Bronchioloalveolar carcinoma: a review of current concepts and evolving issues.

CONTEXT: The concept of bronchioloalveolar carcinoma underwent considerable refinement between the publications of the 1981 and 1999 World Health Organization classifications of lung tumors. Both pathologic and clinical aspects of this carcinoma are the subject of considerable interest. OBJECTIVE: To review and summarize the evolution of the current concept of bronchioloalveolar carcinoma and evolving issues that are under further investigation. DATA SOURCES: Pertinent peer-reviewed literature emphasizing historical classification and evolution as well as current and evolving concepts. CONCLUSIONS: Small, solitary, nonmucinous bronchioloalveolar carcinomas are associated with a markedly better prognosis compared with conventional invasive adenocarcinomas. Such tumors may be cured by surgical resection and may be more responsive to epidermal growth factor receptor-targeted therapy. The prognosis and staging of multifocal disease remain unresolved, as does the question of whether a small amount of invasion adversely affects prognosis. Mucinous bronchioloalveolar carcinoma appears to be a markedly different entity than the nonmucinous subtype.

Bronchioloalveolar carcinoma of mixed mucinous and nonmucinous type: immunohistochemical studies and mutation analysis of the p53 gene.

Bronchioloalveolar carcinoma of mixed mucinous and nonmucinous type fulfilling the 1999 WHO criteria is rare. Here, we report a case of this type of tumor determined entirely by histological examinations. A 57-year-old man was incidentally found to have a demarcated 3cm mass in his lower lobe of the right lung. The tumor was composed of tall columnar cells containing cytoplasmic mucins, cuboidal cells without mucins, and intermediate cell types with lepidic growth patterns. Tumor cells were distributed within a region of 2cm in diameter, and no stromal, vascular, or pleural invasion was observed. Immunohistochemically, both the mucinous and nonmucinous components were positive for cytokeratin 7, TTF-1, and E-cadherin, and negative for cytokeratin 20, consistent with the results for nonmucinous bronchioloalveolar carcinoma. No mutations were detected in exons 5-8 of the p53 gene. The present tumor was composed mainly of morphologically mucinous bronchioloalveolar carcinoma, but presented different immunohistochemical profiles of ordinary mucinous bronchioloalveolar carcinoma. This case suggests that the mucinous component in bronchioloalveolar carcinoma of mixed mucinous and nonmucinous type has characters dissimilar to conventional mucinous bronchioloalveolar carcinoma, and is probably derived from the nonmucinous component.

Multiple bronchioloalveolar carcinomas in acromegaly: a potential role of insulin-like growth factor I in carcinogenesis.

The molecular pathogenesis of lung cancer, especially multiple and synchronous bronchioloalveolar carcinomas (BACs), is still unknown. Here, we report two cases of multiple BACs associated with acromegaly, and discuss about the possible relationship between these two pathological condition. The first patient was a 52-year-old female with a history of Hardy's surgery for pituitary growth hormone cell adenoma 2 years earlier. The second patient was a 57-year-old female with acromegaly and obstructive sleep apnea syndrome. Both patients were non-smokers and showed a high serum level of insulin-like growth factor I (IGF-I) at the time of admission, even though the level of growth hormone had decreased. High-resolution computed tomography (HRCT) revealed multiple small nodules with pure ground-glass opacity (GGO) in both lungs of the first patient and a small nodule with pure GGO in the right lung of the second one. Partial resection for these tumors were performed under video-assisted thoracoscopic surgery. Resected lung specimens of the first case revealed one papillary adenocarcinoma, seven BACs, and 11 atypical adenomatous hyperplasias (AAHs). The second case showed two foci of BACs. Immunohistochemically, all BACs were strongly positive for IGF-IR which is a specific receptor for IGF-I, and all AAHs were also weakly positive for IGF-IR. Since IGF-I is known as a potent growth factor for normal as well as cancerous cells, it might play an important role for tumorigenesis and/or tumor progression of BACs through its interaction with and/or upregulation of IGF-IR. In addition, much attention should be paid to detect lung lesions in acromegaly with high serum level of IGF-I.

