Mixed Bronchioloalveolar Carcinoma Research Articles

Prognostic Effect of Stromal Myofibroblasts in Lung Adenocarcinoma

Myofibroblasts are special cells with the features of both fibroblasts and smooth muscle cells, which are one of the most important cells in tumor stroma. The role of myofibroblasts in tumor stroma remains disputable. Some authors suggested that myofibroblasts can facilitate tumor progress, and another considered that myofibroblasts could prevent tumor cells diffusing. Bronchioloalveolar carcinoma (BAC) is a kind of adenocarcinoma in situ. With the destruction of the alveolar framework by tumor growth, BAC develops into mixed BAC and invasive adenocarcinoma, which is a natural model of transformation from carcinoma in situ to invasive carcinoma. In this study, the expression of myofibroblasts in BAC, mix-BAC and invasive adenocarcinoma was examined by immunohistochemical staining of surgical specimens from 102 patients. The results showed that positive expression of myofibroblasts in pure BAC (2/15, 13.33%) group was lower than in mix-BAC (17/38, 44.74%) and invasive adenocarcinoma (29/49, 59.18%) respectively, (p<0.05, p<0.01). In addition, myofibroblast positive expression was associated with lymph node metastasis, high stage, high grade, vascular invasion and shortened survival time in patients with lung adenocarcinoma. These data suggest that myofibroblasts are likely to facilitate the invasion and metastasis of the lung adenocarcinoma, and can be used as a prognostic marker. Myofibroblasts may become even a new target for treatment.

Clinicopathology of stromal invasion in lung adenocarcinoma

In the World Health Organization classification, lung adenocarcinoma with mixed subtypes is defined as invasive carcinoma with evidence of vascular, pleural, or stromal invasion. The histological criteria for stromal invasion, however, are not clearly established. A total of 157 peripheral pure bronchioloalveolar carcinoma (BAC) or lung adenocarcinoma with mixed BAC and others were reviewed. All cases had been resected between 1986 and 2000 and measured < or =30 mm in maximum dimension. Destruction of alveolar framework (DAF) was defined as distortion or discontinuity of the alveolar framework by tumor growth. The extra-alveolar area involvement (EAAI) was defined as tumor growth outside the alveolar framework, which includes the following areas: bronchial wall, perivascular connective tissue and/or the vascular wall, interlobular septum and the visceral pleura. Survival of patients with adenocarcinoma without DAF (n = 41) was 100%. Even when adenocarcinoma involved DAF and lacked EAAI (n = 21), survival was 100%. The 5 year survival rate of groups with two invasion signs (n = 34) was 90.1%, and that of groups with three to five invasion signs (n = 61) was 66.7%. Tumor growth outside the alveolar framework is the hallmark of stromal invasion.

The Impact of Cigarette Smoking on Prognosis in Small Adenocarcinomas of the Lung: The Association Between Histologic Subtype and Smoking Status

In this retrospective study, we clarified the impact of smoking on prognosis and the association of clinicopathological factors, particularly histologic subtype, in patients with small adenocarcinoma of the lung. Between 1996 and December 2006, 121 patients presenting with adenocarcinomas that had a diameter </=2 cm were analyzed. The clinicopathological records of the patients were examined for age, gender, nodal status (c-N and p-N), tumor size, serum carcinoembryonic antigen level, histologic subtype, and smoking history. A histologic subtype was defined using a modified World Health Organization classification. These subtypes are bronchioloalveolar carcinoma (BAC), adenocarcinoma with little or no BAC component (Non or min BAC), and mixed bronchioloalveolar carcinoma with other adenocarcinoma components. The overall 5-year survival rates were 94.4% for never-smokers (N = 55) and 79.2% for smokers (N = 66) (p = 0.05). Cancer-specific 5-year survival rates were 98.0% for never-smokers and 80.4% for smokers (p = 0.03). Gender, serum carcinoembryonic antigen level, and histologic subtype were significantly associated with smoking status. Histologic subtype (Non or min BAC) was the only significant prognostic factor in multivariate analyses. The prevalence of smoking by histologic subtype was 27.3% for BAC, 43.2% for mixed bronchioloalveolar carcinoma, and 74.6% for Non or min BAC. The prevalence was significantly higher in Non or min BAC than in the others. Furthermore, the smoking index (daily cigarette consumption times years of smoking) was significantly higher in Non or min BAC than in the other two subtypes. In addition, patients with a high smoking index showed a greater percentage of Non or min BAC subtypes. Finally, male gender was associated with Non or min BAC independent of smoking status (p = 0.03). When adenocarcinomas were small (diameter </=2 cm) cigarette smoking and male gender were associated with Non or min BAC histologic subtypes, which are thought to have more aggressive biologic features resulting in poorer outcome compared with other subtypes.

