Bronchioloalveolar Carcinoma Research Articles

Adenocarcinomas With Prominent Lepidic Spread

Recently, a new classification of lung adenocarcinomas has been proposed for tumors with lepidic spread. The greatest diameter of the invasive component determines minimally invasive cancers, and the term bronchioloalveolar carcinoma is no longer used. We retrospectively reviewed 87 resected adenocarcinomas of the lung; 30 tumors with lepidic growth and without high-grade invasive areas were identified, and the invasive component was measured morphometrically and categorized. A dimension of 5 mm was the cutoff for invasion. Regional lymph node involvement and short-term follow-up were compared among subtypes of these well-differentiated and moderately differentiated adenocarcinomas. There were 11 well-differentiated adenocarcinomas with lepidic growth: 3 adenocarcinomas in situ (nonmucinous) and 8 minimally invasive adenocarcinomas (MIAs) (4 mucinous and 4 nonmucinous). There were 19 invasive moderately differentiated adenocarcinomas with a prominent lepidic growth pattern (LPAs). The mean size of the 3 adenocarcinomas in situ cases was 0.9±0.7 mm; the total size of the 8 MIA cases was 1.4±1.8 cm and that of the 19 LPA cases was 3.2±2.1 cm. The invasive size of the MIA was 0.3±0.6 and that of the LPA was 2.2±0.3. The invasive pattern of the LPAs was papillary and acinar without desmoplasia (n=3) and acinar with desmoplasia (n=16). Seven of the invasive desmoplastic tumors showed complex single-cell invasion or lymphatic invasion. Identification of the transition from lepidic to invasive acinar was straightforward because of the presence of elastotic desmoplasia. The transition between complex acinar papillary invasion and lepidic growth was often difficult to discern. Lymph node metastases were present in 5 cases (26%), all in tumors with an acinar, desmoplastic invasive component of >1 cm, with areas of single-cell invasion. With follow-up, progressive nodal involvement or distant metastases occurred in 4 patients, all with complex invasive patterns; 3 with invasion >1 cm and 1 with lymphatic invasion in smaller invasive tumors. Recurrent lung nodules occurred in 5 patients, including 1 patient with MIA, 1 with nondesmoplastic invasion, 2 with desmoplastic invasion, and 1 with complex desmoplastic invasion. Approximately one third of lung adenocarcinomas have significant lepidic spread, and of these nearly one third are minimally invasive. Measurement of the invasive component may be difficult without elastotic desmoplasia. In this small series, lymph node and distant metastases occurred only in those with complex invasive patterns, but lung recurrence occurred in all subtypes, including MIAs.

A population-based cohort study of chest x-ray screening in smokers: lung cancer detection findings and follow-up.

BackgroundCase-control studies of mass screening for lung cancer (LC) by chest x-rays (CXR) performed in the 1990s in scarcely defined Japanese target populations indicated significant mortality reductions, but these results are yet to be confirmed in western countries. To ascertain whether CXR screening decreases LC mortality at community level, we studied a clearly defined population-based cohort of smokers invited to screening. We present here the LC detection results and the 10-year survival rates.MethodsThe cohort of all smokers of > 10 pack-years resident in 50 communities of Varese, screening-eligible (n = 5,815), in July 1997 was invited to nonrandomized CXR screening. Self-selected participants (21% of cohort) underwent screening in addition to usual care; nonparticipants received usual care. The cohort was followed-up until December 2010. Kaplan-Meier LC-specific survival was estimated in participants, in nonparticipants, in the whole cohort, and in an uninvited, unscreened population (control group).ResultsOver the initial 9.5 years of study, 67 LCs were diagnosed in screening participants (51% were screen-detected) and 178 in nonparticipants. The rates of stage I LC, resectability and 5-year survival were nearly twice as high in participants (32% stage I; 48% resected; 30.5% 5-year survival) as in nonparticipants (17% stage I; 27% resected; 13.5% 5-year survival). There were no bronchioloalveolar carcinomas among screen-detected cancers, and median volume doubling time of incidence screen-detected LCs was 80 days (range, 44-318), suggesting that screening overdiagnosis was minimal. The 10-year LC-specific survival was greater in screening participants than in nonparticipants (log-rank, p = 0.005), and greater in the whole cohort invited to screening than in the control group (log-rank, p = 0.001). This favourable long-term effect was independently related to CXR screening exposure.ConclusionIn the setting of CXR screening offered to a population-based cohort of smokers, screening participants who were diagnosed with LC had more frequently early-stage resectable disease and significantly enhanced long-term LC survival. These results translated into enhanced 10-year LC survival, independently related to CXR screening exposure, in the entire population-based cohort. Whether increased long-term LC-specific survival in the cohort corresponds to mortality reduction remains to be evaluated.Trial registration numberISRCTN90639073

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.

Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma

Classification of adenocarcinoma has undergone recent evaluation to better align histological classification with clinical outcomes. One terminology, in particular, that of bronchioloalveolar carcinoma (BAC), has been debated for many decades. Although initial discussion surrounded the cell-of-origin of this tumor, more recent confusion has been generated from the use of this term both as a pattern of growth within an otherwise invasive adenocarcinoma and as a term for a pre-invasive tumor synonymous with adenocarcinoma in situ. As a result, adenocarcinomas with quite different radiology, gross morphology and metastatic potential have been associated with the BAC term. Focusing on invasion and using an illustrative case, we will explore the current recommendations that incorporate assessment of invasion to clarify the confusion caused by the different uses of the historical term ‘BAC'.

The Long-term Survival of a Patient with Adenosquamous Lung Carcinoma Harboring EGFR-activating Mutations Who was Treated with Gefitinib

A 56-year-old woman diagnosed with squamous cell lung carcinoma after a transbronchoscopic examination underwent left upper lobectomy, which revealed a pathological diagnosis of adenosquamous carcinoma containing moderately differentiated squamous cell carcinoma and bronchioloalveolar carcinoma. The epidermal growth factor receptor (EGFR) exon 19 delE746-A750 mutation was detected in deoxyribonucleic acid (DNA) isolated from specimens of both components using microdissection. Treatment with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in a long-term tumor response lasting three years. Adenosquamous carcinoma is difficult to diagnose using transbronchoscopic procedures. Therefore, the examination of EGFR mutation status is important in order to determine the appropriate treatment, even in patients with non-adenocarcinoma.

The Role of KRAS Mutational Analysis to Determine the Site of Origin of Metastatic Carcinoma to the Lung: A Case Report

Metastatic carcinomas involving the lung are a common specimen encountered in surgical pathology. These metastases may have different morphologic, and architectural patterns and may mimic primary pulmonary adenocarcinoma, especially the intra-alveolar (lepidic) pattern of spread which may simulate a primary pulmonary bronchioloalveolar carcinoma (adenocarcinoma in situ). We present the case of a metastatic pancreatic adenocarcinoma that morphologically mimicked bronchioloalveolar carcinoma of the lung in that the tumor had an exclusive intra-alveolar pattern of spread and had an immunophenotype that was noninformative as to the site of origin (cytokeratin 7+, cytokeratin 20−, TTF-1−). In this case, we used KRAS gene mutation analysis to support that the lung carcinoma represented a metastatic pancreatic carcinoma as they both possessed identical codon 12 KRAS mutations. We show that this method may be a useful way to prove site of origin of metastatic carcinoma—particularly if standard morphologic or immunohistochemical analysis is not definitive.

Papillary carcinoma of thyroid metastatic to adenocarcinoma in situ of lung: report of an unusual case.

The tumor-to-tumor metastasis is a rare event. The lung tumors are the most common donor tumors in tumor-to-tumor metastasis, but are exceedingly rare as a recipient. Here, we report a case of papillary thyroid carcinoma (PTC) metastasizing to adenocarcinoma in situ (AIS, formerly bronchioloalveolar carcinoma) of the lung in a 44-year-old woman who underwent total thyroidectomy for PTC 8 years ago. To the best of our knowledge, the present case is the first case reporting on PTC metastasized to AIS. A review of the relevant literature is presented.

INCIDENTAL EARLY LUNG ADENOCARCINOMA AFTER SURGERY FOR CATAMENIAL PNEUMOTHORAX

A 40-year-old female patient underwent surgery at our hospital for recurrent pneumothorax. A defect on the right diaphragm was diagnosed as ectopic endometriosis. However, air leakage continued 2 days after surgery. Chest computed tomography identified a 5-mm ground glass opacity in the right S3 field, suggestive of lung cancer. Ten days after the initial surgery, she underwent curative surgery for both pneumothorax and the lung tumor. The tumor was diagnosed as bronchioloalveolar carcinoma, but no other endometriosis was identified. The patient has remained well with no recurrence of lung cancer or pneumothorax since the second surgery.