Pulmonary adenocarcinoma: the expanding spectrum of histologic variants.

Pulmonary adenocarcinoma is one of the most common types of lung cancer. Traditionally, adenocarcinomas have been divided based on their degree of resemblance to their parent tissues into 3 histopathologic types: well, moderately, and poorly differentiated. In the majority of cases, this schema is sufficient to categorize these lung tumors. However, there is a considerable group of tumors in which the histology is not that of the classic gland-forming neoplasm. Thus, although the terminology of adenocarcinoma is applied in such cases, the histopathologic features are different from those of the more conventional variants. The current review addresses these unusual variants and the importance of recognizing and properly categorizing them to avoid unnecessary additional workup or possible misdiagnosis.

Synchronous pulmonary carcinoma and pleural diffuse malignant mesothelioma.

Synchronous pulmonary carcinoma and pleural diffuse malignant mesothelioma is rare. Cases from the archives of 2 large referral centers were reviewed to identify cases of synchronously occurring pulmonary carcinoma and pleural diffuse malignant mesothelioma. Three cases of synchronous pulmonary carcinoma and pleural diffuse malignant mesothelioma were identified from more than 16,000 pleuropulmonary cases and were reviewed for demographic, clinical, radiographic, histologic, and immunohistochemical findings. The patients were men who were 63, 67, and 77 years old. Two had positive smoking histories; the smoking history of the other patient is unknown. One patient had a positive history of asbestos exposure; one patient had no history of asbestos exposure; and one patient's history of asbestos exposure is unknown. The patients underwent surgery for treatment of adenocarcinoma that was diagnosed preoperatively. Two of the adenocarcinomas were of a predominantly bronchioloalveolar pattern. No diffuse malignant mesothelioma was identified preoperatively. Diffuse malignant mesothelioma was suspected on the basis of pleural involvement by tumor with histology differing from that of the adenocarcinoma. Tumor immunostaining supported the diagnoses. The average survival after diagnosis was 6 weeks or less. In summary, the paucity of cases at 2 large referral centers and the paucity of cases reported in the English language literature highlights the rarity of synchronous pulmonary carcinoma and pleural diffuse malignant mesothelioma. These synchronous neoplasms occur in patients who have risk factors for both neoplasms independently. Length of survival following diagnosis is bleak.

Papillary adenocarcinoma of the lung is a more advanced adenocarcinoma than bronchioloalveolar carcinoma that is composed of two distinct histological subtypes.

To clarify the clinicopathological nature of papillary adenocarcinoma (PA) of the lung, 20 cases of PA were collected consecutively from resected adenocarcinoma of the lung, studied immunohistochemically and, using molecular techniques, compared with bronchioloalveolar carcinoma (BAC). Clinicopathologically, PA occurred in 7.4% and dominantly in female patients. Morphologically, PA was divided into two subtypes according to the presence of residual alveolar structures, detected by elastica van Gieson stain. One of these subtypes was closely related to the morphology of BAC and might be diagnosed as adenocarcinoma with mixed subtypes. The other PA subtype was composed of tall columnar cells and grew compressively, which was similar to type F adenocarcinoma previously reported by Noguchi et al. Immunohistochemical studies using lung tissue-specific antigens, progression markers and tumor suppressor products found that PA seemed a more advanced adenocarcinoma than BAC, but no differences were observed among PA subtypes. Molecular biological analysis using three microsatellite markers at chromosome 3p revealed more frequent loss of heterozygosity in PA than BAC, with no differences among PA subtypes. These findings suggest that PA is a more advanced adenocarcinoma subtype than BAC. Further investigations are needed to clarify true PA as clinicopathologically and biologically independent from other histological subtypes of adenocarcinoma of the lung.

SCCRO expression correlates with invasive progression in bronchioloalveolar carcinoma.

