Excellent Prognosis of Patients With Invasive Lung Adenocarcinomas During Surgery Misdiagnosed as Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, or Minimally Invasive Adenocarcinoma by Frozen Section.

BACKGROUND: Our previous study revealed that intraoperative frozen section (FS) analysis could differentiate invasive lung adenocarcinoma (LUAD) accurately from preinvasive lesions. However, few articles have analyzed the clinical impact of FS errors such as underestimation of invasive adenocarcinomas (IACs), and whether complementary therapy is needed remains controversial. RESEARCH QUESTION: What is the prognosis of patients undergoing limited resection for invasive LUAD misdiagnosed as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive adenocarcinoma (MIA) by intraoperative FS analysis? STUDY DESIGN AND METHODS: From 2012 through 2018, data on 3031 patients undergoing sublobar resection of AAH, AIS, or MIA diagnosed by FS analysis were collected. The concordance rate between FS analysis and final pathologic results was evaluated. To assess the clinical significance of a discrepancy between FS and final pathologic results, patients with final pathologic results of IAC were identified for prognostic evaluation. RESULTS: When AAH, AIS, and MIA were classified together as a group, the overall concordance rate between FS and final pathologic results was 93.7%, and 192 patients (6.3%) received an upgraded diagnosis from the final pathologic results. Misdiagnosed IACs consisted of 94 patients (48.9%) with lepidic-predominant adenocarcinoma, 77 patients (40.1%) with acinar predominant adenocarcinoma, 19 patients (9.9%) with papillary predominant adenocarcinoma, one patient with solid predominant adenocarcinoma, and one patient with invasive mucinous adenocarcinoma. Among these patients, no positive N1 or N2 lymph node findings were observed. Moreover, the 5-year recurrence-free survival was still 100%, although the final pathologic results turned out to be IAC. INTERPRETATION: Patients undergoing limited resection of invasive LUAD misdiagnosed as AAH, AIS, or MIA by FS analysis showed excellent prognoses. Sublobar resection guided by FS diagnosis would be adequate for these underestimated cases of invasive LUAD.

Foxp3+ Regulatory T Cells Associated With CCL17/CCR4 Expression in Carcinomas of Dogs.

Regulatory T cells (Tregs) can be targeted in cancer immunotherapy. A previous study has shown that the chemokine CCL17 and the receptor CCR4 play a role in Treg recruitment in canine urothelial carcinoma. Here, we describe the association of tumor-infiltrating Tregs with CCL17/CCR4 expression in dogs with other carcinomas. In this study, we investigated 23 dogs with mammary carcinoma, 14 dogs with oral squamous cell carcinoma, 16 dogs with pulmonary adenocarcinoma, and 8 healthy control dogs. Immunohistochemistry showed that Foxp3+ Tregs and CCR4+ cells were increased in the tumor tissues of mammary carcinoma, squamous cell carcinoma, and pulmonary adenocarcinoma, when compared with the healthy tissues. The number of CCR4+ cells was associated with that of Foxp3+ Tregs. Double immunofluorescence labeling confirmed that most tumor-infiltrating Foxp3+ Tregs expressed CCR4. In vitro, canine carcinoma cell lines expressed CCL17 mRNA. Quantitative RT-PCR (reverse transcriptase-polymerase chain reaction) showed that CCL17 mRNA expression in canine carcinomas was increased approximately 10- to 25-fold relative to that of healthy tissues. These results suggest that the CCL17/CCR4 axis may drive Treg recruitment in a variety of canine carcinomas. CCR4 blockade may be a potential therapeutic option for tumor eradication through Treg depletion.

Glycine supplementation extends lifespan of male and female mice.

Diets low in methionine extend lifespan of rodents, though through unknown mechanisms. Glycine can mitigate methionine toxicity, and a small prior study has suggested that supplemental glycine could extend lifespan of Fischer 344 rats. We therefore evaluated the effects of an 8% glycine diet on lifespan and pathology of genetically heterogeneous mice in the context of the Interventions Testing Program. Elevated glycine led to a small (4%-6%) but statistically significant lifespan increase, as well as an increase in maximum lifespan, in both males (p = 0.002) and females (p < 0.001). Pooling across sex, glycine increased lifespan at each of the three independent sites, with significance at p = 0.01, 0.053, and 0.03, respectively. Glycine-supplemented females were lighter than controls, but there was no effect on weight in males. End-of-life necropsies suggested that glycine-treated mice were less likely than controls to die of pulmonary adenocarcinoma (p = 0.03). Of the 40 varieties of incidental pathology evaluated in these mice, none were increased to a significant degree by the glycine-supplemented diet. In parallel analyses of the same cohort, we found no benefits from TM5441 (an inhibitor of PAI-1, the primary inhibitor of tissue and urokinase plasminogen activators), inulin (a source of soluble fiber), or aspirin at either of two doses. Our glycine results strengthen the idea that modulation of dietary amino acid levels can increase healthy lifespan in mice, and provide a foundation for further investigation of dietary effects on aging and late-life diseases.