Diagnosis and treatment of bronchioloalveolar carcinoma

Bronchioloalveolar carcinoma accounts for 5% of lung cancers, although histologically mixed bronchioloalveolar carcinoma and adenocarcinoma account for up to 20%. Bronchioloalveolar carcinoma histology is present in a majority of tumors found on lung-cancer screening by computed tomography. We review issues surrounding the diagnosis and treatment of bronchioloalveolar carcinoma, which often differs from other types of lung cancer. A spectrum of disease from histologically pure bronchioloalveolar carcinoma to adenocarcinoma exists. The approach to treatment of diseases within this spectrum is still evolving. Evidence on the role of sub-lobar resection, resection of multifocal disease, and pulmonary transplantation is reviewed. We also discuss epidermal growth factor receptor tyrosine kinase inhibitors, and their role in patients with bronchioloalveolar carcinoma. An understanding of recent developments in the diagnosis and treatment of patients with bronchioloalveolar carcinoma histology is important as early detection of lung cancer becomes more common. Ongoing clinical trials will provide important information on the role of limited resection. The use of epidermal growth factor receptor tyrosine kinase inhibitors should currently be limited to patients with advanced or recurrent disease who have failed cytotoxic chemotherapy. New targeted therapies are emerging for patients with bronchioloalveolar carcinoma histology.

Comparison in prognosis after VATS lobectomy and open lobectomy for stage I lung cancer

Video-assisted thoracoscopic surgery (VATS) has become an attractive surgical procedure, but several issues remain to be resolved. Prognosis after VATS lobectomy is important to evaluate the adequacy of VATS lobectomy as a cancer operation. Interestingly, several investigators, including us, have reported that prognosis after VATS lobectomy was superior to that after open lobectomy in early non-small-cell lung cancer (NSCLC). One of the possible reasons is the low invasiveness of VATS lobectomy. But we considered that patient bias might have some influence favoring VATS lobectomy. To evaluate our hypothesis, we reviewed medical records of stage I NSCLC patients undergoing operation between 1993 and 2002. We compared and evaluated the relationship between patient characteristics and prognosis after VATS and open lobectomy. We focused particularly on histological type, classifying it into four subgroups; (1) bronchioloalveolar carcinoma (BAC), (2) mixed BAC + papillary adenocarcinoma (BAC + Pap), (3) other adenocarcinoma (Other adeno), (4) squamous cell carcinoma + others (Sq + others). A total of 165 patients underwent VATS lobectomy, and 123 patients underwent open lobectomy. The 5-year survival rate of the VATS lobectomy group was 94.5% and that of the open lobectomy group was 81.5%. Univariate Cox regression of survival revealed that male, CEA > 5, Other adeno, Sq + others, open lobectomy, and tumor size > 3 cm were significant negative prognostic variables. Multivariate Cox regression of survival revealed that histological subtype and tumor size were independent prognostic factors, but surgical procedure was not an independent prognostic factor. Prognosis after VATS lobectomy was superior to that after open lobectomy, but patient bias influenced the prognosis in favor of VATS lobectomy, and the surgical procedure itself was not a prognostic factor.

Misclassification of Bronchioloalveolar Carcinoma with Cytologic Diagnosis of Lung Cancer

Cytology is commonly used to diagnose non-small cell lung cancer (NSCLC) but is an inaccurate means of diagnosis of bronchioloalveolar carcinoma (BAC). The aims of this study were to calculate the sensitivity and specificity of cytologic diagnosis of BAC and to estimate the misclassification of BAC as other subtypes of NSCLC. Preoperative fine-needle aspiration cytology diagnoses were compared to histology diagnoses in 222 patients, including 51 patients with pure or mixed BAC, who underwent lung resection for NSCLC at our institution since 1999. The sensitivity and specificity of a cytologic diagnosis of BAC were 12% and 99%, respectively. Based on cytologic diagnosis, 63% of BAC was misclassified as adenocarcinoma, and 18% was misclassified as undifferentiated NSCLC. In this cohort, 35% of adenocarcinomas and 12% of undifferentiated NSCLC diagnosed by cytology had BAC histology. Diagnosis of NSCLC by cytology alone results in significant misclassification of BAC, most commonly as adenocarcinoma or undifferentiated NSCLC. Because patients with BAC respond differently to certain treatments such as endothelial growth factor receptor inhibitors and surgical resection of multifocal lung cancer, misclassification of BAC may have important therapeutic implications.