BACKGROUND: Overexpression of squamous cell carcinoma-related oncogene (SCCRO) is associated with invasive progression and poor outcomes in non-small cell lung cancer. We assessed the role of SCCRO as a tumor marker in bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma exhibiting evidence of histologic tumor progression. We hypothesized that SCCRO expression would correlate with invasive tumor phenotypes and worse survival in BAC. METHODS: We classified 150 tumors as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. A tissue microarray was constructed from areas of benign lung, BAC, and invasive adenocarcinoma in these tumors. Squamous cell carcinoma-related oncogene expression was graded by immunohistochemistry from 0 to 3 (absent, low, moderate, or high), with positive SCCRO phenotype defined as grade 3. Squamous cell carcinoma-related oncogene specificity was determined by Wilcoxon rank test and area under the receiver-operator curve, survival by the Kaplan-Meier method, and correlation with prognostic factors by log-rank test. RESULTS: Of the 86.0% (129 of 150) of specimens suitable for analysis, positive SCCRO phenotype was seen in 16.3% (21 of 129) and was 100.0% specific for tumor versus benign tissue (area under receiver-operator curve, 0.92). Positive SCCRO phenotype was greater in tumors with increasing degrees of invasive histologic type (7.0% pure BAC, 13.6% BAC with focal invasion, and 28.6% adenocarcinoma with BAC features; p = 0.02). Low-level SCCRO expression was present in 83.9% (99 of 118) of benign tissues and correlated with tobacco use and poor survival (p = 0.05). CONCLUSIONS: Squamous cell carcinoma-related oncogene is a marker of invasive tumor progression in BAC. Low-level expression in adjacent benign lung predicts worse survival, and may represent field cancerization or host-tumor effects.

Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma.

Invasive parenchymal-type lung adenocarcinoma develops from atypical adenomatous hyperplasia (AAH), through an intermediate in situ stage of bronchioloalveolar carcinoma (BAC). We examined the expression of the putative tumour suppressor gene product Fhit, cell adhesion molecules CD44v6, E-cadherin and beta-catenin, and matrix metalloproteinase 2 and its inhibitor, TIMP-2, in a range of AAH lesions, BACs and invasive adenocarcinomas, to determine the changes in molecular expression associated with this form of neoplastic progression. Sections of formalin-fixed wax-embedded archival tissue were stained by standard Immunohistochemical techniques and scored semi-quantitatively, resulting in a grading of negative/low- or high-level staining. Fhit protein was retained at high levels in over 90% of AAH and 83% of BAC, but was found in only 6% of stromally invasive tumours (p < 0.0001). CD44v6 staining was high-level in 64% of AAH but fell to 26% in stromally invasive tumour (p = 0.007). E-cadherin and beta-catenin showed the opposite, with more high-level staining as adenocarcinoma developed (p < 0.001). High-level MMP-2 and TIMP-2 expression was relatively infrequent in AAH (32% and 40% respectively), rose in BAC (89% each) but fell in stromally invasive tumour (31% and 17% respectively) (p < 0.01). Unlike in central bronchial carcinogenesis, loss of Fhit expression is a relatively late event in this putative progression of lung adenocarcinogenesis, and has potential as a surrogate marker of invasion, which could be of value in screening patients for lung cancer. Loss of CD44v6 expression follows the convention of falling adhesion molecule expression as malignancy develops. Increased expression of E-cadherin and beta-catenin may reflect increased cell-cell contact as tissue architecture changes in the transition from AAH to adenocarcinoma. Loss of MMP-2 and TIMP-2 in stromally invasive tumour may reflect a particular role for MMP-2 at the BAC stage, with later down-regulation of this particular enzyme.

Immunohistochemical analysis of lung carcinomas with pure or partial bronchioloalveolar differentiation.

