is low for chest CT when the fetus is outside the field of scan and if necessary, the examination should not be withheld from the pregnant woman; while the utilization of iodine 131 should be avoided. But in practice, how to weigh the absolute necessity for radiation exposure and avoid potential risk and stochastic the effect for fetus is the crucial problem.
Perspective
As with studies about the effects of radiological examinations on the fetus, we may not be able to conduct controlled trials to explore the outcomes of different interventions for young women with pulmonary nodules who have pregnant intention. Thus, we put forward this question in the hope of raising awareness on this topic and specifying the management of the targeted population in a more humanized and standard manner. Herein, we propose a preliminary, rough, and certain subjective management process based on the above reviews and the other guidelines [Figure 2]. In the process, we take into account the condition of complex gynecological diseases. For patients completing the pregnant plan first, a chest CT examination could be performed after the 15th week of gestation if necessary for high-risk GGNs or solid nodules especially when the interval after the last radiological surveillance exceeds 12 months. But the reality is more complicated, and we do not specifically discuss the significance of nodule size, the cumulative radiational exposure, and the influence of surgery with general anesthesia during the whole pregnancy process in clinical decision-making. A multidisciplinary treatment model may benefit patient decision-making. Chest CT-based radiomics has potential for the recognition of radiological high-risk population. Like lung diagnostic assessment programs across Ontario, Canada,[73] our team wants to provide efficient and accessible diagnostic evaluation and treatment planning for suspected lung cancer in young female patients with pregnant intent. We will continue to improve this management process and seek out the beneficiary.
Figure 2: The preliminary management process for pulmonary nodules in young women with pregnant intention. GGN: Ground glass nodule, GGO: Ground glass opacity, pGGN: Pure GGN
The management of incidental pulmonary nodules in young women with pregnant intention is an intricate and indecisive problem we have to encounter. The heredity of lung cancer and effects of sexual hormone on lung cancer are not the decisive factors, and the balance between the natural history of pulmonary nodules and the radiation exposure of imaging should be weighed.
Financial support and sponsorship
This study was financially supported by the National Key Research and Development Program of China (Grant 2020YFB1313700) and China Medical Foundation (Grant ZZ-2022004).
Conflicts of interest
There are no conflicts of interest.
References
1. National Lung Screening Trial Research Team Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409.
2. de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, Heuvelmans MA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med 2020;382:503–13.
3. Becker N, Motsch E, Trotter A, Heussel CP, Dienemann H, Schnabel PA, et al. Lung cancer mortality reduction by LDCT screening-Results from the randomized German LUSI trial. Int J Cancer 2020;146:1503–13.
4. Barta JA, Powell CA, Wisnivesky JP. Global epidemiology of lung cancer. Ann Glob Health 2019;85:8.
5. Arnold BN, Thomas DC, Rosen JE, Salazar MC, Blasberg JD, Boffa DJ, et al. Lung cancer in the very young:Treatment and survival in the national cancer data base. J Thorac Oncol 2016;11:1121–31.
6. Levi F, Bosetti C, Fernandez E, Hill C, Lucchini F, Negri E, et al. Trends in lung cancer among young European women:The rising epidemic in France and Spain. Int J Cancer 2007;121:462–5.
7. Shi J, Li D, Liang D, He Y. Epidemiology and prognosis in young lung cancer patients aged under 45 years old in northern China. Sci Rep 2021;11:6817.
8. Coté ML, Liu M, Bonassi S, Neri M, Schwartz AG, Christiani DC, et al. Increased risk of lung cancer in individuals with a family history of the disease:A pooled analysis from the International Lung Cancer Consortium. Eur J Cancer 2012;48:1957–68.
9. Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, et al. Familial risk and heritability of cancer among twins in nordic countries. JAMA 2016;315:68–76.
10. Cannon-Albright LA, Carr SR, Akerley W. Population-based relative risks for lung cancer based on complete family history of lung cancer. J Thorac Oncol 2019;14:1184–91.
11. Ang L, Chan CP, Yau WP, Seow WJ. Association between family history of lung cancer and lung cancer risk:A systematic review and meta-analysis. Lung Cancer 2020;148:129–37.
12. Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting Li-Fraumeni syndrome From TP53 mutation carriers. J Clin Oncol 2015;33:2345–52.
