Madeline Vazquez

Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: Histopathologic features and their prognostic implications

PURPOSE To study the histopathologic features of CT screen-detected Stage IA adenocarcinomas to determine whether survival differed by the proportion of bronchioloalveolar component (BAC) or by the presence of multiple lesions in node-negative patients. METHODS Five pathologists with expertise in pulmonary pathology examined 279 resected cases of adenocarcinomas, 30 mm or less in length diagnosed by CT screening for lung cancer. The panel determined the consensus diagnosis for each case, identified additional cancers, and classified each case as solitary or non-solitary. The presence and proportion of BAC was also documented. RESULTS Of the cases of adenocarcinoma, 20 (7%) were BAC subtype, 246 (88%) mixed subtype and 13 (5%) adenocarcinoma-OTHER. BAC cases manifested as non-solid and part solid nodules, mixed as solid and part-solid, and other as solid only. Kaplan-Meier 10-year survival rates were 100% for BAC and adeno-MIXED with 90-99% BAC cases, 95% for mixed with 1-90% BAC, 90% for those without a BAC component, and 75% for other cases. Fifty (18%) cases were non-solitary carcinomas and 44 of these were node negative; the non-solitary node-negative cases had the same excellent prognosis as solitary node-negative cases. CONCLUSIONS The proportion of BAC component was a positive prognostic factor and correlated with CT consistency. Contrary to staging predictions, cases of non-solitary node-negative adenocarcinoma had the same excellent prognosis as solitary node-negative cases, suggesting that most of the small, node-negative multiple carcinomas probably represent multiple primaries rather than intrapulmonary metastasis.

Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria.

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.

CXCL12 and CXCR4 in adenocarcinoma of the lung: Association with metastasis and survival

OBJECTIVES Although the chemokine CXCL12 and its receptor CXCR4 have been implicated in metastasis of non-small cell lung carcinoma, the prognostic significance of these molecules is poorly defined. This study aimed to determine whether expression of these molecules is associated with clinicopathologic features and disease-free survival in non-small cell lung carcinoma. METHODS Immunohistochemical staining for CXCL12 and CXCR4 was performed on 154 primary non-small cell lung carcinomas. Staining intensity was compared with tumor histotype, TNM stage, and disease-free survival; correlation was assessed by using the Fishers exact test, and Kaplan-Meier and Cox multivariate proportional hazards regression analysis. RESULTS Intense CXCL12 immunostaining was associated with nodal metastasis, although no difference in survival was observed. The prognostic relevance of CXCR4 was dependent on its subcellular location: in univariate analysis intense nuclear staining was significantly associated with lower T classification and improved disease-free survival in patients with adenocarcinoma, whereas cytomembranous staining was associated with distant metastasis and decreased disease-free survival. On multivariate analysis, cytomembranous CXCR4 expression conferred a significantly worse disease-free survival (relative risk, 2.8; 95% confidence interval, 1.4-5.7; P = .004). CONCLUSIONS Cytomembranous expression of the chemokine receptor CXCR4 in adenocarcinoma of the lung is an independent risk factor associated with worse disease-free survival, whereas nuclear staining confers a survival benefit. These findings are consistent with a model in which CXCR4 promotes tumor cell proliferation and metastasis when present in the cytoplasm or cell membrane, whereas localization of this molecule in the nucleus prevents it from exerting these effects.

Pathologic findings of lung tumors diagnosed on baseline CT screening.