CONTEXT: In 1999, the World Health Organization redefined bronchioloalveolar carcinomas (BACs) as those neoplasms with only a pure lepidic growth pattern and no invasion. OBJECTIVES: The present study examined 45 lung cancers with a BAC component (1) to determine whether these tumors would be classified as BACs by current World Health Organization standards, (2) to quantitate the BAC component within these tumors, and (3) to see if phenotypic differences exist between the so-called invasive and noninvasive regions of these tumors. DESIGN: Retrospective review of hematoxylin-eosin-stained slides and classification of histologic grade, tumor subtype, and percentage of pure BAC pattern, with further characterization by immunohistochemical staining for thyroid transcription factor 1, cytokeratin 7, cytokeratin 20, and Ki-67 antibodies. RESULTS: Only 7 (15.6%) of the 45 tumors examined could be classified as BAC by current strict World Health Organization criteria. Those tumors, classified as nonmucinous and mixed, showed similar immunohistochemical staining for cytokeratin 7, cytokeratin 20, and thyroid transcription factor 1; mucinous tumors showed disparate staining. Significant differences in immunohistochemical staining and tumor cell proliferation were seen for the regions of tumors designated as lepidic, infiltrative, and leading edge and for the regions of tumors with different histologic grades (ie, well, moderately, and poorly differentiated). CONCLUSIONS: Nonmucinous and mixed BACs are phenotypically similar and show identical immunohistochemical staining patterns; mucinous tumors, on the other hand, show disparate immunohistochemical staining. Pulmonary neoplasms designated as adenocarcinomas with a BAC component represent a heterogenous group with a range of cell types, differentiation, growth, and immunophenotypes. Within an individual neoplasm, there are regional differences in these parameters as well.

Survivin expression in atypical adenomatous hyperplasia of the lung.

Few studies have investigated apoptosis-related factors in atypical adenomatous hyperplasia (AAH) and nonmucinous bronchioloalveolar carcinoma. We studied the expression of survivin, bcl-2, and p53 in 29 AAH lesions (low-grade, 11; high-grade, 18) and 40 nonmucinous BACs using immunohistochemical analysis and of survivin messenger RNA in 6 nonmucinous BACs using reverse transcription-polymerase chain reaction (RT-PCR). The incidence of positive survivin expression was 9% (1/11) in low-grade AAH, 89% (16/18) in high-grade AAH, and 100% (40/40) in nonmucinous BAC. Statistically significant differences were found between low-grade and high-grade AAH and between high-grade AAH and nonmucinous BAC. The percentages obtained for positive bcl-2 and p53 expression were 18% (2/11) and 0% (0/11) in low-grade AAH, respectively, and 28% (5/18) for both in high-grade AAH and 48% (19/40) for both in nonmucinous BAC. In RT-PCR, the intensity of survivin messenger RNA expression was stronger in nonmucinous BACs than in normal lung tissue samples. Thus, the expression of the 3 antibodies in high-grade AAH was intermediate between low-grade AAH and nonmucinous BAC. High-grade AAH may be closely related to nonmucinous BAC.

Ultrastructural findings in metastatic bronchioloalveolar carcinoma.

This study was prompted by the recent revision of the definition of bronchioloalveolar carcinoma (BAC) that defines BAC, light microscopically, as a non-invasive carcinoma. Doubt has been raised whether BACs retain certain specific microscopic features after becoming invasive or metastatic. We studied 7 cases of metastatic, non-mucinous BAC by electron microscopy. Of these cases, 5 showed Clara cell granules and 1 revealed lamellar bodies. The remaining case did not show ultrastructural features of BAC. These findings suggest that most BACs retain some of their ultrastructural features after becoming metastatic neoplasms.

Detection of early invasion on the basis of basement membrane destruction in small adenocarcinomas of the lung and its clinical implications.

