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Revolution in lung cancer: new challenges for the surgical pathologist.

Lung cancer continues to be the leading cause of cancer deaths in the United States, in Europe, and in the world (>1 million deaths per year worldwide). (1-4) Despite the great progress made in the treatment of other cancers in recent decades, the 5-year survival of patients with lung cancer has remained poor, ranging from 6% to 14% for men and 7% to 18% for women. (4) Worldwide, since 1985, the estimated number of lung cancer cases has increased by 51%. (3)

Traditionally, lung cancer has been viewed as an aggressive, relentlessly progressive disease with few treatment options and poor survival because most patients presented with an advanced stage of disease. The traditional role of the pathologist has been primarily to differentiate small cell carcinoma from non-small cell carcinoma on biopsy and cytology specimens and to stage non-small cell carcinomas that underwent resection.

In recent years, our concepts of lung cancer have undergone a revolution, including (1) the advent of successful new molecular-targeted therapies for lung cancer, many of which are associated with specific histologic cell types and subtypes (5-10); (2) new observations on the natural history of lung cancer derived from ongoing high-resolution computed tomography screening studies and recent histologic findings (11-15); and (3) proposals to revise the classification of lung cancers, particularly adenocarcinomas, in part, because of the first 2 developments. (6,10,16-27) With these significant, recent developments in lung cancer, surgical pathologists need to be comfortable in their role in the new personalized medical care of patients with lung cancer. Many of the new, targeted therapies are associated with specific histologic cell types and subtypes and, therefore, surgical pathologists will continue to employ the familiar procedures of histologic, cytologic, and immunohistochemical diagnosis for patients with lung cancer. In addition, the surgical pathologist must identify and properly triage tissues for additional molecular biomarker studies.

In this brief review, we highlight the aforementioned developments in lung cancer pathology. For greater detail, the reader is referred to the references and to the new book Advances in Surgical Pathology: Lung Cancer written by several of the authors of this review. (25-28)


Most lung cancers are at an advanced stage when diagnosed, and because resection is often not a viable option for these patients, the only tissue sampled in about 70% of lung cancer cases is a small biopsy and/or cytology specimen. Traditionally, selection of therapy required that the pathologist only differentiate between small cell carcinoma and non-small cell carcinoma. With current therapies, advanced stage adenocarcinomas may respond to pemetrexed therapy, but squamous cell carcinomas do not. The advent of successful molecular-targeted therapies, directed at specific cell types and subtypes of lung cancer, has increased the need for a more specific cell-type diagnosis. Pulmonary adenocarcinomas may respond to bevacizumab therapy, but severe, even life-threatening, hemorrhage has been reported in patients with squamous cell carcinoma who receive bevacizumab therapy. Although the latter may be related to the bulky size of centrally located squamous cell carcinomas, this observation has been considered particularly urgent for patient care.5-10,28

Experts currently recommend that, whenever possible, a specific diagnosis of adenocarcinoma or squamous cell carcinoma be made and the diagnosis of non-small cell carcinoma should be avoided whenever possible. In most cases, routine histology and routine cytology, supplemented, if needed, with immunohistochemistry (thyroid transcription factor 1 and/or napsin A for adenocarcinoma and p63 for squamous cell carcinoma), will suffice for diagnosis (Figures 1 and 2). Commercial immunohistochemical panels are also available. As much as possible, cancer tissue, including cell blocks from cytology specimens, should be preserved for molecular diagnostic studies to identify specific targets for molecular thera In a few cases, the specific cell type will not be identifiable because of poor differentiation, and the term nonsmall cell carcinoma should still be used. The term large cell carcinoma is also seldom used today and could disappear from lung cancer classification. It has been largely replaced by specific entities, such as large cell neuroendocrine carcinoma, and recognition that many other cases are specific cell types, particularly adenocarcinomas. (10,25,27)

Diagnosis of cell type based on a limited biopsy or cytology specimen raises the issue of lung cancer heterogeneity. Potential problems should be recognized, but those tumors that hemorrhage with bevacizumab therapy tend to be centrally located, bulky, squamous cell carcinomas, and most lung cancer heterogeneity is of the subtype variety within a single cell type. Adenosquamous carcinomas in which there is a 10% or greater component of adenocarcinoma and a 10% or greater component of squamous cell carcinoma are rare. (10,25,27)

Other potential targets of molecular-targeted therapy have associations with specific adenocarcinoma histologic subtypes. Examples include K-ras mutations in mucinous adenocarcinomas, epidermal growth factor receptor mutations in nonmucinous bronchioloalveolar carcinomas in specific populations, and the echinoderm microtubule-associated proteinlike 4 and anaplastic lymphoma kinase fusion genes in adenocarcinomas with solid or other patterns in specific populations. (5-10,28)