Pneumonic-type Adenocarcinoma with Dissemination Similar to That of Bronchioloalveolar Carcinoma

背景．気道を介した病変の多発・両側性進展（aerogenous dissemination）は細気管支肺胞上皮癌に典型的であるが，腺癌でも同様の進展を示す場合があり，肺炎型肺腺癌として報告されている．症例．65歳，男性．血痰を主訴に受診，喀痰細胞診で腺癌と診断された．胸部X線写真で，右下葉に一致した肺炎様硬化像を認め，胸部CTでは右下葉内に嚢胞性変化を伴った病変であり，中葉にもわずかに陰影がみられた．術中所見で肉眼的に中葉に異常を認めず，右下葉切除，リンパ節郭清を施行，pT2N0M0，ステージIB期であった．術後UFTを内服していたが，4ヵ月目で中葉病変が拡大し，対側にも病変が出現したため化学療法を開始した．しかしその後も病変は拡大し，レジメンを変更して化学療法を継続したが治療抵抗性であり，術後1年5ヵ月で癌死した．結論．腺癌には，肺胞上皮癌と同様の進展を示す肺炎型肺腺癌が存在する．特異的な臨床経過を示し，予後不良なため注意が必要である．

Expression of Transforming Growth Factor β1 and Cadherins in Lung Adenocarcinoma

Purpose: There is evidence supporting the concept of tumor progression from pulmonary adenocarcinoma in situ (formerly bronchioloalveolar carcinoma, BAC) to adenocarcinoma with varying degrees of invasion. The aim of this study was to investigate the role of transforming growth factor β1 (TGFβ1) in tumor invasiveness in lung adenocarcinoma, and to determine the potential relationships between its expression and immunophenotypes of cell adhesion molecules. Materials and Methods: Tumor samples from adenocarcinoma in situ (n=13), minimally invasive adenocarcinoma (formerly BAC with ≤5 mm invasion, n=2), and lepidic predominant invasive adenocarcinoma (formerly mixed adenocarcinoma showing non-mucinous BAC features with >5 mm invasion, n=25) were examined for the expression of TGF β1, E-cadherin, N-cadherin, and H-cadherin proteins using immunohistochemistry. Results: Of a total of 40 cases, 25 (63%) were positive for TGFβ1. The frequency of immunoreactivity in patients with adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma was 23% (3/13), 50% (1/2), and 84% (21/25), respectively (p=0.001). TGF β1 correlated with T classification (p=0.006) and stage (p=0.001). Loss of E-cadherin expression was more frequently observed in invasive adenocarcinomas than in adenocarcinomas in situ (p=0.034). E-cadherin expression inversely correlated with T classification (p=0.009). TGFβ1 expression showed a statistically significant correlation with H-cadherin expression (p=0.040), but not with E-cadherin expression (p=0.752). Conclusion: These results suggest that TGFβ1 and E-cadherin may play an important role in invasive progression of lung adenocarcinoma through regulating epithelial-to-mesenchymal transition. (J Lung Cancer 2012;11(1):38�� 44)

Mesenchymal Hamartoma: Prenatal and Postnatal Diagnosis by Imaging

We present a case of a twin pregnancy in which one fetus developed a rapidly growing unilateral intrathoracic tumor. While a cystic adenomatoid malformation was suspected in the ultrasound scan, the magnetic resonance scan suggested a pulmonary blastoma or a bronchioalveolar carcinoma. Postnatal chest radiography and contrast-enhanced computed tomography of the affected newborn were performed, and it was ruled out the possibility of malignant origin. Finally, the anatomopathologic exam revealed the presence of a mesenchymal hamartoma in the chest wall. Nevertheless, parents refused any treatment for the newborn.

