Resolving Dilemmas in Lung Cancer Staging and Histologic Typing

With the recent lung cancer deaths of two high-profile individuals, Peter Jennings and Dana Reeve, the public has come to learn what physicians know all too well—most patients with lung cancer present at an inoperable stage, and the vast majority of them die of their disease. Pathologists certainly play an important role in the care of patients with advanced lung cancer, primarily through confirming the presence of malignancy and establishing its histologic subtype. However, it is the 20% of patients whose lung cancer is deemed operable for whom pathologists can have the greatest impact.The pathologic findings that we report for lung cancer resection specimens often dictate whether patients receive chemotherapy or radiation in addition to surgery. Such is the case in patients who are clinically considered to have T1 tumors without nodal or distant metastases (stage IA) but on pathologic examination are found to have T2 tumors (stage IB). Recent studies have demonstrated a survival benefit from chemotherapy in addition to surgical resection in such patients.1 Understanding pathologic findings that upstage lung cancer and other histologic variables with clinical impact are issues Dr Douglas Flieder addressed as part of the 2006 United States and Canadian Academy of Pathology (USCAP) Pulmonary Pathology Society Companion Meeting, “Resolving Dilemmas in Lung Cancer Staging and Histologic Typing,” and is more fully discussed in the first article of this special section.Any pathologist whose practice includes evaluating lung cancer resection specimens can certainly appreciate the difficulties in assessing the pathologic features that correspond to different tumor (T) categories. Even tumor size is subject to interpretation. The apparent tumor size on gross inspection is sometimes an overestimate of actual tumor size because of adjacent obstructive pneumonia. Assessment of visceral pleural involvement is another feature that causes considerable diagnostic confusion. The sixth edition of the American Joint Committee on Cancer staging manual provides no guidelines on what constitutes visceral pleural involvement, a surprising omission given that the presence of visceral pleural involvement upstages a tumor that otherwise only meets pT1 criteria to pT2.2 Some guidance can be found in Dail and Hammar's Pulmonary Pathology textbook,3 which depicts penetration of tumor through the visceral pleural elastic layer as the minimum criterion for visceral pleural involvement, as well as several articles that detail how elastic stains can aid in detecting involvement of the visceral pleura.2–7 It is certainly hoped that the next version of these staging guidelines provides a clearer definition of this important staging variable.As with several other organ sites, such as the larynx and breast, accurate assignment of some pT categories in cancer of the lung requires information that is outside of the pathologist's direct purview. Sometimes the best “special technique,” especially for centrally located lung carcinomas, is a quick call to the surgeon or radiologist to determine the distance from the carina or to ascertain whether unresected mediastinal or other extrapulmonary structures are involved.Whether the presence of tumor in separate lobes represents synchronous primary tumors or metastatic spread is another issue that Dr Flieder examines. Some exciting work has already been done in comparing the molecular profile of tumors from cases in which more that one lobe is involved.8 It seems likely that in the not-too-distant future these techniques will move from the research realm to become useful diagnostic tools that aid in the separation of synchronous lung carcinomas from tumors that have metastasized to other lobes.In the past two decades, many articles have examined small peripheral adenocarcinomas of the lung, with particular focus on those with a bronchioloalveolar growth pattern.9–12 Such studies have resulted in an evolution in the definition of bronchioloalveolar carcinoma in the World Health Organization classification of lung tumors. Additionally, the advent of epidermal growth factor receptor– tyrosine kinase inhibitors has increased the interest in bronchioloalveolar carcinoma from a clinical standpoint, as adenocarcinomas with a prominent bronchioloalveolar growth pattern appear to have the greatest response to these agents.13 In the second article in this special section, Dr Samuel Yousem elaborates on the findings he presented at the 2006 USCAP Pulmonary Pathology Society Companion Meeting. Dr Yousem and his coauthor, Dr Mary Beth Beasley, explore the evolution of the concept of bronchioloalveolar carcinoma, the significance of an invasive component with regard to behavior and prognosis, and several evolving issues, such as staging, treatment, molecular biology, precursor lesions, and subtyping. The definition of bronchioloalveolar carcinoma has been modified over time and is at present restricted to tumors that show no pleural, vascular, or stromal invasion. For clinicians and pathologists alike, not only is it a challenge to keep up with the changing definition of bronchioloalveolar carcinoma, but this shift also creates problems when comparing current trends in bronchioloalveolar carcinoma with historical data. Even recent articles, particularly those outside of the pathology literature, do not always adhere to the current definition when discussing bronchioloalveolar carcinoma, which further complicates this issue. Equally problematic is the tendency for most studies on bronchioloalveolar carcinoma to consider mucinous and nonmucinous subtypes as a single entity. Given that the immunoprofiles of mucinous and nonmucinous bronchioloalveolar carcinoma are somewhat different, it seems tenable that important and potentially therapeutically exploitable distinctions exist at the subcellular level. More studies that separately assess mucinous and nonmucinous bronchioloalveolar carcinomas would be a welcome addition to the literature.According to at least one study, the pathologic stage assigned after examination of lung cancer resection specimens differs from the preoperative clinical stage in slightly more than 50% of cases, a formidable figure given that a change in stage often affects what, if any, postsurgical therapeutic interventions are administered.14 With so much riding on the accurate assessment of pathologic stage in lung cancer and with the increasing interest in subtyping of non–small cell lung cancer that has resulted from the discovery of epidermal growth factor receptor– tyrosine kinase inhibitors, we present the following articles with the hope that they will offer a practical perspective to approaching the challenges that lung cancer resection specimens often present.

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