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More than 50 years ago, Slaughter et al. (1) noted that smokers developed multiple preneoplastic lesions and synchronous (ie, those detected simultaneously) or metachronous (ie, those detected within a relatively short period) tumors in the squamous epithelium of the oral cavity, a phenomenon they termed “field cancerization.” They attributed these findings to tobacco carcinogens damaging the entire field at risk—the oral mucosa. Several years later, Strong et al. (2) extended this concept (and the clinical implications) to the entire upper aerodigestive tract. Multifocal primary tumors having similar histological appearance have been described in many organs but are especially common in lung cancer. In this issue of the Journal, Wang et al. (3) investigate the mechanisms by which these tumors arise. The results of these studies pose both important biological and clinical management questions.
Smokers cured of one aerodigestive cancer, including lung cancer, are at greatly increased risk of developing a second primary malignancy (4). This event may occur several years later, may involve tumors of differing histological types, or the tumors may arise in different anatomical regions of the field (such as larynx and lung). The origin of these tumors has been attributed to a “field” effect. More controversial are multifocal tumors of similar histology that arise synchronously or metachronously in the same organ. Multifocal tumors may be localized to multiple (satellite) nodules within a small region of the lung, involve a single lobe or multiple lobes within a single lung, or be present in both lungs.
Two major mechanisms have been proposed by which histologically similar multifocal tumors arise: 1) a single clonal event resulting in a tumor that subsequently spreads within one or both lungs and 2) multiple tumors arising independently in a carcinogen-damaged field. Nearly 30 years ago, Martini and Melamed (5) suggested clinicopathological criteria to help identify the origin of multifocal tumors. However, their criteria are guidelines for making clinical decisions, not definitive proof of origin. Martini and Melamed wished to provide guidance for lung cancer surgery; if the two lesions were thought to be separate lung cancers, they should be treated “independently” (and resected as such). By contrast, if they were thought to represent metastases, this could be taken as an indication of unresectable disease. Laboratory investigations to distinguish between these possibilities have resulted in multiple publications for more than 20 years. A search of the PubMed database in January 2009 using the MESH terms “Lung neoplasms” and “Neoplasms, multiple primary” resulted in retrieval of 1934 citations. Although many of these publications do not specifically address the question at hand, the sheer number of reports indicate substantial interest in the subject.
Wang et al. (3) have studied two or more synchronous or metachronous tumors (n = 70) found in 30 patients undergoing resection(s) for lung cancer at multiple centers. The investigators do not, however, tell us the frequency of multifocal tumors in their series. In earlier relatively small studies, frequencies ranging from 0.2% to 2% were reported, as referenced by Wang et al. (3). However, several more recent larger studies have found frequencies of 3.7%–8.0% (6–10). It is not known whether these findings reflect a rising incidence, as has been suggested (11), or simply better imaging procedures, especially the widespread use of computed tomography (CT) for screening and diagnosis. CT is especially efficient for the detection of small peripherally arising adenocarcinomas and their putative precursor lesions, atypical adenomatous hyperplasias. In a recent study, multifocal adenocarcinomas were identified in 15 of 77 (approximately 20%) resections for CT screening–identified lung cancers (12). Thus, this clinical problem is likely to become a common event with the widespread application of CT-based screening programs.
Wang et al. (3) have used techniques for the determination of clonality similar to those used by many other investigators: a panel of six polymorphic satellite markers, procedures to determine the presence and type of TP53 gene mutation, and X-chromosome inactivation analysis. Tumors for which findings were largely concordant were considered clonal in origin, and those with discordant findings were considered to be independently arising tumors. Wang et al. conclude that “evidence for common clonal origin of multifocal lung cancers” was present in 23 (77%) of 30 cases.
Does the evidence justify these conclusions? In all probability, the answer is yes, although a third possible mechanism for the origin of multifocal tumors must be considered besides those described above. Similar patterns of allelic loss may be present throughout the respiratory epithelium of smokers with or without lung cancer (13–15). At least one report describes the widespread presence of a single somatic TP53 point mutation in the bronchi of a smoker (16). These findings suggest that a single progenitor epithelial clone may expand to populate widespread areas of the respiratory mucosa. Further independent events occurring in such a uniformly mutant preneoplastic field may yield independent tumors that have common as well as novel molecular changes. Some evidence for such tumors exists (17). To identify tumors arising by this postulated mechanism, we need to apply newer genomewide approaches that are now widely available. Commercially available microarray chips permit analyses of more than 1 million single nucleotide polymorphic loci in a single test. Such analyses can identify numerous sites of allelic imbalance, both gains and losses, and accurately map their boundaries. These patterns can provide not only information on clonal relatedness but also detailed information on genetic “drift” in separate lesions. In addition, the application of large-scale DNA sequencing of tumors and comparison of tumor-acquired “driver” vs “passenger” mutations provide a “molecular clock” to compare the time of evolution of tumors (18).