肺炎治療後の浸潤影で発見された細気管支肺胞上皮癌の1例

肺炎治療後の浸潤影で発見された細気管支肺胞上皮癌の1例

Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for Small Pulmonary Lesions with Ground-Glass Attenuation

The aim of this study was to investigate the diagnostic value of percutaneous computed tomography (CT)-guided coaxial transthoracic needle biopsy (TNB) for small pulmonary lesions (≤ 3 cm) with persistent ground-glass opacity (GGO). From January 2004 to February 2010, consecutive patients with persistent small GGO lesions (≤ 3 cm) who underwent CT-guided TNB were analyzed. The pathologic results of CT-guided TNB were compared with final diagnoses, and the GGO percentage on CT was correlated with the stromal invasion in surgical pathology. We performed CT-guided TNB on 1612 patients during the study period. Among them, 55 patients had persistent small GGO lesions (size range 0.5-3.0 cm; 1.72 ± 0.73 cm), 47 were diagnosed with lung adenocarcinomas, and 8 with benign nonspecific lesions. Minor procedure-related complications occurred in 26 patients (47.3%) with small pneumothorax and 11 patients (20.0%) with self-limited mild hemoptysis. The final diagnoses of the 43 patients receiving lobectomy were invasive adenocarcinoma (n = 23), pure bronchioloalveolar carcinoma (n = 19), and mucosa-associated lymphoid tissue lymphoma (n = 1). The diagnostic accuracy was 93.0% (40/43) using CT-guided TNB. Pure GGO lesions had a higher incidence of pure bronchioloalveolar carcinoma than GGO-dominant lesions (70.0% versus 21.7%; p = 0.004). Compared with surgical pathology, stromal invasion was underestimated in 43.5% (10/23) of the TNB specimens, especially in pure GGO lesions (83%, 5/6). In logistic regression analysis, the GGO percentage correlated inversely with stromal tumor invasion (p = 0.0028). CT-guided coaxial TNB is a safe and useful method for diagnosing small (≤ 3 cm) persistent GGO lesions. Stromal invasion may be underestimated by TNB in GGO lesions.

New classification of adenocarcinoma: what radiologists need to know

The International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society recently introduced a new classification of lung adenocarcinoma addressing the latest advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma. In this classification, new uniform terminology and diagnostic criteria are described, including the introduction of adenocarcinoma in situ as a second preinvasive lesion, as well as the concept of minimally-invasive adenocarcinoma and new subtyping of invasive adenocarcinomas stratified according to predominant patterns. In addition, the previously widely-used term bronchioloalveolar carcinoma is no longer considered valid and has been recategorized. This classification also provides, for the first time, guidance for small biopsies and cytology specimens. This new classification has profound implications for radiology, as much investigation will be needed to correlate these newly introduced concepts (such as histologic subtypes) with radiologic features. Understanding the newly described concept of minimally-invasive adenocarcinoma will be essential in determining sublobar resection for adenocarcinomas. In this manuscript, we briefly review the new classification of lung adenocarcinoma and discuss its radiologic relevance to the reporting, biopsy, and future studies of adenocarcinoma.

Congenital pulmonary airway malformation with mucoepidermoid carcinoma: A case report and review of literature

Congenital cystic adenomatoid malformations (CCAM) are rare developmental anomalies of the lung characterized by cysts of varying sizes and/or adenomatoid proliferation. Type I CCAM, the most frequent subtype, is associated with an increased incidence of malignant transformation, principally bronchioloalveolar carcinoma, with a reported incidence of around 1%. We report the first case of mucoepidermoid carcinoma arising in a type 1 CCAM.

Carcinome bronchioloalvéolaire et transplantation pulmonaire

Bronchiolo-alveolar carcinoma is a controversial indication for lung transplantation because of the risk of recurrence. We report three cases and propose some risk factors for recurrence. Our study concerns three patients transplanted at the Louis-Pradel Hospital between 1991 and 2010. The first patient relapsed 86 months after transplantation, benefited from surgical treatment, then died of renal failure. A second patient died of infection, without recurrence, 72 months after transplantation. The third had an early recurrence at 7 months and died 27 months after transplantation. The risk factors for recurrence appear to be: clinically "aggressive" presentation and histological stromal pulmonary invasion by the carcinoma. Diffuse bronchiolo-alveolar carcinoma is a possible indication of lung transplantation. The risk of recurrence imposes some requirements: a precise histological diagnosis and a slow clinical course.

Bronchioloalveolar differentiation in lung adenocarcinomas.