In addition to providing an initial diagnosis of cell subtype, which indicates a lung cancer may harbor a particular molecular target, pathologists need to select, process, store, and transport tissue for evaluation of specific molecular targets, possibly performing those tests if they have a molecular diagnostics laboratory and possibly interpreting and reporting the results. The pathologist should make an effort to preserve as much of the cancer tissue as possible for molecular diagnostic studies when diagnosing a small biopsy or cytology specimen. Cytology cell blocks are appropriate tissue for molecular diagnostic studies. Currently, in most hospitals, lung cancer tissues are sent for specific molecular diagnostic tests only at the request of the oncologist, but this is likely to change in the future, and protocols are already in place for automatic molecular testing of lung cancers in some larger institutions. Under the auspices of the College of American Pathologists (CAP) Pathology and Laboratory Quality Center, the CAP and the International Association for the Study of Lung Cancer currently have a Lung Cancer Biomarkers Guideline Committee which will publish guidelines for lung cancer biomarkers, including those molecular biomarker tests that should be ordered and when they should be ordered, appropriate processing and handling of tissues and performance, and appropriate interpretation and reporting of tests. These guidelines are expected to be jointly published in the Archives of Pathology & Laboratory Medicine and in the Journal of Thoracic Oncology and posted on the CAP Pathology and Laboratory Quality Center's Web site in the future.





Lung cancer screening with chest x-ray and sputum cytology in the 1970s resulted in the detection of more early stage lung cancers, but failed to reduce the number of advanced lung cancers or to reduce lung cancer mortality. As a result, lung cancer screening was abandoned. Currently, studies using high-resolution computed tomography to screen for lung cancer are also detecting additional cases of early stage lung cancers. Once again, the detection of a greater number of early lung cancers has not caused a decreased incidence of advanced lung cancers (the impact on lung cancer mortality is not yet known). Indeed, the so-called doubling times of many of the early lung cancers detected by high-resolution computed tomography suggest that many of these cancers progress at a much slower rate than was traditionally expected for lung cancers. These observations, combined with histologic observations that some peripheral adenocarcinomas invade at an unexpectedly small size, have led some authors (11-15) to question traditional concepts about the natural history of lung cancer, especially peripheral adenocarcinomas.

Some authors (11-15) have suggested the possibility that not all early lung cancers progress rapidly, if at all, to lethal advanced cancers as was once believed. In addition, some authors question whether the sequence from atypical adenomatous hyperplasia to bronchioloalveolar carcinoma/adenocarcinoma in situ to invasive carcinoma is the only pathway in the development of invasive adenocarcinomas. These are intriguing suggestions that will require considerable further investigation to establish their veracity. However, the issue of aggressive versus less-aggressive cancers has already arisen in other organs, such as breast and prostate. (11-15)


For several reasons, many of the new developments in lung cancer have focused on pulmonary adenocarcinoma: (1) adenocarcinomas are the most frequent and histologically complex cell type of lung cancer; (2) investigations have resulted in evolving concepts of the natural history of peripheral adenocarcinomas, including precursor and preinvasive lesions; and (3) many of the targeted molecular therapies currently applied to lung cancer are targeted toward adenocarcinomas or subtypes of adenocarcinoma. In light of new observations, many authors (6,10,18-27) have suggested revisions to the 2004 World Health Organization (WHO) classification of pulmonary adenocarcinomas, (17) and recently, the International Association for the Study of Lung Cancer, in collaboration with the American Thoracic Society and the European Respiratory Society, have worked on an International Multidisciplinary Classification of Lung Adenocarcinoma. This tremendous endeavor has been under the leadership of William Travis, MD, with assistance from Elisabeth Brambilla, MD. These 2 individuals chaired the 1999 and 2004 WHO thoracic tumor classifications. (10,16,17)

Adenocarcinomas accounted for as few as 5% of all lung cancers in the 1950s, whereas, today, adenocarcinomas account for 35% to 50% of lung cancers. Adenocarcinomas have traditionally been recognized as the most frequent cell type in women, the most frequent cell type in patients who have never smoked, and the most frequent cell type in Asians. Because of the general increase in the frequency of adenocarcinoma, adenocarcinoma is now also the most frequent cell type in men. Although adenocarcinomas are still the most frequent cell type in patients who have never smoked, most adenocarcinomas occur in smokers. (25)