Finally, although they are outside the scope of this editorial, there are other important biological questions posed by multifocal tumors, including whether they came from a distant “cancer stem or progenitor cell,” whether metachronous tumors could represent cases of “tumor dormancy” [where a tumor cell is shed but remains “dormant” until activated by some biological signal such as an “angiogenic switch” (19,20)], and what are the “seed” (ie, tumor) and “soil” (ie, metastatic site) characteristics that determine whether a tumor cell is capable of metastasizing to specific organs. Future application of such global molecular approaches will identify with precision which one of the several possible mechanisms is operative and the genetic “distance” between tumors in the same patient that have evolved from a common progenitor.
Wang et al. (3) report that a relatively high percentage (77%) of multifocal tumors were clonally related. The data from some selected reports indicate a highly variable percentage of multifocal tumors identified as clonally related (17,21,22). The precise percentage cannot be determined from these reports because of 1) the relatively small number of cases analyzed, 2) the inclusion or exclusion of metachronous tumors, and 3) different techniques of laboratory analyses and interpretation. However, all reports agree that multifocal tumors may arise either as metastases from a single tumor or as independent tumors resulting from field cancerization. Although it is relatively easy to understand how multiple independent tumors arise in a background of widespread epithelial damage, how do tumors spread within the ipsilateral lung or to the contralateral lung, often without clinical evidence of widespread distant metastasis? We can postulate at least three mechanisms: 1) formation of satellite nodules by direct extension or possibly via lymphatics, 2) aerogenous spread by tumor shedding into central or peripheral airways and dissemination during respiration or coughing, and 3) hematogenous metastases. The latter would require an extensive journey: spread via the pulmonary veins to the left side of the heart and the systemic circulation (bypassing favorite sites for lung metastases such as liver, adrenals, bone, and central nervous system), return to the right side of the heart, and spread to both lungs via the pulmonary arterial system.
The current management of non–small cell lung cancer is largely guided by the international TNM classification of lung cancers. Although the latest (sixth) edition was published in 2002 (23), it contained no clinically important changes for lung cancer classification from the fifth edition (published in 1997), which was based on the outcomes of a relatively small patient database from a single institution (24). The classification places patients with bilateral multifocal disease into the M1 (and thus stage IV) classification, a group considered largely unresectable and incurable. However, several studies have concluded that aggressive surgical resection of multiple intralobar, ipsilateral, or even bilateral multifocal nodules is much better when compared with historical reports on patients with distant metastases or other variants of T4 tumors (6,8,9,11,25). In preparation for the latest revision of the TNM classification (anticipated publication date 2009), a very large multi-institutional patient base has been assembled. Based on the new database (and published reports), proposed changes to the TNM classification include subdivision of the M category (24). The proposed new M1a category, which will include cases with bilateral pulmonary nodules, will be separated from the M1b category for those cases with other distant metastases. In addition, cases with additional nodules in an ipsilateral nonprimary tumor-bearing lobe will be reassigned into a T4 descriptor rather than M. These changes, and other proposed relocations of the T4 category, reflect the relatively good prognosis of multifocal tumors without distant metastases receiving aggressive surgical intervention.
Tumor materials from multifocal nodules are unlikely to be available for molecular analyses before surgery. In fact, there are no data available to suggest that the outcome for patients with intrapulmonary metastatic spread is different from the outcome for those with multiple synchronous tumors. Thus, management decisions should be made after careful clinicopathological evaluation by a multidisciplinary team (11). Clearly, multifocal lung cancers (without distant metastases) constitute a unique set of tumors having heterogeneous origins and better than expected prognosis and should be classified and treated appropriately. Although the origin of multifocal lung cancers is a fascinating biological problem and has major implications for understanding tobacco-related carcinogenesis, patient management has to be guided, for the most part, without the availability of this information.
National Cancer Institute Lung Cancer Specialized Program of Research Excellence grant P50CA70907 and Early Detection Research Network, National Cancer Institute.