13. Gazdar A, Robinson L, Oliver D, Xing C, Travis WD, Soh J, et al. Hereditary lung cancer syndrome targets never smokers with germline EGFR gene T790M mutations. J Thorac Oncol 2014;9:456–63.
14. Liu M, Liu X, Suo P, Gong Y, Qu B, Peng X, et al. The contribution of hereditary cancer-related germline mutations to lung cancer susceptibility. Transl Lung Cancer Res 2020;9:646–58.
15. Chen LS, Baker T, Hung RJ, Horton A, Culverhouse R, Hartz S, et al. Genetic risk can be decreased:Quitting smoking decreases and delays lung cancer for smokers with high and low CHRNA5 risk genotypes –A meta-analysis. EBioMedicine 2016;11:219–26.
16. Jiang X, Finucane HK, Schumacher FR, Schmit SL, Tyrer JP, Han Y, et al. Shared heritability and functional enrichment across six solid cancers. Nat Commun 2019;10:431.
17. Zhang P, Chen PL, Li ZH, Zhang A, Zhang XR, Zhang YJ, et al. Association of smoking and polygenic risk with the incidence of lung cancer:A prospective cohort study. Br J Cancer 2022;126:1637–46.
18. Azim HA Jr, Peccatori FA, Pavlidis N. Lung cancer in the pregnant woman:To treat or not to treat, that is the question. Lung Cancer 2010;67:251–6.
19. Ganti AK, Sahmoun AE, Panwalkar AW, Tendulkar KK, Potti A. Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol 2006;24:59–63.
20. Katcoff H, Wenzlaff AS, Schwartz AG. Survival in women with NSCLC:The role of reproductive history and hormone use. J Thorac Oncol 2014;9:355–61.
21. Schwartz AG, Ray RM, Cote ML, Abrams J, Sokol RJ, Hendrix SL, et al. Hormone use, reproductive history, and risk of lung cancer:The women's health initiative studies. J Thorac Oncol 2015;10:1004–13.
22. Chlebowski RT, Anderson GL, Manson JE, Schwartz AG, Wakelee H, Gass M, et al. Lung cancer among postmenopausal women treated with estrogen alone in the women's health initiative randomized trial. J Natl Cancer Inst 2010;102:1413–21.
23. Chlebowski RT, Schwartz AG, Wakelee H, Anderson GL, Stefanick ML, Manson JE, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial):A post-hoc analysis of a randomised controlled trial. Lancet 2009;374:1243–51.
24. Abdel-Rahman O. Lung cancer incidence and mortality in relationship to hormone replacement therapy use among women participating in the PLCO trial:A posthoc analysis. Int J Clin Oncol 2020;25:885–91.
25. Titan AL, He H, Lui N, Liou D, Berry M, Shrager JB, et al. The influence of hormone replacement therapy on lung cancer incidence and mortality. J Thorac Cardiovasc Surg 2020;159:1546–56 e4.
26. Wen H, Lin X, Sun D. The association between different hormone replacement therapy use and the incidence of lung cancer:A systematic review and meta-analysis. J Thorac Dis 2022;14:381–95.
27. Li W, Lin X, Wang R, Wang F, Xie S, Tse LA. Hormone therapy and lung cancer mortality in women:Systematic review and meta-analysis. Steroids 2017;118:47–54.
28. Stabile LP, Davis AL, Gubish CT, Hopkins TM, Luketich JD, Christie N, et al. Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res 2002;62:2141–50.
29. Tekpli X, Skaug V, Bæra R, Phillips DH, Haugen A, Mollerup S. Estrogen receptor expression and gene promoter methylation in non-small cell lung cancer –A short report. Cell Oncol (Dordr) 2016;39:583–9.
30. Raso MG, Behrens C, Herynk MH, Liu S, Prudkin L, Ozburn NC, et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin Cancer Res 2009;15:5359–68.
31. Rouquette I, Lauwers-Cances V, Allera C, Brouchet L, Milia J, Nicaise Y, et al. Characteristics of lung cancer in women:Importance of hormonal and growth factors. Lung Cancer 2012;76:280–5.
32. Sun HB, Zheng Y, Ou W, Fang Q, Li P, Ye X, et al. Association between hormone receptor expression and epidermal growth factor receptor mutation in patients operated on for non-small cell lung cancer. Ann Thorac Surg 2011;91:1562–7.