[The new classification of lung adenocarcinoma]. / Adenokarzinome der Lunge--die neue Klassifikation.

The new, interdisciplinary IASLC/ATS/ERS classification of lung adenocarcinoma has achieved a considerable impact since its publication in the year 2011. It separates tumours into preinvasive, minimally invasive and invasive subtypes. The preinvasive lesions atypical, adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) together with the minimally invasive adenocarcinoma (MIA), have an excellent prognosis after complete resection with 100 % survival. It enables a reproducible tumour grading by the determination of the predominant histological growth pattern which could be confirmed in several follow-up studies. Thereby the mixed subtype was eliminated which formerly represented about 80 % of all adenocarcinomas. Similarly, the terms bronchioloalveolar adenocarcinoma and bronchioloalveolar tumour growth were eliminated because they represented several distinct entities, specifically the in-situ lesions AAH and ACIS as well as the non-in-situ/invasive tumours like minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma (LPA) and invasive mucinous adenocarcinoma (IMA). Although the classification is based on data from tumour resections it accommodates the fact that most tumours are diagnosed on biopsies and cytological specimens and includes recommendations for an efficient work-up to preserve tissue for molecular testing. Furthermore, the morphological analysis may provide hints for molecular changes including mutations with therapeutic relevance that may enable targeted molecular diagnostics. This review presents essentials facts of the new classification that will be part of the next WHO classification of lung tumors and its follow-up publications.

[Preneoplastic lesions of pulmonary carcinoma]. / Vorläuferläsionen des Lungenkarzinoms.

The World Health Organization (WHO) 2004 classification includes 3 categories of pulmonary preneoplastic lesions, including squamous dysplasia and carcinoma in situ (CIS) for squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) for the majority of adenocarcinomas and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) for carcinoids. The distinction of the 3 grades of squamous dysplasia and CIS is mainly based on the degree by which the basal cell zone is expanded, the degree of cellular atypia and the level of mitoses. The category AAH consists of a proliferation of atypical epithelial cells with Clara cells or type 2 pneumocyte features. They grow along the alveolar septae in a lepidic fashion, sometimes reaching into the terminal bronchioles. In contrast to the newly described adenocarcinoma in situ (AIS), AAH is smaller (≤ 5 mm), has a lower cell density and a lower degree of cellular atypia. The putative cancer stem cells of peripheral adenocarcinomas reside in the bronchioloalveolar duct junction, while those of central squamous cell carcinomas are located in the basal cell compartment of the bronchi. This review provides an overview of the current knowledge on preneoplastic lesions of the lungs and their clinical impact.

Localization of the invadopodia-related proteins actinin-1 and cortactin to matrix-contact-side cytoplasm of cancer cells in surgically resected lung adenocarcinomas.

OBJECTIVES: Actin-associated proteins at cell-matrix-contact sites form invadopodia in cancer cells and participate in migration, matrix degradation and invasion. We investigated an alteration of subcellular localization of invadopodia-related actin-associated proteins, actinin-1 and cortactin, in lung adenocarcinomas, its clinical significance, and its possible regulatory factors. METHODS: Invadopodia-related proteins, actinin-1 and cortactin, were immunohistochemically examined in 90 cases of lung adenocarcinomas. Expression of invadopodia-associated proteins and their possible regulators in lung adenocarcinomas were examined by real-time RT-PCR, database search, and immunohistochemistry. RESULTS: Actinin-1 and cortactin showed matrix-contact-side localization in adenocarcinoma cells, but rarely in normal bronchiolar epithelial cells, alveolar cells, or precursor lesion atypical adenomatous hyperplasia cells. Immunoelectron-microscopic examination of adenocarcinoma cells revealed actinin-1 localization to matrix-contact-side cytoplasm with cytoplasmic protrusions. Matrix-contact-side localization of actinin-1 and cortactin was correlated with tumor stages, lymph node metastasis, vascular permeation, and loss of basement membrane. The tumor-specific survival rate was worse for the group in which matrix-contact-side localization of cortactin was high than for the low group. mRNA of the Rho guanine exchange factor epithelial cell transforming sequence-2 (Ect2) tended to be overexpressed in lung adenocarcinomas and cytoplasmic expression of Ect2 tended to be correlated with matrix-contact-side localization of actinin-1. CONCLUSION: Matrix-contact-side localization of invadopodia-related proteins in the lung adenocarcinoma cells were correlated with invasion, metastasis, and poor prognosis. Ect2 was a possible regulator of matrix-contact-side localization of invadopodia-related proteins.

Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung.

INTRODUCTION: A progression model of atypical adenomatous hyperplasia (AAH) to bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma (ADC) has been proposed. However, the genetic alterations of the AAH-BAC-ADC sequence are not clearly established. We examined the mutation of the epidermal growth factor receptor (EGFR) gene and p53 protein overexpression in the AAH, BAC, and small ADC to understand their role in the pulmonary ADC pathogenesis. METHODS: Twenty AAH, 43 BAC (21 Noguchi type A and 22 type B), and 47 small ADC (Noguchi type C) were enrolled in this study. EGFR mutations at exons 18-21 and p53 protein overexpression were examined by polymerase chain reaction-direct sequencing and immunohistochemistry, respectively. RESULTS: Mutations of the EGFR gene were noted in 45 (40.9%) lesions, which included 7 (35.0%) of AAH, 15 (34.9%) of BAC, and 23 (48.9%) of ADC. Twenty-six (23.6%) of the mutations were detected as exon 19 deletion, 18 (16.4%) as exon 21 point mutation, and 1 (0.9%) as exon 18 point mutation. Overexpression of p53 protein was found in 19 (17.2%) lesions, none of AAH, 4 (9.8%) of BAC, and 15 (31.9%) of ADC. Multivariate analysis showed that p53 overexpression was associated with invasive ADC (P = 0.003). CONCLUSIONS: High frequency and similar incidence of EGFR mutation in AAH, BAC, and ADC support that EGFR gene mutation occurs in the early stage of pulmonary ADC development and tumor initiation from the preneoplastic lung parenchyma to neoplastic conditions. On the contrary, p53 overexpression is a late event during tumor development and plays a role in the progression of the peripheral pulmonary ADC.

Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung.

INTRODUCTION: We investigated EGFR and KRAS alterations among atypical adenomatous hyperplasia and small lung adenocarcinomas with bronchioloalveolar features to understand their role during multistage pathogenesis. METHODS: Sixty lesions measuring 2 cm or less were studied, including 38 noninvasive lesions (4 atypical adenomatous hyperplasias, 19 Noguchi type A and 15 type B) and 22 invasive lesions (type C) based on the World Health Organization classification and Noguchi's criteria. EGFR and KRAS mutations were examined using PCR-based assays. EGFR copy number was evaluated using fluorescence in situ hybridization. RESULTS: EGFR and KRAS mutations were found in 26 (43.3%) and 5 (8.3%) lesions, respectively. Increased EGFR copy number status was identified in 10 lesions (16.7%), both mutant and wild type. EGFR or KRAS mutations were present in 39.5% and 7.9% (respectively) of noninvasive lesions and 50% or 9.1% (respectively) of invasive lesions. EGFR copy number was increased in 7.9% and 31.8% of noninvasive and invasive lesions (P = 0.029). Multivariate analysis revealed that increased EGFR copy number was the only significant factor to associate with invasive lesions (P = 0.035). CONCLUSIONS: EGFR and KRAS mutations occur early during the multistage pathogenesis of peripheral lung adenocarcinomas. By contrast, increased EGFR copy number is a late event during tumor development and plays a role in the progression of lung adenocarcinoma independent of the initiating molecular events.

Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias.

The pulmonary adenoma susceptibility 1 (Pas1) gene affects susceptibility to the development of lung adenomas in mice with a subset of the adenomas progressing to adenocarcinoma (ADC). In this study, genotype distributions for 10 polymorphisms in the human counterparts for three mouse candidate Pas1 genes, KRAS, CASC1/LAS1 and LRMP, were examined in a hospital-based case-control study consisting of 364 lung ADC cases and 253 controls. All the ADC cases were subjected to lobectomy and subsequent pathological investigation of atypical adenomatous hyperplasia (AAH), a putative precursor for peripheral lung ADC, including bronchioloalveolar carcinoma, in the resected lobes. Eighty-one (22%) of the ADC cases carried at least one AAH lesion in addition to the primary ADC and 34 (9%) of them carried multiple AAH lesions. None of the 10 polymorphisms examined showed significant associations with overall lung ADC risk (P > 0.05). However, minor allele carriers for two polymorphisms in the KRAS gene, KRAS-1 and -6, showed significantly increased odds ratios (ORs) for ADC accompanied by multiple AAHs [OR = 3.0; 95% confidence interval (CI) = 1.4-6.2, P = 0.004 and OR = 2.4; 95% CI = 1.1-4.7, P = 0.02, respectively]. Minor haplotypes including the minor allele for the KRAS-6 polymorphism showed increased ORs for ADC accompanied by multiple AAHs, and KRAS transcripts from the minor allele for this polymorphism were more abundantly detected in lung tissues than those from the major allele. Thus, KRAS polymorphisms were indicated to be involved in risk for the development of AAHs that progress to ADC by causing differential KRAS oncogene expression in the lungs.

