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To assess the vascular component of small lung cancers.We identified 105 resected non-small-cell lung carcinomas without pathologic evidence of vascular, lymphatic, bronchial, or pleural invasion. The percentage of BAC (% BAC) of all adenocarcinomas was determined by a pulmonary pathologist. A representative histology slide of each carcinoma was digitally scanned and the number of blood vessels (#V) with at least a diameter of 200microm was identified as well as the area of these blood vessels (VA) and of the tumor (TA) was obtained. The CT consistency of the cancers was also recorded as non-solid (NS), part-solid (PS) and solid.The number of blood vessels per cm(2) of tumor area (#V/TA) was higher for adenocarcinoma (7.3+/-4.7) as compared with large- and squamous-cell carcinoma (3.6+/-2.1, 2.3+/-1.1, respectively, P0.0001). For adenocarcinoma, #V/TA decreased with decreasing % BAC from 10.3 vessels per cm(2) of tumor area for 100% BAC to 5.1 vessels per cm(2) of tumor area for 0% BAC. The ratio of the total vascular area to tumor area (VA/TA), however, did not differ significantly by cell type nor for the adenocarcinoma by % BAC (P=0.87). While #V/TA decreased from 9.6 for non-solid nodules, to 7.5 for part-solid nodules and to 5.1 for solid nodules, there was no significant difference (P=0.27) in the VA/TA ratio by nodule consistency. Overall, VA comprised 2.7% of the total tumor area (TA) for 105 cancers.These results suggest that tumor vessels experience a continuous temporal and spatial remodeling as tumors grow and that bigger tumors tend to have fewer but larger blood vessels. It also suggests that, on average, squamous- or large-cell carcinomas have a larger average vessel diameter as compared with adenocarcinomas and that the vasculature of an adenocarcinoma might remodel as the % BAC decreases. The overall proportion of tumor volume comprised of vessels 200microm or larger is small and unlikely to influence overall tumor volume and doubling time estimates.

Introduction: Advances in the pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC) have demonstrated important new prognostic features that have led to changes in classification and diagnostic criteria. Methods: The literature and a set of cases were reviewed by a pathology/CT review panel of pathologists and radiologists who met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The group addressed the question of whether sufficient data exist to modify the 2004 World Health Organization (WHO) classification of adenocarcinoma and BAC to define a "minimally invasive" adenocarcinoma with BAC. The problems of diffuse and/or multicentric BAC and adenocarcinoma were evaluated. Results: The clinical concept of BAC needs to be reevaluated with careful attention to the new 2004 WHO criteria because of the major clinical implications. Existing data indicate that patients with solitary, small, peripheral BAC have a 100% 5-year survival rate. The favorable prognostic impact of the restrictive criteria for BAC is already being detected in major epidemiologic data sets such as the Surveillance Epidemiology and End-Results registry. Most lung adenocarcinomas, including those with a BAC component, are invasive and consist of a mixture of histologic patterns. Therefore, they are best classified as adenocarcinoma, mixed subtype. This applies not only to adenocarcinomas with a solitary nodule presentation but also to tumors with a diffuse/multinodular pattern. The percentage of BAC versus invasive components in lung adenocarcinomas seems to be prognostically important. However, at the present time, a consensus definition of "minimally invasive" BAC with a favorable prognosis was not recommended by the panel, so the 1999/2004 WHO criteria for BAC remain unchanged. In small biopsy specimens or cytology specimens, recognition of a BAC component is possible. However, it is not possible to exclude an invasive component. The diagnosis of BAC requires thorough histologic sampling of the tumor. Conclusion: Advances in understanding of the pathology and CT features of BAC and adenocarcinoma have led to important changes in diagnostic criteria and classification of BAC and adenocarcinoma. These criteria need to be uniformly applied by pathologists, radiologists, clinicians, and researchers. The 2004 WHO classification of adenocarcinoma is readily applicable to research studies, but attention needs to be placed on the relative proportion of the adenocarcinoma subtypes. Other recently recognized prognostic features such as size of scar, size of invasive component, or pattern of invasion also seem to be important. More work is needed to determine the most important prognostic pathologic features in lung adenocarcinoma.