The goals of the study were to determine what percentage of neoplasms with a bronchioloalveolar (BAC) component were considered pure BAC by current World Health Organization (WHO) criteria. Next, we wanted to determine the number of mucinous BACs using histochemical staining with Alcian Blue PAS. Finally, we aimed to elucidate by immunohistochemistry the thyroid transcription factor-1 (TTF-1) frequency and cytokeratin 7 (CK7) expression, particularly in regard to the mucinous and non-mucinous subtypes of BAC tumors. We made a retrospective review of Hematoxylin and Eosin stained slides and classification of histologic grade, tumor subtype, and percentage of pure BAC pattern, with further characterization by histochemical staining for Alcian Blue PAS and Immunohistochemical staining for thyroid TTF-1 and CK7. Only 10 of 30 tumors examined could be classified as BAC by current strict WHO criteria. Nine cases were classified into non-mucinous and only one case was recognized as mucinous BAC, which showed positive staining for Alcian Blue PAS. TTF-1 positivity was in 100% of the non-mucinous BACs and complete absence of staining was in one case of mucinous BACs. CK7 expression in bronchioloalveolar carcinoma has demonstrated CK7 marked staining in 90% of non-mucinous BACs, also one case of mucinous BACs showed marked staining for TTF-1. BACs of mucinous morphology were notable for their conspicuous absence of TTF-1 immunoreactivity.

Clinical analysis of nodular ground- glass opacity appearance of lung cancer on computerized tomography (CT)

The aim of the study is to investigate the diagnosis and treatment of patients who had appearance of nodular ground- glass opacity (NGGO) on computerized tomographic (CT). We retrospectively analyzed 14 cases who appeared NGGO on thin section CT: Male 5, female 9, aged from 31 to 76 years, average 56.3 years old; NGGO diameter was 1.0 to 3.0 cm, average 2.1 cm. Among all the cases, 12 patients have solid parts in the center, called mixed nodular ground- glass opacity (MNGGO). All the cases accepted operations of lobe resection, and were followed up for 4 to 24 months. The pathologic diagnosis of all the cases were malignant, 3 were adenocarcinoma while 11 were bronchioloalveolar carcinoma. All the cases did not find the metastasis of lymph node or far organ, and were alive in the period of following up. Most of the MNGGO were malignant, and it is better for the patients to receive an operation. For pure nodular ground-glass opacity (PNGGO), we suggested the patients should be followed up for 3 month; if the PNGGO did not absorbed, or even became larger, or started to consolidate, operation should be done as soon as possible. Key words: Lung cancer, nodular ground-glass opacity, operation.

Expression of ER stress and autophagy‐related molecules in human non‐small cell lung cancer and premalignant lesions

Stress that impairs endoplasmic reticulum (ER) function leads to an accumulation of unfolded or misfolded proteins in the ER (ER stress). Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles, which emerging data indicate that ER stress is also a potent inducer of autophagy. ER stress and autophagy are involved in human cancer. We examined the expression of ER stress-related proteins [GRP78 and C/EBP homologous protein (CHOP)] and autophagic proteins (Beclin-1 and LC3) in non-small cell lung carcinomas (NSCLCs), bronchioloalveolar carcinomas (BACs) and atypical adenomatous hyperplasias (AAHs) to understand their role in the NSCLC pathogenesis. The expression of GRP78 and CHOP, Beclin-1 and LC3 were analyzed using immunohistochemistry on tissue sections from 133 NSCLC (69 squamous cell carcinomas, 56 adenocarcinomas (AC) and eight other NSCLCs), 21 BAC and 9 AAH. Expression of GRP78 and Beclin-1 was correlated with low tumor stage (p < 0.001 and p = 0.019, respectively) and longer survival (p = 0.007 and p <0.001, respectively) by Kaplan-Meier analysis. However, CHOP was correlated with high tumor stage (p = 0.038) and shorter survival (p = 0.012). Expression of GRP78 and Beclin-1 was positively correlated (p = 0.006). Our study showed that the expression of GRP78, CHOP, Beclin-1 and LC3 in lung cancer and its relation with clinicopathologic factors and patients survival. These results suggest that GRP78, CHOP and Beclin-1 may play an important role in tumorigenesis of lung AC and may serve as new prognostic indicators for outcome of the patients with NSCLC.

Epidermal growth factor receptor (EGFR) mutations in a series of non-small-cell lung cancer (NSCLC) patients and response rate to EGFR-specific tyrosine kinase inhibitors (TKIs)

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes.