Prognostic Patterns in the Histopathology of Pulmonary Adenocarcinoma

In the evaluation of tumors, pathologic assessment includes determination of tumor type, grade, and extent of tumor invasion, which is a primary consideration in determining tumor stage. The nomenclature for these features is an ever-evolving field. Recently, marked strides in the treatment of non–small-cell lung carcinoma using targeted therapy have additionally driven a re-evaluation of the classification and staging of this all-too-common tumor type. Pathologists regard epithelial tumor cells as invasive when they acquire the capacity to cross the basement membrane of the epithelial surface from which they arise, which usually elicits a sclerotic response in underlying stromal tissue. Typically, invasiveness is associated with lethality, and its absence is usually regarded as an indication that a tumor is not likely to be lethal. Pulmonary neoplasia is exceptional in this regard because it can cause marked functional impairment that leads to death in the absence of definitive, pathology-proven invasion. A single layer of pulmonary adenocarcinoma cells may spread along the expanse of alveolar surfaces without invading alveolar septal stroma in a pattern of growth that has come to be referred to as lepidic because of its vague resemblance in crosssection to a butterfly. Furthermore, this process is commonly multifocal. Enlarged and poorly functional malignant alveolar cells may block gas exchange and cause respiratory failure and death without destroying underlying lung tissue. Partly because of this biologic behavior, the nomenclature of lung adenocarcinoma has been controversial since the 1950s, when it was first recognized that adenocarcinomas could arise from the peripheral airway epithelium. More than 50 years ago, Liebow and a panel of pathology experts adopted the term bronchioloalveolar carcinoma (BAC) to refer to these peripheral lung tumors, with the admonition that “To insist that the tumor called BAC grows on the unaltered walls of alveoli . . . is to add confusion . . .” to the definition. BAC then was originally defined as a well-differentiated tumor that grew along the alveolar septae and could be either invasive or noninvasive. This definition combined invasive and noninvasive tumors together into a single category and persisted unchanged until studies, largely from Japan, indicated that small ( 2 to 3 cm) noninvasive (in situ) tumors were all virtually cured by resection. These data prompted a re-evaluation and ultimately a redefinition of BAC to refer to noninvasive (in situ) adenocarcinoma, whereas invasive tumors were classified according to their dominant growth pattern. This classification was adopted, largely unchanged, in the WHO 2004 classification. As Liebow predicted, the 1999/2004 WHO classification that redefined BAC as an in situ lesion proved to be a source of confusion. Reference to invasive BAC or BAC with nonpulmonary metastases continued to appear on pathology reports and in the medical literature, thus defying the premise that the term BAC be constrained to preinvasive lesions. Perhaps the greatest problem with the new classification was a reluctance to adopt the redefinition of BAC as an in situ lesion, so that BAC meant different things to different people. Also, the molecular characterization of adenocarcinoma greatly expanded and computed tomography imaging technology was continuously refined during this time period, generating a large amount of molecular and imaging information that could be compared with cell type. A series of workshops sponsored by the International Association for the Study of Lung Cancer was convened to solicit the ideas of a panel of pathology experts on how to revise the adenocarcinoma classification to overcome this and other limitations of the 2004 classification and to accommodate the new information that was emerging with respect to common molecular findings in adenocarcinoma. The workshops took into account radiologic/computed tomography appearances of these tumors, widespread molecular alterations, and prognosis of proposed histologic subtypes. Invasive tumors are classified according to their predominant histologic pattern or that pattern that occupies the greatest cross-sectional area in histologic sections. The final revised classification from these workshops is summarized in Figure 1, with arrows indicating five major changes in nomenclature and diagnostic groupings from the most recent previous classification. The first change was elimination of the term BAC and the adoption of the term adenocarcinoma in situ (AIS) to refer to solitary nodules that are no larger than 3 cm in size and are purely lepidic. Second, because tumors with a small ( 5 mm) invasive component have a prognosis similar to AIS, the category of minimally invasive adenocarcinoma (MIA) was introduced. Third, lepidic tumors that are larger than 3 cm in size, contain an invasive focus of more than 5 mm, or are multifocal are to be referred to as lepidic predominant. Importantly, the inability to exclude invasive behavior on small samplings of lesions is accounted for in this classification, with the recommendation that the terms AIS and MIA not be applied to such specimens. An additional pattern, micropapillary adenocarcinoma, which is characterized by a piling up and clustering of tumor cells in the alveoli, was added because of the reported poor prognosis of tumors with this pattern of growth. Finally, because mucinous BAC JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 13 MAY 1 2012