To evaluate the correlation between the degree of basement membrane (BM) preservation and clinicopathological characteristics in the replacement-growth type (lepidic growth type) of small peripheral adenocarcinomas of the lung, the BM components of 72 surgically resected replacement-growth type adenocarcinomas of the lung, 2 cm or less in diameter, were evaluated immunohistochemically by using a monoclonal antibody to Type IV collagen and polyclonal antibodies to 7S collagen and laminin. The tumors were classified into the following three distinctive histological types according to the condition of the elastic framework: Type I, bronchioloalveolar carcinoma without fibrotic foci; Type II, sclerosing bronchioloalveolar carcinoma without elastic framework destruction; and Type III, sclerosing bronchioloalveolar carcinoma with elastic framework destruction. The BM was well preserved in the area of bronchioloalveolar spread along fully expanded alveoli in all tumor types; however, BM preservation was significantly lost in the areas of collapsed alveoli in Type III tumors. There were no BM component staining reactions in the scarred regions of Type III tumors. In addition, lymph node metastasis was significantly greater in Type III tumors and BM-destroyed tumors. We concluded that the BM was largely destroyed by tumor cell invasion in the scarred region of Type III adenocarcinomas. Type III tumors had discontinuous BMs in the area of collapsed alveoli, indicating that this BM-destructive pattern must be the first step in tumor invasion. Type I and II tumors were concluded to be noninvasive adenocarcinomas, because their BM components were well preserved and they had a good outcome.

Prognostic significance of percentage of bronchioloalveolar pattern in adenocarcinomas of the lung.

Bronchioloalveolar (BA) carcinoma of the lung is considered to have a better prognosis than that of common adenocarcinomas of the lung. However, a minor component of the BA pattern is common in many lung adenocarcinomas and the criteria for designating an adenocarcinoma as BA are not well defined. We assessed the clinicopathologic features of 238 cases of lung adenocarcinoma with a partial or predominant BA pattern. Tumors were classified as BA if more than 75% of the tumor had a BA growth pattern. In other words, the tumor grew along pre-existing lung structures without invasion or destruction of parenchyma. Tumors with 50% to 75% BA pattern were considered mixed and tumors with less than 50% BA pattern were designated as solid/acinar (S/A). Fixed, paraffin-embedded tissue sections of each neoplasm were also assessed using immunohistochemical methods with a panel of antibodies specific for p53, retinoblastoma protein, p16, cyclin D1, and cyclin E, and the results were correlated with clinical and pathologic parameters. Our results show that the 5-year survival rate of patients with BA and mixed tumors, 63% and 60%, respectively, was significantly better than that of patients with S/A tumors (P =.026). Patients with BA tumors were more frequently women (55.9%) compared with patients with mixed (48.3%) and S/A (43.8%) tumors. Bronchioloalveolar and mixed tumors were similarly associated with tobacco use, 88.2% and 85%, respectively; slightly less than S/A tumors (93.8%). Clinical and pathologic parameters did not correlate with immunohistochemical results. In conclusion, patients with BA or mixed tumors have similar 5-year survival, better than that of patients with S/A tumors, suggesting that adenocarcinomas can be designated as BA when at least 50% of the tumor has a BA pattern.

Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies.

We studied 14 mucinous and 26 nonmucinous bronchioloalveolar adenocarcinomas (BACs) with thyroid transcription factor (TTF), cytokeratin (CK) 7, CK20, and villin to characterize their staining patterns with these antibodies and identify staining differences between the neoplasms. We also stained 11 mucinous colon adenocarcinomas with the same antibodies to compare their reaction patterns with mucinous BACs. All pulmonary neoplasms were confirmed pulmonary primary BACs. Three (21%) of 14 mucinous neoplasms had weak TTF reactivity in fewer than 25% of neoplastic cell nuclei, and the other 11 (79%) were nonreactive. In contrast, 24 (92%) of 26 nonmucinonus BACs were strongly TTF reactive. Eleven mucinous BACs (79%) had CK20 reactivity in more than 25% of neoplastic cells, whereas only 1 nonmucinous BAC (4%) had reactivity in fewer than 50% of the cells. One mucinous BAC (7%) had villin reactivity in approximately 10% of the neoplastic cells. All mucinous colon adenocarcinomas were diffusely reactive with CK20 and villin. Mucinous and nonmucinous BACs have disparate staining patterns with TTF and CK20. Mucinous BACs are usually TTF nonreactive and CK20 reactive, but nonreactive with villin, which distinguishes them from mucinous colon adenocarcinomas.

[Combined neoplasia of the lung: description of a case of adenocarcinoma mixed with typical carcinoid]. / Neoplasie combinate del polmone: descrizione di un caso di adenocarcinoma combinato con carcinoide tipico.

