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Originally published as JCO Early Release 10.1200/JCO.2009.22.3420 on May 11 2009 © 2009 American Society of Clinical Oncology.
Nonsmoking: A Surrogate Factor in Primary Lung Cancer in Survivors of Cervical Adenocarcinoma?Finnish Cancer Society, Tampere, Finland To the Editor: In a recent report in Journal of Clinical Oncology,1 risk for second cancers was assessed among survivors of cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) who underwent follow-up from 1 to 20 years after initial cancer diagnosis, as reported to cancer registries in Denmark, Finland, Norway, Sweden, and the United States. Incident second primary cancers were identified by linkage within the respective cancer registry. In assessing cigarette smoking–related risk for second cancers, Chaturvedi et al1 observed an increase in the incidence of lung cancer not only among survivors of SCC but notably among survivors of AC as well. The increased incidence of lung cancer—an event related to smoking—in both groups of patients was contrary to expectations, because only SCC, in contrast to AC, has been shown to be a smoking-related cancer. It was argued that metastases, misclassified as primary lung cancers, possibly could have contributed in part but not entirely to the increased risk for lung cancer among survivors of cervical cancers. Nevertheless, because lung cancer—in contrast to AC—has been shown to be a smoking-related event, the increased risk for lung cancer among survivors of cervical AC was seen to suggest a role for factors other than cigarette smoking. However, use of the contraceptive pill has been shown to be a risk factor for both histologic types of cervical cancer.2 The use of the pill has been associated with increased occurrence of cervical ectopy (ie, eversion of endocervical cells from the neutral acidic milieu to highly acidic vaginal milieu, where the cells are replaced—to protect the underlying stroma—by squamous cells through a phase of metaplasia involving remarkable cellular activity in an area of transformation zone, in which undifferentiated target cells are exposed to infection by human papillomavirus).3 It was proposed more recently that the degree of postcoital vaginal acidity could make an infected target cell choose between glandular and squamous differentiation. If the combined neutralizing capacity of ejaculate and vaginal coital fluid could overcome the normal vaginal acidity, the degree of acidity would become neutral (high pH), which would be native for the endocervical cells; if the neutralizing capacity were insufficient, the milieu would remain acidic (low pH), which would be native for the squamous cells lining the vagina and exocervix. Intense unprotected sex life, aided by use of the pill since its introduction in the 1960s and lately also by erectile dysfunction drugs, was interpreted to increase the occurrence of postcoital neutral degree of acidity. This native acidity of endocervical cells would signal a human papillomavirus–infected target cell to enter the glandular cell line of differentiation, ultimately leading to increased occurrence of AC (first observed in a cohort of women who had reached sexual maturity when the contraceptive pill became available4). Partly in terms of the concurrent decreased occurrence of acid postcoital milieu, an infected target cell would be signaled less often than it had been before the pill era to enter the squamous cell differentiation.5 It would seem that the target cell is a stem cell capable of responding to the degree of vaginal acidity both in "peace and war" (ie, in the process of epithelial coverage of the transformation zone and in the differentiation of cervical cancer). The risk period of pill use is likely to encompass the period around initiation and differentiation of the malignancy. In the study by Chaturvedi et al,1 patients with AC should have been considered nonsmokers only for the time period during which they were taking the pill. This is because women who adopted the use of the pill were likely to abstain from smoking, because some adverse vascular events had proved fatal for pill users and received much publicity.6 It may be assumed that before and after the time period of pill use, the average portion of those nonsmoking women were, in fact, smokers. This would imply that the incident second primary lung cancers were likely to have been smoking-related events, despite the relative period of time when the patients with AC, then pill users, probably did not smoke. Thus, nonsmoking among survivors of cervical AC would have been a surrogate factor for their early use of the hormonal contraceptive pill. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Chaturvedi AK, Kleinerman RA, Hildesheim A, et al: Second cancers after squamous cell carcinoma and adenocarcinoma of the cervix. J Clin Oncol 27:967, 973; 2009. 2. Smith JS, Green J, Berrington de Gonzalez A, et al: Cervical cancer and hormonal contraceptives: A systematic review. Lancet 361:1159, 1167; 2003.[CrossRef][Medline] 3. Leppäluoto PA: The pill and cervical cancer: The causal association. Acta Cytol 50:704, 706; 2006.[Medline] 4. Zheng T, Tiffany MF, Oualls CR: The rising increase of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix: A birth cohort phenomenon. Int J Epidemiol 25:252, 258; 1996. 5. Leppäluoto PA: A model of the differentation and relative incidence of glandular versus squamous cell neoplasia of the uterine cervix: Connection between incidence and etiology. Acta Obstet Gynec Scand 87:800, 803; 2008.[CrossRef][Medline] 6. Marks LV. Sexual Chemistry: A History of the Contraceptive Pill, ed 1 New Haven, CT: Yale University Press, 2001. p.138–156.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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