Tumor fluoro-2-deoxy- d-glucose avidity on positron emission tomographic scan predicts mortality in patients with early-stage pure and mixed bronchioloalveolar carcinoma

Bronchioloalveolar carcinoma is a clinically heterogeneous subtype of non-small cell lung carcinoma that frequently has low 2-[18F]fluoro-D-glucose (FDG) uptake on positron emission tomographic scanning. We investigated whether tumor FDG avidity was associated with worse survival among patients with completely resected node-negative pure and mixed bronchioloalveolar carcinoma. We performed a cohort study of 36 patients who had completely resected pure and mixed bronchioloalveolar carcinoma between 1998 and 2004, who had no hilar or mediastinal lymph node metastases, and who had undergone a preoperative positron emission tomographic scan. Tumor FDG avidity was defined as a standardized uptake value of 2.5 or greater. Survival analysis was performed with a proportional hazards model. Of 36 patients studied, 26 patients (72%) were alive and 10 patients (28%) were dead after a median follow-up of 31 months (interquartile range 17-41 months). Seventeen patients (47%) had FDG-avid tumors, and 19 patients (53%) had non-avid tumors. Three-year survival was 49% in the FDG-avid group and 95% in the non-avid group (P = .005). FDG avidity had a hazard ratio of death of 8.6 (95% confidence interval 1.4-244.7, P = .02) after adjusting for tumor size, the presence of multifocal bronchioloalveolar carcinoma, and the presence of histologically mixed bronchioloalveolar carcinoma. Preoperative tumor FDG standardized uptake value of 2.5 or greater on positron emission tomography is a powerful predictor of long-term mortality in patients with lymph node-negative pure and mixed bronchioloalveolar carcinoma who undergo complete surgical resection. Patients with a high level of FDG uptake (standardized uptake value > or = 2.5) may benefit from adjuvant chemotherapy or more frequent clinical follow-up.

Bronchioloalveolar Carcinoma Is Not Associated with Younger Age at Diagnosis: An Analysis of the SEER Database

Bronchioloalveolar carcinoma (BAC) is a unique subtype of non-small cell lung cancer (NSCLC) that is associated with female gender, Asian ethnicity, and never-smoking status. Although BAC is commonly reported to occur more frequently in young people with lung cancer, there is a lack of evidence to support this association. We analyzed the association between age at diagnosis and NSCLC histology among 293,417 incident cases of NSCLC in the Surveillance Epidemiology, and End Results (SEER) database during the years 1973 to 2002. The mean age of patients with BAC (66.99 years) was similar to the mean age of all patients with NSCLC (66.44 years). The proportion of patients younger than 50 years of age was significantly smaller among patients with BAC than the overall cohort (6.06% compared with 6.90%). Although a greater percentage of women and Asian patients with lung cancer were younger than 50 years old, the proportion of patients with BAC was similar to the proportion of men and non-Asians with BAC. Finally, the prevalence of BAC histology among patients younger than 50 years did not change significantly after revision of the 1999 World Health Organization pathologic criteria for the diagnosis of BAC (risk ratio 0.93 versus 0.87, p = 0.31). BAC is not associated with a younger mean age at diagnosis, nor is it associated with an age of less than 50 years at diagnosis. Patients with mixed BAC probably have similar age characteristics compared with patients with pure BAC.