Purpose The aim of this study was to assess the significance of Stage I diagnoses of lung cancer in the baseline cycle of screening for this disease, with special reference to the potential for overdiagnosis. Methods We reviewed all 69 cases of Stage I lung cancer diagnosis resulting from our baseline CT screening. Among these 69 cases of lung cancer, 24 presented as solid, 30 as part-solid, and 15 as nonsolid nodules. The extent to which these represented genuine malignancy was assessed by a panel of experts on lung pathology, and the “aggressiveness” of these cases was addressed by the criterion of the tumor's volume doubling time being less than 400 days. Results The expert panel confirmed all 69 cases as representing genuine malignancy. Among the 69 cases without evidence of metastases, the proportion that satisfied the aggressiveness criterion was 60/69=87%. The corresponding proportions by presentation as solid, part-solid, and nonsolid nodule were 23/24 (96%), 27/30 (90%), and 10/15 (67%), respectively. Conclusions In baseline CT screening for lung cancer, overdiagnosis of the disease is uncommon, with cases presenting as a nonsolid nodule a possible exception to this.

Increased use of chest computed tomography (CT) as well as improvements in CT resolution has led to increased detection of subcentimeter pulmonary nodules. Although the majority of these nodules are benign in etiology, a subset will harbor bronchioloalveolar carcinoma. The diagnosis of malignancy in this setting can be challenging to radiologists, surgeons, and occasionally pathologists as well. The challenge is compounded by a lack of knowledge about the natural course of these lesions--specifically, whether they represent life-threatening aggressive malignancies or indolent lesions of little or no consequence. Given the relative infrequency of these abnormalities, it will be essential to establish a sufficiently large database, to organize multi-institutional registries, and to collaborate on correlative studies. Only in this way will we be able to determine the clinical and molecular characteristics of these lesions and thus hopefully gain insight into their clinical relevance.

Evaluation of screening for lung cancer depends on accurate pathologic diagnosis of the disease. The majority of CT-detected malignancies are peripheral adenocarcinomas; therefore, patient specimens include putative precursor lesions such as atypical adenomatous hyperplasia, solitary noninvasive, nonmucinous bronchioloalveolar adenocarcinomas (BAC), and small invasive adenocarcinomas. Although not all cytologists and surgical pathologists are familiar with the current 1999 World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC) classification of lung tumors, the diagnosis of lung cancer is made with a high degree of accuracy. Difficulties in diagnosis most often are related to tumor sampling, the size of the sample, and artifacts. A potential problem of CT screening for lung cancer is the detection, or overdiagnosis, of carcinomas that do not interfere with the life or outcome of the patient. The concept of overdiagnosis should not be confused with a false-positive diagnosis of lung cancer by pathologists as these are exceedingly rare. When they occur, false-positive diagnoses most frequently are in the setting of atypical hyperplasia associated with granulomatous inflammation, fibrous scars, and in reactive atypia after radiation and chemotherapy (Fig. 1) . 4 The WHO/IASLC recently has completed a new proposal for the histologic classification of lung tumors. 34 Two major changes are the addition of atypical adenomatous hyperplasia as a preinvasive lesion and a new definition of BAC that requires the tumor to have a purely lepidic pattern without invasive growth. These lesions are likely to be encountered in surgical specimens from patients who are found to have growing nodules on CT.

Lung tumors with neuroendocrine (NE) morphology constitute only 20% of lung malignancies, yet no other group of lung neoplasms has generated so much interest and conflicting opinions among pathologists over the past several decades. The classification of these tumors has evolved with our understanding of the human NE system. Diverse morphologic patterns, a never-ending variety of immunohistochemical markers demonstrating NE function, and molecular techniques have led to complex classification schemes and confusion among not only clinicians, tumor registries, and patients, but also among the surgical pathologists responsible for reproducible tumor diagnoses. For many years lung tumors with NE morphology were diagnosed as either bronchial carcinoid tumors or small cell carcinomas (SCLC). Since 1972, these lesions have been classified as low-grade, intermediate-grade, and high-grade carcinomas. 10 The recently published 1999 World Health Organization (WHO) Histological Typing of Lung and Pleural Tumors serves as an impetus to review our current understanding of pulmonary NE cells, present the current classification scheme, and explore some of the peculiarities of lung NE tumors. Neuroendocrine cells, also known as Kulchitsky's cells, were first recognized by Feyrter 14 in 1938 and referred to as epithelial clear cells as part of a "diffuse epithelial endocrine system." The ability of these cells to take up and decarboxylate amine precursors including 3,4-dihydroxyphenylalanine (l-dopa) and 5-hydroxytryptophan (serotonin) led to the term amine precursor uptake and decarboxylase cells , which were thought to be neural crest cells. 46 The currently accepted dispersed NE system theory postulates that NE cells in different sites of the body are linked by a common NE phenotype and that these cells originated from pluripotent cells that differentiated locally under the control of unique site or organ factors. These cells are postulated to be of three derivations: (1) neural crest derivatives, such as adrenal medulla, paraganglia, and melanocytes; (2) neural tube and ridge-derived cells, such as epiphyseal, hypophyseal, and hypothalamic cells; and (3) derivatives of the NE programmed ectoblast including the gastroenteropancreatic system and bronchopulmonary tree. 47 Frohlich 16 first described NE cells of the lung in 1949 and he postulated that the solitary and nodular cellular aggregates in the walls of bronchi had a chemoreceptive or neurosecretory function. The nonciliated basally located cylindrical cells with clear cytoplasm are individually scattered throughout the bronchi and bronchioles and when clustered in groups of 4 to 10 cells with neural attachments are known as neuroepithelial bodies . NE cells are not found along the alveolar septa. Serotonin immunoreactive pulmonary NE cells are first seen at 8 weeks of gestation, increase in density through embryonic and fetal life, and peak in density at term suggesting a role in pulmonary morphogenesis and maturation. 12 Pulmonary NE cell hyperplasia is seen in a variety of physiologic and pathologic states. Increased numbers and small clusters of pulmonary NE cells are seen in persons living at high altitude; in children with bronchopulmonary dysplasia, cystic fibrosis, and bronchiectasis; in cigarette smoke–associated adult pulmonary diseases, including lung cancer; and in patients with carcinoid tumors. 19,21,30 Increased concentrations of bombesin-like peptides in bronchoalveolar lavage fluid of cigarette smokers and nonsmokers with diffuse idiopathic NE cell hyperplasia with obliterating small airways disease have also been reported. 1,2,21 In 1954, Feyrter 15 suggested that bronchial carcinoid tumors arose from NE cells, and in the mid-1960s Bensch et al 5 and Gmelich et al 18 first described the ultrastructural appearance of NE cells and related these cells to bronchial carcinoid tumors and SCLC. Many now consider the NE cell to be the cell of origin for most NE tumors of the lung, 4,20 a concept that impacts not only on histogenesis but also on classification. One group of investigators describes dysplastic NE cells in the lungs of patients with pulmonary neoplasms and chronic bronchitis and bronchiectasis, 21 and larger aggregates of NE at least partially outside the confines of airway basement membrane are termed carcinoid tumorlets (Fig. 1). These possible precursor lesions usually are incidental lesions found in normal lung or in patients with lung cancer, carcinoid tumors, pulmonary fibrosis, and granulomatous nodules. 10 Rare lymph node metastases have been reported, sometimes in the setting of multiple tumorlets. 13 Interestingly, one recent study reported that almost one third of patients, predominantly women, with resected peripheral carcinoid tumors also had diffuse NE cell hyperplasia and obliterative bronchiolitis. 40 These findings support the association between tumorlets and carcinoid tumors and raise the possibility that the NE hyperplasia causes obliterative bronchiolitis, and not vice versa as previously believed. 40 Although tumorlets of macroscopic size and carcinoid tumor merge as a pathologic entity, 9,39 an arbitrary 0.5 cm cutoff is used by the WHO to distinguish between these entities. 66 It must be emphasized that despite early speculation that carcinoid tumorlets might represent early or in situ SCLC, 6,48 there is no established clinical or pathologic association between these lesions. The current WHO classification recognizes four distinct tumors with NE morphology among the nine major histologic types of malignant epithelial neoplasms 66 : Squamous cell carcinoma Small cell carcinoma Adenocarcinomas Large cell carcinoma Large cell neuroendocrine carcinoma Adenosquamous carcinoma Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements Carcinoid tumor Typical carcinoid tumor Atypical carcinoid tumor Carcinomas of salivary gland type Unclassified carcinoma Typical carcinoid tumor (TC) is a low-grade carcinoma; atypical carcinoid tumor (AC) is an intermediate-grade carcinoma; SCLC and large cell NE carcinoma (LCNEC) are considered high-grade carcinomas (Table 1). Although consideration was given to a conceptual grouping of tumors with NE morphology, differences in epidemiologic, clinical, and biologic characteristics argue against such a classification (Tables 2 and 3).