OBJECTIVE: To report about a lung tumor that was a combination of typical carcinoid and adenocarcinoma. RESULTS AND CONCLUSIONS: The patient, a 71-year-old male, presented with a 2.5-cm pulmonary nodule that, microscopically, was a combination of an adenocarcinoma (tubular with clear cell features and bronchioloalveolar) and a typical carcinoid. Immunohistochemically, both components were positive for cytokeratin, but only the carcinoid component was positive for chromogranin and synaptophysin. In the range of neuroendocrine tumors of the lung, a combination with other histological types of carcinoma (squamous, adeno, large cell and pleomorphic) can be found with both small cell carcinoma and large cell neuroendocrine carcinoma, but is very rare with typical and atypical carcinoids.

Mucinous bronchioloalveolar carcinomas display a specific pattern of mucin gene expression among primary lung adenocarcinomas.

Lung adenocarcinomas are heterogeneous clinically and histologically. Expression of the mucin genes was analyzed as a molecular marker of glandular cytodifferentiation in primary lung adenocarcinomas. Expression was correlated with histopathologic subtypes of World Health Organization classification with the aim of investigating the histogenesis of primary lung adenocarcinomas. Thirty-four primary lung adenocarcinomas were examined by in situ hybridization for mucin gene expression (MUC1-4, MUC5AC, MUC5B, MUC6-7) and by immunohistochemistry for MUC5AC and MUC5B apomucin expression. Mucinous bronchioloalveolar carcinoma (BAC) had a homogeneous pattern of mucin gene expression different from those of other types of lung adenocarcinoma, involving secreted mucins (MUC5AC, MUC5B, and MUC6) and membrane-bound mucins (MUC1, MUC3, and MUC4). Non-BAC adenocarcinoma and mucinous BAC aberrantly expressed mucin genes MUC3, and MUC3 and MUC6, respectively, which are undetectable in normal fetal and adult lung. Our results show the particular phenotype of mucin gene expression in mucinous type of BACs and the heterogeneous expression of respiratory and nonrespiratory mucins in the other types. This finding supports the theory of a common progenitor cell with the potential of multicellular differentiation. From a practical point of view, the aberrant expression of MUC3 and MUC6 could serve as a diagnostic marker in the management of the mucinous type of bronchioloalveolar carcinomas. HUM PATHOL 32:274-281.

Immunohistochemically detected micrometastases in peribronchial and mediastinal lymph nodes from patients with T1, N0, M0 pulmonary adenocarcinomas.

The T1, N0, M0 subset of stage I lung adenocarcinoma is a tumor that has a 5-year disease-free survival rate of 66% to 85%. To date, there has not been a rigorous immunohistochemically detected lymph node micrometastasis study composed of patients with identical stage and type of tumors, and in which standard histologic features were incorporated into multivariate analyses. We immunohistochemically examined the peribronchial and mediastinal lymph nodes from 80 consecutively accrued patients with T1, N0, M0 adenocarcinomas and bronchioloalveolar carcinomas unselected for distant metastasis, and an additional 39 patients with similar stage and type neoplasms who were selected for their development of metastases to evaluate the prevalence of micrometastases, their association with distant metastases, and their relationship with other pathologic prognostic features. All slides were stained with keratin AE1/3. Micrometastases were confirmed with Ber-Ep4. Three immunohistochemically detected lymph node micrometastases were identified in three of 80 consecutively accrued patients (4%). These three positive stains constituted 0.5% of the 573 stains required to immunohistochemically screen all of the lymph node blocks from these patients. Among the 39 patients who were selected because they developed distant metastases, three immunohistochemically detected lymph node micrometastases from three patients were identified, which constituted 8% of patients in this group and 1% of the 280 stains required to screen all of these patients' lymph nodes. Small vessel invasion, maximum tumor dimension, and immunohistochemically detected lymph node micrometastases were independently associated with metastases on multivariate analysis. Among patients who developed metastases, there was no significant difference in the disease-free survival rate between those with and those without immunohistochemically detected lymph node micrometastases. Given the low sensitivity in terms of the number of immunohistochemical stains performed, and the prognostic significance of standard histologic features, the use of immunohistochemical screening lymph nodes from all patients with T1, N0, M0 adenocarcinomas is questionable.