Sixty-five people had a resection of their baseline screen-diagnosed lung cancers in the Early Lung Cancer Action Program. Forty-nine of the carcinomas were solitary, and 42 of these were adenocarcinomas. More than 1 carcinoma was found in 16 patients after pathologic examination of the lobectomy specimen; 15 of the 16 second carcinomas were adenocarcinomas, mixed subtype. Eighteen cases were submitted by local pathologists as Bronchioloalveolar carcinomas but were found to be invasive adenocarcinomas according to the World Health Organization classification by the Pathology Review Panel. Of the 65 resected cases, 57 were N0, 7 were N1, and 1 was N2. Upon careful review of the lobectomy specimens, 49 cases had solitary malignancies, 30 were Stage IA, 13 Stage IB, 3 Stage IIA, 2 Stage IIB, and 1 Stage IIIA on the basis of the American Joint Committee on Cancer/International Union for Cancer Control criteria. In the 16 cases found to have multiple malignancies, 6 had histologically different carcinomas and the remaining 10 had histologically identical malignancies. Eighty-three percent (76/92) of the carcinomas invaded the stroma with destruction of normal lung, and 21% (19/92) also showed either pleural or angiolymphatic invasion, even though 88% (57/65) of the carcinomas were free of lymph node metastases. This report describes the pathologic findings of the resected cases. Histopathologic distinctions among atypical adenomatous hyperplasia, bronchioloalveolar carcinomas, and invasive adenocarcinoma are described in detail.

SPECIAL TECHNIQUES IN TRANSTHORACIC NEEDLE BIOPSY OF PULMONARY NODULES

We believe that each aspect of the performance of TNB needs to be considered carefully. Meticulous attention to detail allows any nodule in the chest to successfully undergo biopsy. There are techniques of needle tip repositioning that can be quite helpful for obtaining diagnostic material from lung lesions, particularly small nodules. A strong working relationship with pathologists experienced in lung cytology is a vital element of any successful biopsy program. Techniques available to the pathologist allow for quick and decisive determination of the adequacy of the aspirated specimen and help guide the radiologist performing the procedure. Newer cytopathologic techniques help the pathologist make more complex diagnoses from the aspirated material. Finally, techniques used to minimize complications should be considered by the operator before the performance of the biopsy.

Reliability of cytologic diagnosis of early lung cancer

Baseline screening for lung cancer of 2968 high‐risk men and women utilizing HRCT enrolled in ELCAP (Early Lung Cancer Action Project) was performed between 1993‐2002. Among them, 65 people had surgical resection of their screen‐diagnosed lung cancer, 53 of them on the basis of a diagnosis of malignancy or atypical bronchioloalveolar proliferation (ABP) on fine needle aspiration (FNA) biopsy at Weill Medical College of Cornell University (WMC) prior to surgery. The authors compared the diagnosis obtained from the FNA with the subsequent diagnosis from the surgical specimen to assess the reliability of a cytologic diagnosis of lung cancer on FNA of these screen‐diagnosed lung cancers.

PAX-5 expression in pulmonary neuroendocrine neoplasms: its usefulness in surgical and fine-needle aspiration biopsy specimens.

The World Health Organization classification of lung tumors recognizes 4 histologic subtypes of pulmonary neuroendocrine carcinomas (NECs), which include typical carcinoids (TCs), atypical carcinoids (ACs), small cell carcinomas (SCCs), and large cell NECs (LCNECs). These tumors can be misclassified owing to morphologic parallels, indicating the necessity for adjunctive tests for correct classification. We evaluated immunohistochemical expression of PAX-5 in histologic and fine-needle aspiration (FNA) specimens of pulmonary NECs. Staining was stratified by intensity (0 to 3+) and percentage of cells stained as focal (<10%) or diffuse (=10%). PAX-5 expression was present in 29/37 (78%) of high-grade NECs (22/26 SCCs, 1/2 LCNECs, and 6/9 combined tumors) and none of 51 TCs and ACs; FNA specimens showed concordant staining. This study confirmed that PAX-5 is a useful marker in FNA and surgical specimens for the discrimination of low- to intermediate-grade NECs from high-grade NECs with 100% specificity and 79% sensitivity in surgical specimens.

CT features of intrapulmonary lymph nodes confirmed by cytology

We retrospectively assessed the computed tomography features of intrapulmonary lymph nodes confirmed by cytology in 18 patients. The median size of the lymph nodes was 5.8 mm (range=3.3-8.5 mm). All were below the carina, and only one nodule, which was associated with an interlobar fissure, was over 20 mm from the chest wall. The nodules were oval, round, triangular, or trapezoidal; had sharply defined borders; were solid and homogenous; and were without calcification. Six nodules (33.3%) had a discrete thin tag extending to the pleura. Intrapulmonary lymph nodes can reliably be confirmed by fine needle aspiration with cytological diagnosis.