In the most recent WHO classification published in 2004, (17) pulmonary adenocarcinomas were divided into acinar, papillary, bronchioloalveolar, solid adenocarcinoma with mucin production, and mixed subtypes, as well as several variants (fetal adenocarcinoma, mucinous or colloid carcinoma, mucinous cystadenocarcinoma, signet ring adenocarcinoma, and clear cell carcinoma). (17) As noted above, multiple issues have been raised regarding this classification of pulmonary adenocarcinomas and are addressed in recent articles and the proposed new classification. Although there is some consensus about the problems of the previous classification and their possible solutions, the following recommendations on classification will no doubt be further debated, and the WHO has not yet officially adopted any of the recommendations. (10)

It has been recognized that mixed subtype is a rather meaningless term because most adenocarcinomas are heterogeneous and contain more than one adenocarcinoma histologic subtype (eg, acinar mixed with solid areas and bronchioloalveolar pattern at the periphery). Using the 2004 WHO classification, all but a relatively few lung cancers were classified as mixed subtype. It is now felt that adenocarcinomas are best classified according to their predominant subtype rather than as a mixed subtype. Examples would be lepidic predominant, acinar predominant, papillary predominant, micropapillary predominant, and solid predominant. Because most cancers have more than one histologic subtype component, it is possible that any of the histologic subtypes within a cancer could have some type of clinical significance or imply response to a particular targeted therapy; if so, that remains to be elucidated. Therefore, after classification according to predominant subtype, the new classification may recommend that all of the histologic subtype components of each cancer be semiquantitatively estimated in 5% increments for clinical and molecular correlation. (6,10,27)




The term bronchioloalveolar carcinoma is very confusing because it is used in differing ways. (6,10,26,27) Averill Liebow, MD, originally coined the term to refer to peripheral adenocarcinomas in which the malignant cells grew in a row along the intact alveolar septa, replacing the healthy epithelial cells that lined the alveolar septa (called the lepidic pattern of cancer growth).29 At that time, bronchioloalveolar carcinomas were thought to arise from the peripheral pulmonary epithelium, that is, from the bronchiolar epithelium (Clara cells or metaplastic goblet cells) or from the alveolar epithelium (type II pneumocytes). These cancers were thus distinguished from those lung cancers that supposedly arose from the bronchial epithelium. (30-39) This classification recognized both nonmucinous and mucinous bronchioloalveolar carcinomas. The latter were distinctly less common, and we will address them later. The next several paragraphs refer to the nonmucinous variety of bronchioloalveolar carcinomas.

Beginning with the 1999 WHO classification, (16) bronchioloalveolar carcinoma was defined as an adenocarcinoma growing in a lepidic pattern along intact alveolar septa without invasion into the underlying stroma, pleura, or lymphovascular spaces (Figures 3 and 4). (17,30-39) This definition meant that bronchioloalveolar carcinoma was adenocarcinoma in situ and, as such, could not be reliably diagnosed on a small biopsy or cytology specimen that did not allow examination of the entire tumor, to exclude any foci of invasion. Studies of atypical adenomatous hyperplasia led to the theory of a sequence from premalignant adenoma (adenomatous hyperplasia) to preinvasive adenocarcinoma in situ (bronchioloalveolar carcinoma) to invasive adenocarcinoma for peripheral adenocarcinomas of the lung. This sequence is analogous to the stepwise development of colonic adenocarcinoma from a tubular adenoma. (40-47)

Currently, the term bronchioloalveolar carcinoma should correctly be used only to diagnose a small, purely lepidic cancer that does not invade into the alveolar interstitium or other tissues. However, even today, it is also used to describe the lepidic pattern often seen at the periphery of mixed-pattern adenocarcinomas. The latter varies from cases in which the lepidic pattern is predominant, suggesting a good prognosis, to cases in which the lepidic pattern is a minor component and the cancer typically has a worse prognosis. However, studies in the literature do not always distinguish between these types of cancers (purely lepidic pattern, mostly lepidic pattern, or partially

lepidic pattern). In addition, clinicians and radiologists often use the term bronchioloalveolar without regard to the strict WHO definition and will speak of metastatic bronchioloalveolar carcinoma. Studies by Noguchi and others (48-56) have made it clear that not all small peripheral adenocarcinomas with a bronchioloalveolar component have the same prognosis.