[Concentration of heavy elements and their compounds in the cells from BALF and pulmonary tumors in radiation-exposed subjects]. / Soderzhanie tiazhelykh élementov i ikh soedinenii v kletkakh bronkhoaal'veoliarnykh smyvov i v tkaniakh opukholei legkikh u lits, podvergavshikhsia radiatsionnomu vozdeistviiu.

AIM: Measurement of heavy elements in alveolar macrophages (AM) of bronchoalveolar lavage (BAL) and pulmonary tumor tissue (PTT); investigation of spacial distribution of the heavy particles in the tissues. MATERIALS AND METHODS: Laser mass-spectrometry estimated quantitative and qualitative characteristics of heavy elements (Mn, Fe, Co, Cu, Zr, etc.) in diagnostic and therapeutic BAL of 6 patients exposed to radiation after the Chernobyl accident and in pulmonary tumor tissue of patients operated for central small-cell and peripheral bronchoalveolar cancer who also had been exposed to radiation after the Chernobyl. RESULTS: Heavy elements concentration in the secondary BAL was less than in the primary one. This shows effectiveness of the procedures aimed at removal of heavy particles from the respiratory organs. Heavy elements content was quite different in two histologically different tumors. CONCLUSION: Laser mass-spectrometry proved its usefulness in simultaneous study of the quantity and quality of heavy elements in AM of BAL and tumors in radiation-exposed subjects, in investigation of the elements distribution in the pulmonary tissues and changes of elements composition in the tissues in the course of tumors development.

The role of pRb2/p130 protein in diagnosing lung carcinoma on fine needle aspiration biopsies.

The retinoblastoma gene family is composed of three members: the retinoblastoma gene, one of the most studied tumor suppressor genes, and two related genes: p107 and pRb2/p130. These proteins are also known as the pocket proteins due to a unique structural and functional domain composed of subdomains A and B separated by a spacer region that is highly conserved among each of the proteins. These proteins exhibit unique growth suppressive properties that are cell type specific, suggesting that although the pocket proteins may complement each other, they are not fully functionally redundant. With the development of antibodies recognizing these three proteins it is now possible to detect expression in formalin-embedded specimens. Recent studies on 235 lung cancers, using immunohistochemical techniques, suggested an independent role for Rb2/p130 in the development and/or progression of human lung carcinoma. We found a statistically significant inverse relationship between the histological grading (degree of malignant potential) and the expression of pRb/p105, p107 and pRb2/p130 in squamous cell carcinomas, meaning that an increase in grading resulted in a significant decrease in protein expression. This phenomenon was particularly evident for pRb2/p130 (p < .0001) which had the highest percentage of undetectable levels in all the specimens examined and the tightest inverse correlation (p value) with both the histological grading and PCNA expression in the most aggressive tumor types, suggesting an important role for pRb2/p130 in the pathogenesis and progression of certain lung cancers. We further explored the expression of pRb2/p130 protein in routine archival FNAB cytological material from 30 Patients with lung cancer using immunocytochemical techniques, comparing protein expression with tumor type. Two pathologists evaluated the staining pattern and scored the percentage of positive cells. Of the 30 neoplasms, 27 displayed a positive staining for pRb2/p130. In particular, we detected pRb2/p130 in 9 (100%) squamous carcinomas, 11 (84%) adenocarcinomas, 5 (100%) BAC, and 2 (66%) SCC. The percentage of positive nuclei varied in different tumors with the highest expression level in adenocarcinomas. Immunocytochemistry represents a sensitive method for detection of pRb2/p130 expression in cytological or archival specimens, and the level of detection seems to be comparable to paraffin sections. Therefore, this methodology could be used in the preoperative evaluation of routine cytological specimens in order to improve the diagnostic and prognostic evaluation of lung cancer patients.