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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e318265a7ef
Editorials

Mycobacterium Avium Complex and Lung Cancer: Chicken or Egg? Both?

Daley, Charles L. MD*†; Iseman, Michael MD*†

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*Department of Medicine, National Jewish Health, Denver, Colorado; and the University of Colorado Denver, Denver, Colorado.

Disclosure: The authors declare no conflicts of interest.

Address for Correspondence: Charles L. Daley, MD, National Jewish Health, 1400 Jackson Street, Denver, CO 80206. E-mail: daleyc@njhealth.org

In this issue, Lande et al.1 in Philadelphia report unexpectedly high rates of lung cancer among individuals with prior or concurrent Mycobacterium avium complex (MAC) lung infection. Two striking aspects of this comorbidity were noted: 1) cancer was considerably more prominent among nonsmoking women with MAC than among nonsmoking women without MAC, and 2 there were unexpectedly high rates of squamous cell carcinoma in the peripheral airways of these MAC-infected women.

The possible relationship of lung cancer to another mycobacterial lung infection, M. tuberculosis, is a good launching point in considering the potential role of MAC in oncogenesis. In the prechemotherapy era of tuberculosis (TB) (before 1950), clinicians widely held that because TB resulted in high mortality in early adulthood, lung cancer (which has always been most common in those > 50 years of age) would be uncommon among those with TB.2 But, with the advent of curative therapy for TB, lung cancers began appearing among TB survivors. Among the hypotheses entertained for this relationship was transition from the inflammatory dysplasia of the infection to malignant neoplasia.3 There was also a briefly held theory that isoniazid, the most significant drug of the early chemotherapy era, was oncogenic.

Ultimately, the notion of infection-engendered dysplasia/metaplasia transforming to cancer became the widely accepted paradigm and there are now many other examples of cancers being associated with prior infection.4 Thus, the supposition that pulmonary MAC may serve as a predisposition for lung cancer is an appealing one. MAC, in contrast to untreated TB, is unlikely to cause rapidly progressive disease and premature death. Rather, the natural history of MAC, particularly in women who commonly manifest indolent, ­airway-centered disease with bronchiectasis, is a chronic disease extending over decades.5 This pattern is compatible anatomically with the observation among patients in the Philadelphia series, who presented predominantly with peripheral airway squamous carcinomas. End of story, or is it?

One of the striking curiosities of MAC lung disease over the past three decades is increasing prevalence rates among women.6 Early series of pulmonary MAC in the United States, Europe, and Japan featured men who typically suffered tobacco-related chronic obstructive pulmonary disease or work-related pneumoconiosis.5 These men most commonly had upper-lobe, cavitary destructive disease very similar to classic TB.

However, in 1989, a series of patients with pulmonary MAC was reported from these same hospitals (Lankenau and Thomas Jefferson) in Philadelphia, the authors including one of the contributors to the current article, Donald Peterson.7 In addition to the typical male/chronic obstructive pulmonary disease form of disease and disseminated MAC in patients with AIDS, they described 21 patients without predisposing conditions; of the latter group, 17 were women in whom progressive nodular opacities predominated.

Over subsequent decades, multiple reports have documented that the preponderance of pulmonary MAC disease was being seen among women, the majority with bronchiectasis (the recognition of bronchiectasis widely reflects increased use of computed tomographic scanning, the optimal tool for identifying airway morphology).6,8 Striking elements of the epidemiology include a female preponderance that increases with age, a remarkably high percentage of cases among white women, and a paucity of cases in African Americans. Looking at the female MAC patients, a variety of morphological features were described by various observers: narrowing of the anterior-posterior chest dimensions, occasional frank pectus excavatum, taller-than-average stature, and slenderness/low body mass index.7,9,10

MAC is widely distributed in the environment, particularly in water. It has been postulated that exposure to MAC may be related to potable home water systems.11 However, this model should expose both sexes and all morphotypes in roughly equal degrees. Hence, it might be postulated that women with this morphotype may have some inherent susceptibility to MAC infection. Do they also have an inherent susceptibility to lung cancer?

A simple construct would be that, because of this vulnerability, women develop chronic MAC infection of their airways leading to inflammation, dysplasia and—ultimately—neoplasm. Unfortunately, the study by Lande et al.1 cannot address this construct as it is impossible to determine which came first, the chicken or the egg, given the retrospective design. So we are left with the question, did the chronic inflammatory environment created by MAC lead to the development of lung cancer or did lung cancer allow the establishment of infection with MAC? It is likely that both constructs are playing a role in this association but determining which is the more important will be challenging. Hopefully, further research will be able to determine whether the altered biology, which allows invasive MAC infection, may also be permissive of preneoplastic changes that eventuate in the lung cancers that are the focus of the series from Philadelphia.

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REFERENCES

1. Lande L, Peterson DD, Gogoi R, et al. Association Between Pulmonary Mycobacterium Avium Complex Infection and Lung Cancer. J Thorac Oncol. 2012;7:1345–1351

2. Bender F. Primary pulmonary carcinoma associated with active pulmonary tuberculosis. Dis Chest. 1952;21:184

3. Nalbandian A, Yan BS, Pichugin A, Bronson RT, Kramnik I. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene. 2009;28:1928–1938

4. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13:607–615

5. Griffith DE, Aksamit T, Brown-Elliott BA, et al.; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175:367–416

6. Adjemian J, Olivier KN, Seitz AE, Holland SM, Prevots DR. Prevalence of nontuberculous mycobacterial lung disease in U.S. Medicare beneficiaries. Am J Respir Crit Care Med. 2012;185:881–886

7. Prince DS, Peterson DD, Steiner RM, et al. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med. 1989;321:863–868

8. Winthrop KL, McNelley E, Kendall B, et al. Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease. Am J Respir Crit Care Med. 2010;182:977–982

9. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis. Thoracic anomalies associated with pulmonary disease caused by Mycobacterium avium complex. Am Rev Respir Dis. 1991;144:914–916

10. Kim RD, Greenberg DE, Ehrmantraut ME, et al. Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med. 2008;178:1066–1074

11. Falkinham JO 3rd. Nontuberculous mycobacteria from household plumbing of patients with nontuberculous mycobacteria disease. Emerging Infect Dis. 2011;17:419–424

© 2012International Association for the Study of Lung Cancer

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