Micropapillary pattern: a distinct pathological marker to subclassify tumours with a significantly poor prognosis within small peripheral lung adenocarcinoma (≤20 mm) with mixed bronchioloalveolar and invasive subtypes (Noguchi's type C tumours)

A micropapillary pattern (MPP) in lung adenocarcinoma, characterized by papillary structures with epithelial tufts lacking a central fibrovascular core, has been reported to be a new pathological marker of poor prognosis. However, its clinicopathological and prognostic significance in small lung adenocarcinomas (</=20 mm) remains undetermined. A new histological classification of small lung adenocarcinoma proposed by Noguchi et al. has been found to be useful since it has defined surgically curable bronchioloalveolar carcinoma (BAC)-type tumours (Noguchi's type A and B) based on the absence of active fibroblastic proliferation. However, BAC-type tumours with active fibroblastic proliferation (Noguchi's type C), which is adenocarcinoma with mixed subtypes including BAC and invasive carcinoma in the new World Health Organization (WHO) classification, account for most of the small adenocarcinomas and represent a heterogeneous group ranging from minimal to overtly invasive cancer with variable prognoses. Therefore, in this study the aim was to investigate whether MPP can be an additional histological marker(s) to subclassify this heterogeneous group in small lung adenocarcinoma. One hundred and twenty-two cases of small lung adenocarcinomas (</=20 mm in maximum dimension) classified according to the new WHO classification and Noguchi's proposal were analysed with reference to the presence of MPP. Of the 122 cases, 67 (55%) were MPP-positive and 55 (45%) were MPP-negative. Lymph node metastasis and pleural invasion were significantly more frequent in the MPP-positive group: 74% and 66% in the positive group versus 26% and 34% in the negative group, respectively. The 5-year survival of the MPP-positive group was 54%, whereas that of the MPP-negative group was 81% (P=0.024). The 5-year survival rates of BAC (Noguchi's type A and B) (n=14), mixed BAC and invasive adenocarcinoma (Noguchi's type C) (n=85) and invasive adenocarcinoma (Noguchi's type D and F) (n=23) were 100%, 68% and 36%, respectively. In patients with mixed BAC and invasive adenocarcinoma (Noguchi's type C tumours), the 5-year survival of the MPP-positive group (n=51) was 54%, significantly lower than that of the MPP-negative group (n=23) of 100% (P=0.02). MPP is a simple and distinct pathological marker to subclassify tumours with a significantly poor prognosis within small (</=20 mm) mixed BAC and invasive adenocarcinoma (Noguchi's type C tumours).

Dynamic MR imaging: value of differentiating subtypes of peripheral small adenocarcinoma of the lung

Purpose: To determine the utility of dynamic magnetic resonance imaging (MRI) in the differential subtyping of small adenocarcinomas of the lung. Materials and methods: Twenty-nine pathologically diagnosed peripheral adenocarcinomas (less than 20 mm in diameter) underwent dynamic contrast-enhanced MRI. Maximum relative enhancement ratio, slope of enhancement, and corrected start time of enhancement were calculated from signal intensity–time curve of pulmonary lesion for each subject, and were statistically compared among bronchioloalveolar carcinoma (BAC) group (7 cases), mixed BAC group (10 cases), and adenocarcinoma group (12 cases). Results: Maximum relative enhancement ratio ( P<0.001) and slope of enhancement ( P<0.001) of BAC group were significantly higher than those of mixed BAC and adenocarcinoma groups. Start times of BAC group were significantly earlier than those of mixed BAC ( P=0.0001) and adenocarcinoma groups ( P<0.0001). Adapting the thresholds values of MR indexes from the positive tests, sensitivity, specificity, positive predictive value, negative predictive value and accuracy for differentiating BAC from other subtypes were 85.7, 100.0, 100.0, 95.7, and 96.6%, respectively. Conclusions: Dynamic MRI is useful for differentiating subtypes of small peripheral adenocarcinoma.

Differential Expression of Cytokeratins 7 and 20 and Thyroid Transcription Factor-1 in Bronchioloalveolar Carcinoma