33. Toh CK, Ahmad B, Soong R, Chuah KL, Tan SH, Hee SW, et al. Correlation between epidermal growth factor receptor mutations and expression of female hormone receptors in East-Asian lung adenocarcinomas. J Thorac Oncol 2010;5:17–22.
34. Hsu LH, Chu NM, Kao SH. Estrogen, estrogen receptor and lung cancer. Int J Mol Sci 2017;18:1713.
35. Wu CT, Chang YL, Shih JY, Lee YC. The significance of estrogen receptor beta in 301 surgically treated non-small cell lung cancers. J Thorac Cardiovasc Surg 2005;130:979–86.
36. Nose N, Uramoto H, Iwata T, Hanagiri T, Yasumoto K. Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung. Lung Cancer 2011;71:350–5.
37. Rothenberger NJ, Somasundaram A, Stabile LP. The role of the estrogen pathway in the tumor microenvironment. Int J Mol Sci 2018;19:611.
38. Hamilton DH, Griner LM, Keller JM, Hu X, Southall N, Marugan J, et al. Targeting estrogen receptor signaling with fulvestrant enhances immune and chemotherapy-mediated cytotoxicity of human lung cancer. Clin Cancer Res 2016;22:6204–16.
39. Bai J, Deng C, Fu F, Li D, Ma Z, Ma X, et al.
Pregnancy may have little influence on ground-glass opacities suspected for lung adenocarcinoma. J Cancer Res Clin Oncol 2022 [doi:10.1007/s00432-022-03999-y].
40. Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society:Glossary of terms for thoracic imaging. Radiology 2008;246:697–722.
41. Naidich DP, Bankier AA, MacMahon H, Schaefer-Prokop CM, Pistolesi M, Goo JM, et al. Recommendations for the management of subsolid pulmonary nodules detected at CT:A statement from the Fleischner Society. Radiology 2013;266:304–17.
42. Kudo Y, Matsubayashi J, Saji H, Akata S, Shimada Y, Kato Y, et al. Association between high-resolution computed tomography findings and the IASLC/ATS/ERS classification of small lung adenocarcinomas in Japanese patients. Lung Cancer 2015;90:47–54.
43. Kastner J, Hossain R, Jeudy J, Dako F, Mehta V, Dalal S, et al. Lung-RADS Version 1.0 versus Lung-RADS version 1.1:Comparison of categories using nodules from the national lung screening trial. Radiology 2021;300:199–206.
44. Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K, et al. Aprospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751–6.
45. Ohde Y, Nagai K, Yoshida J, Nishimura M, Takahashi K, Suzuki K, et al. The proportion of consolidation to ground-glass opacity on high resolution CT is a good predictor for distinguishing the population of non-invasive peripheral adenocarcinoma. Lung Cancer 2003;42:303–10.
46. Garland LH, Coulson W, Wollin E. The rate of growth and apparent duration of untreated primary bronchial carcinoma. Cancer 1963;16:694–707.
47. Weiss W, Boucot KR, Cooper DA. Growth rate in the detection and prognosis of bronchogenic carcinoma. JAMA 1966;198:1246–52.
48. Usuda K, Saito Y, Sagawa M, Sato M, Kanma K, Takahashi S, et al. Tumor doubling time and prognostic assessment of patients with primary lung cancer. Cancer 1994;74:2239–44.
49. Arai T, Kuroishi T, Saito Y, Kurita Y, Naruke T, Kaneko M. Tumor doubling time and prognosis in lung cancer patients:Evaluation from chest films and clinical follow-up study. Japanese lung cancer screening research group. Jpn J Clin Oncol 1994;24:199–204.
50. Hasegawa M, Sone S, Takashima S, Li F, Yang ZG, Maruyama Y, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol 2000;73:1252–9.
51. Oda S, Awai K, Murao K, Ozawa A, Utsunomiya D, Yanaga Y, et al. Volume-doubling time of pulmonary nodules with ground glass opacity at multidetector CT:Assessment with computer-aided three-dimensional volumetry. Acad Radiol 2011;18:63–9.
52. Song YS, Park CM, Park SJ, Lee SM, Jeon YK, Goo JM. Volume and mass doubling times of persistent pulmonary subsolid nodules detected in patients without known malignancy. Radiology 2014;273:276–84.