Because responses to molecular-targeted therapies are specifically associated with the adenocarcinoma subtype and more therapies and studies of therapies are anticipated in the future, precision in the subtype classification takes on greater importance than ever. To eliminate confusion over the term bronchioloalveolar carcinoma, several authors, (6,10,24-27) including the International Association for the Study of Lung Cancer, American Thoracic Society, and the European Respiratory Society, have suggested eliminating the term bronchioloalveolar carcinoma and replacing it with adenocarcinoma in situ. In addition, the term minimally invasive adenocarcinoma is proposed for peripheral lung cancers that are predominantly lepidic but have one or more foci of minimal invasion (it has been suggested that the latter be defined as any one focus of 5 mm or less invasion) (Figure 5). (6,10,18,24-27) Because it is proposed that invasive adenocarcinomas be classified according to their predominant subtype, as noted above, frankly invasive adenocarcinomas with a lepidic component, predominant or otherwise, can now be properly recognized as separate entities from the in situ and minimally invasive lepidic cancers. It is hoped that this proposal will address the dilemma of lumping pure lepidic-pattern cancers, mostly lepidic-pattern cancers, and partially lepidic-pattern cancers into the so-called bronchioloalveolar carcinoma category. Both adenocarcinoma in situ and minimally invasive adenocarcinoma have essentially a 100% 5-year survival rate if completely excised, whereas the frankly invasive adenocarcinomas with a lepidic component, predominant or otherwise, have a worse prognosis. (6,10,18,24-27)

As mentioned earlier, classification systems since 1960 have included a mucinous variant of bronchioloalveolar carcinoma (Figure 6). These cancers are typically multifocal and, often, spread in a so-called pneumonic pattern. By definition, cancers with these gross features cannot be in situ. Close examination of most of the cases previously called mucinous bronchioloalveolar carcinomas shows that most have foci of invasion, even when solitary lesions (Figure 7). Mucinous adenocarcinoma in situ has been recommended as the new term for noninvasive cancers with goblet cells, but, using this proposed classification, mucinous adenocarcinoma in situ and mucinous minimally invasive adenocarcinoma are extremely rare. It is now recognized that most cancers previously called mucinous bronchioloalveolar carcinomas were actually invasive cancers and should be designated mucinous adenocarcinomas with predominant lepidic pattern. (6,10,24-27)

Some other revisions to the pulmonary adenocarcinoma classification have been suggested but have yet to be adopted by the WHO. It has been recommended that the micropapillary subtype, which is associated with a poor prognosis and specific molecular targets, be added to the major histologic subtypes (Figure 8). It has been suggested that clear cell adenocarcinoma and signet ring cell adenocarcinoma no longer be separate variants because no significant clinical associations with these features are currently recognized. A suggested addition to the variants is enteric adenocarcinoma, which consists of columnar cells that histologically mimic adenocarcinoma of the colon. (10,24-27)


We have briefly highlighted several revolutionary developments in the field of lung cancer. Discovery and revision in this field are ongoing, and we are at the beginning of this journey, not its end. For decades, we have perceived lung cancer as a relentlessly aggressive and mostly incurable disease for which the surgical pathologist had a limited role. Today, surgical pathologists have an important and expanding role in the diagnosis and treatment of lung cancer, and it is essential to keep informed of new advances.


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Philip T. Cagle, MD; Timothy C. Allen, MD, JD; Sanja Dacic, MD, PhD; Mary Beth Beasley, MD; Alain C. Borczuk, MD; Lucian R. Chirieac, MD; Rodolfo Laucirica, MD; Jae Y. Ro, MD, PhD; Keith M. Kerr, MD

Accepted for publication September 16, 2010.

From the Department of Pathology and Laboratory Medicine, The Methodist Hospital, Houston, Texas (Drs Cagle and Ro); the Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York (Drs Cagle and Ro); the Department of Pathology, The University of Texas Health Science Center at Tyler, Texas (Dr Allen); the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Dacic);the Department of Pathology, Mount Sinai Medical Center, New York (Dr Beasley); the Department of Pathology, Columbia University Medical Center, New York (Dr Borczuk);the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Chirieac);the Department of Pathology, Baylor College of Medicine, Houston (Dr Laucirica); the Department of Pathology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Scotland (Dr Kerr);and the School of Medical Sciences, University of Aberdeen, Scotland (Dr Kerr).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Philip T. Cagle, MD, Department of Pathology and Laboratory Medicine, 6565 Fannin St, Main Bldg Room 227, The Methodist Hospital, Houston, Texas 77030 (e-mail:
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Author:Cagle, Philip T.; Allen, Timothy C.; Dacic, Sanja; Beasley, Mary Beth; Borczuk, Alain C.; Chirieac,
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Disease/Disorder overview
Date:Jan 1, 2011
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