We studied the staining patterns of bronchioloalveolar carcinoma (BAC) with antibodies to cytokeratin (CK) 7, CK20, and thyroid transcription factor-1 (TTF-1) to determine the diagnostic usefulness of this panel in differentiating BAC from metastatic adenocarcinoma in material obtained by fine-needle aspiration biopsy (FNAB) of the lung. We identified 16 cases of BAC. Of these, 6 were mucinous, 4 were nonmucinous, and 6 were mixed with focal mucinous differentiation. Immunohistochemical analysis with antibodies to CK7, CK20, and TTF-1 was performed on cell-block sections. Of the 6 mucinous BACs, 4 (67%) were CK7+, CK20+, and TTF-1–. All 4 nonmucinous BACs were CK7+ and CK20–, and 2 (50%) were TTF-1+. All 6 mixed BACs were diffusely positive for CK7 and focally positive for CK20; 5 (83%) were TTF-1+. Nonmucinous BACs display CK7, CK20, and TTF-1 immunoreactivity similar to conventional pulmonary adenocarcinoma. Mucinous and mixed BACs have an immunohistochemical phenotype that is different from that of conventional pulmonary adenocarcinoma. Knowledge of these staining patterns is crucial for distinguishing mucinous and mixed BACs from metastatic adenocarcinoma involving the lungs.

Differential expression of cytokeratins 7 and 20 and thyroid transcription factor-1 in bronchioloalveolar carcinoma: an immunohistochemical study in fine-needle aspiration biopsy specimens.

We studied the staining patterns of bronchioloalveolar carcinoma (BAC) with antibodies to cytokeratin (CK) 7, CK20, and thyroid transcription factor-1 (TTF-1) to determine the diagnostic usefulness of this panel in differentiating BAC from metastatic adenocarcinoma in material obtained by fine-needle aspiration biopsy (FNAB) of the lung. We identified 16 cases of BAC. Of these, 6 were mucinous, 4 were nonmucinous, and 6 were mixed with focal mucinous differentiation. Immunohistochemical analysis with antibodies to CK7, CK20, and TTF-1 was performed on cell-block sections. Of the 6 mucinous BACs, 4 (67%) were CK7+, CK20+, and TTF-1-. All 4 nonmucinous BACs were CK7+ and CK20-, and 2 (50%) were TTF-1+. All 6 mixed BACs were diffusely positive for CK7 and focally positive for CK20; 5 (83%) were TTF-1+. Nonmucinous BACs display CK7, CK20, and TTF-1 immunoreactivity similar to conventional pulmonary adenocarcinoma. Mucinous and mixed BACs have an immunohistochemical phenotype that is different from that of conventional pulmonary adenocarcinoma. Knowledge of these staining patterns is crucial for distinguishing mucinous and mixed BACs from metastatic adenocarcinoma involving the lungs.

Bronchioloalveolar lung cancer: occurrence, surgical treatment and survival.

The prevalence of pulmonary adenocarcinoma has risen worldwide. Bronchioloalveolar carcinoma (BAC) was studied with regard to whether it exhibits a similar tendency, and its typical features were analysed. Between 1992 and 2001, 278 lung resections were carried out for adenocarcinoma. Of these, 67 (24.1%) proved to involve BAC. Whereas BAC accounted for 6.9% of the cases in 1992, in 2001 the proportion was 46.9%. There were 37 men (55.2%) and 30 women (44.7%); the average age was 60.5 years. 58.2% of them had no complaints. Of the 26 non-smokers, 69.2% were women; of the 41 smokers, 29.2% were women. In consequence of the tumour, 49 lobectomies, three bilobectomies, six pneumonectomies and nine wedge resections were performed. The surgical mortality was 1.6%. The pathology revealed that 26 (38.8%) tumours were in stage I/A. In 15 cases (22.4%), tuberculosis (TB) could be revealed besides the BAC: by skin tests in four cases, by CT in three cases, by case history in four cases, and by pathology in four cases. For the overall group of 67 patients, the 5-year survival rate was 61.9%, and the mean survival time was 75.7 months. The 5-year survival rate among the women (74%) was significantly better than that among the men (37%) (P=0.030). There was no significant difference in survival with regard to the multiple BAC (85%). The 5-year survival rate was significantly worse in the mixed BAC group (20%) than in the non-mucinous (62.7%) and in mucinous (59%) group. The overall 5-year survival rate among the smokers and TB patients was 61 and 79%, respectively, which is higher than that among the non-smokers (47%) and non-TB patients (56%). The survival rate for the wedge resection cases was 37%, which was lower than that for the cases involving major resections (60%) (P=0.939). BAC has a favourable survival, particularly in women. In spite of this, resection smaller than lobectomy is recommended only as a compromise. A multiple appearance does not imply a worse survival. The best survival rate was found in the non-mucinous BAC among the histological groups. TB seems to be frequent among BAC patients.