53. Qi LL, Wu BT, Tang W, Zhou LN, Huang Y, Zhao SJ, et al. Long-term follow-up of persistent pulmonary pure ground-glass nodules with deep learning-assisted nodule segmentation. Eur Radiol 2020;30:744–55.
54. Chang B, Hwang JH, Choi YH, Chung MP, Kim H, Kwon OJ, et al. Natural history of pure ground-glass opacity lung nodules detected by low-dose CT scan. Chest 2013;143:172–8.
55. Kakinuma R, Noguchi M, Ashizawa K, Kuriyama K, Maeshima AM, Koizumi N, et al. Natural History of Pulmonary Subsolid Nodules:A prospective multicenter study. J Thorac Oncol 2016;11:1012–28.
56. Sato Y, Fujimoto D, Morimoto T, Uehara K, Nagata K, Sakanoue I, et al. Natural history and clinical characteristics of multiple pulmonary nodules with ground glass opacity. Respirology 2017;22:1615–21.
57. Non-Small Cell Lung Cancer. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Version 1.2022 Available from:
https://www.nccn.org/guidelines/guidelines-detail?category=1 and id=1450 [Last accessed on 2022 Mar 15].
58. Qi LL, Wang JW, Yang L, Huang Y, Zhao SJ, Tang W, et al. Natural history of pathologically confirmed pulmonary subsolid nodules with deep learning-assisted nodule segmentation. Eur Radiol 2021;31:3884–97.
59. Silva M, Prokop M, Jacobs C, Capretti G, Sverzellati N, Ciompi F, et al. Long-term active surveillance of screening detected subsolid nodules is a safe strategy to reduce overtreatment. J Thorac Oncol 2018;13:1454–63.
60. Tremblay E, Thérasse E, Thomassin-Naggara I, Trop I. Quality initiatives:Guidelines for use of medical imaging during
pregnancy and lactation. Radiographics 2012;32:897–911.
61. McCollough CH, Schueler BA, Atwell TD, Braun NN, Regner DM, Brown DL, et al.
Radiation exposure and
pregnancy:When should we be concerned?Radiographics 2007;27:909–17.
62. Committee Opinion No. 723:Guidelines for diagnostic imaging during
pregnancy and lactation. Obstet Gynecol 2017;130:e210–6.
63. Osei EK, Darko J. Foetal radiation dose and risk from diagnostic radiology procedures:A multinational study. ISRN Radiol 2013;2013:318425.
64. Saeed MK. Comparison of estimated and calculated fetal radiation dose for a pregnant woman who underwent computed tomography and conventional X-ray examinations based on a phantom study. Radiol Phys Technol 2021;14:25–33.
65. De Santis M, Cesari E, Nobili E, Straface G, Cavaliere AF, Caruso A. Radiation effects on development. Birth Defects Res C Embryo Today 2007;81:177–82.
66. Green DM, Lange JM, Peabody EM, Grigorieva NN, Peterson SM, Kalapurakal JA, et al.
Pregnancy outcome after treatment for Wilms tumor:A report from the national Wilms tumor long-term follow-up study. J Clin Oncol 2010;28:2824–30.
67. Brent RL. Saving lives and changing family histories:Appropriate counseling of pregnant women and men and women of reproductive age, concerning the risk of diagnostic radiation exposures during and before
pregnancy. Am J Obstet Gynecol 2009;200:4–24.
68. Kumar R, De Jesus O. Radiation Effects on the Fetus. In:StatPearls Treasure Island (FL) StatPearls Publishing 2022.
69. Russell LB, Russell WL. Radiation hazards to the embryo and fetus. Radiology 1952;58:369–77.
70. Mole RH. The so-called 10-day rule. Lancet 1987;2:1138–40.
71. Patel SJ, Reede DL, Katz DS, Subramaniam R, Amorosa JK. Imaging the pregnant patient for nonobstetric conditions:Algorithms and radiation dose considerations. Radiographics 2007;27:1705–22.
72. European Society of Urogenital Radiology. ESUR Guidelines on Contrast Agents (version 10.0) Available from:
https://www.esur.org/fileadmin/content/2019/ESUR_Guidelines_10.0_Final_Version.pdf [Last accessed on 2022 May 20].
73. Habbous S, Khan Y, Langer DL, Kaan M, Green B, Forster K, et al. The effect of diagnostic assessment programs on the diagnosis and treatment of patients with lung cancer in Ontario, Canada. Ann Thorac Med 2021;16:81–101.