SMALL PERIPHERAL GLANDULAR LESIONS DETECTED BY SCREENING CT FOR LUNG CANCER: A Diagnostic Dilemma for the Pathologist

The early detection of lung cancer by helical CT provides an important opportunity for radiologic-pathologic and clinical correlation of borderline glandular lesions. Little is known about the clinical course of atypical adenomatous hyperplasia, solitary noninvasive, nonmucinous BAC, and early-phase invasive adenocarcinomas, therefore, a single protocol for specimen handling and a central tissue registry are essential. The most important separation among the various types of adenocarcinoma is the diagnosis of BAC, a potentially curable malignancy, from invasive adenocarcinoma. Therefore, for small lesions of 2 cm or less, the entire tumor should be processed. For larger lesions, one section per centimeter should be sampled, and if the initial sections show a purely lepidic growth pattern, additional sections should be taken to exclude an invasive component. If foci of invasion are identified, the tumor should be classified as an adenocarcinoma with bronchioloalveolar features. At the International Conference on Screening for Lung Cancer held in October 1997, it was recommended that an international panel be used to reach consensus on difficult lesions of the lung detected by CT screening, and that a tissue bank of these lesions be established to ensure further clinical, radiographic, light microscopic, immunohistochemical, and molecular studies of putative precursor lesions and small carcinomas. Through the collection of these lesions, we can further our understanding of the biologic behavior of lung cancer, particularly because little is known about the progression from a purely lepidic growth pattern to invasive adenocarcinoma.

Transmyocardial laser revascularization dose response: enhanced perfusion in a porcine ischemia model as a function of channel density

BACKGROUND Transmyocardial laser revascularization (TMR) appears to provide symptomatic relief to patients with ischemic heart disease, but evidence that TMR enhances perfusion to ischemic myocardium remains limited. Furthermore, it is uncertain whether there exists a TMR dose-response relationship that is a function of channel number. We therefore compared restoration of blood flow as analyzed by rest and stress 99mTc-sestamibi scans and histologic grading of neovascularization after 50-channel, 25-channel, or 10-channel TMR using the excimer laser in an established model of porcine myocardial ischemia. METHODS Yorkshire swine underwent a thoracotomy and placement of an ameroid constrictor around the proximal circumflex coronary artery. Three weeks later, the animals underwent resting and adenosine stress 99mTc-sestamibi scans for evaluation of ischemia immediately before repeat thoracotomy and TMR with either 50 channels (n = 4), 25 channels (n = 4), or 10 channels (n = 4) in the circumflex territory. The animals underwent repeat perfusion analyses 4 weeks later, after which the animals were sacrificed and the hearts were perfusion fixed for histologic evaluation of neovascularization. RESULTS All animals survived to sacrifice. Semiquantitative analyses of the sestamibi perfusion scans 4 weeks after lasing demonstrated significant improvement (p < 0.04) in stress-induced ischemia in the 50-channel TMR animals, but not in the 25- or 10-channel TMR groups, as compared with scans obtained immediately before lasing. A computerized image analysis of perfusion scans similarly demonstrated an improvement in the area of ischemia of 42% +/- 22% in the scans obtained 4 weeks after lasing compared with scans obtained immediately before lasing in the 50-channel group (p < 0.004), but only a 12% +/- 9% improvement in the 25-channel group and an 8% +/- 4% improvement in the 10-channel group (p > 0.05). Histologic assessment of neovascularization demonstrated significantly greater number of microvessels per low-power field in the 50- versus the 25- and 10-channel groups (p < 0.001). CONCLUSIONS In an animal model of myocardial ischemia, TMR appears to enhance myocardial perfusion. A dose-response relationship related to channel number may be of significance when evaluating the efficacy of various treatment strategies.