A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis.

Atypical adenomatous hyperplasia (AAH) is considered the preinvasive lesion of pulmonary adenocarcinoma, and mutations of EGFR, HER2, and K-ras are involved in the early stage of lung adenocarcinoma carcinogenesis, also predicting clinical response to anti-EGFR small molecule inhibitors. We analyzed 18 cases of primary lung adenocarcinoma with concomitant AAH foci from 13 patients for mutations of EGFR (exons 18-21), HER2 (exons 19-20), and K-ras (exon 2) by direct sequencing polymerase chain reaction. Among mutated cases, concordant mutations of EGFR or K-ras in adenocarcinoma and related AAH were observed in 5 (63%) of 8 cases. In particular, 3 of 4 adenocarcinomas with EGFR mutations (all L858R point mutations in women, never or former smokers) had a concomitant and identical mutation in AAH, and 2 of 4 adenocarcinomas with K-ras mutations (both at codon 12 in women, a never and a current smoker) showed the same mutation in concomitant AAH. All cases were wild-type for HER2. Mutations of EGFR and K-ras genes represent an early event in lung adenocarcinomagenesis, and AAH convincingly seems to be a precursor lesion in a subset of cases of adenocarcinoma.

[Atypical adenomatous hyperplasia of lung: clinicopathologic study of 8 cases and review of literature].

OBJECTIVE: To study the clinicopathologic and immunohistochemical features of atypical adenomatous hyperplasia (AAH) of lung. METHODS: Eight cases of AAH of lung were studied by light microscopy and immunohistochemical staining for p16, thyroid transcription factor-1 (TTF-1), Ki-67, p53, epidermal growth factor receptor (EGFR) and c-erbB-2. RESULTS: The mean age of the patients was 52 years. The male-to-female ratio was 1:3. Two patients were chronic smokers. The clinical symptoms were relatively non-specific. Three patients had past history of non-pulmonary tumors, while 4 patients had lung adenocarcinoma. CT scan revealed solitary or multifocal hyperdense opacities. Histologically, the lesions ranged from 1 mm to 6 mm in size. Two cases were solitary and 6 cases were multifocal. All were of high-grade lesions. Associated low-grade component was noted in 3 cases. There was no evidence of local recurrence or disease progression in the 7 patients with post-operative follow-up information available (mean duration of follow up = 23 months). Four patients had received chemotherapy as well. Immunohistochemical study showed variable positivity for p16 (5/8), TTF-1 (5/8), Ki-67 (with proliferation index ranging from 1% to 10%), p53 (1/8) and EGFR (1/8). The staining for c-erbB-2 was negative (0/8). Four cases of AAH were associated with pulmonary adenocarcinoma. The adenocarcinoma cells were diffusely positive for TTF-1 (4/4), variably positive for p16 (2/4), Ki-67 (with proliferation index ranging from 2% to 40%), p53 (1/4) and EGFR (3/4), and negative for c-erbB-2 (0/4). CONCLUSIONS: AAH of lung is associated with pulmonary adenocarcinoma. Diagnosis of AAH requires correlation with CT findings and pathologic examination.

Epidermal growth factor receptor gene mutations in atypical adenomatous hyperplasias of the lung.

Activating epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung adenocarcinomas, especially adenocarcinomas with a nonmucinous bronchioloalveolar carcinoma component. EGFR-mutated lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors. We previously found that most (88%) pure nonmucinous bronchioloalveolar carcinomas (adenocarcinoma in situ) already harbor EGFR mutations, indicating that the mutations are an early genetic event in the pathogenesis. We examined 54 atypical adenomatous hyperplasias, precursor lesions of lung adenocarcinomas, obtained from 28 Japanese patients for the hotspot mutations of EGFR exons 19 and 21 and K-ras codon 12. EGFR mutations were observed in 17 of the 54 (32%) atypical adenomatous hyperplasias examined: Ten and seven atypical adenomatous hyperplasias had deletion mutations at exon 19 or point mutations (L858R) at exon 21, respectively. We did not observe apparent histological differences between atypical adenomatous hyperplasias with and without EGFR mutations. K-ras mutation (G12S) was detected in only one atypical adenomatous hyperplasia. As EGFR mutational frequency of atypical adenomatous hyperplasias was much lower than that of nonmucinous bronchioloalveolar carcinomas, we surmise that EGFR-mutated atypical adenomatous hyperplasias, but not atypical adenomatous hyperplasias with wild-type EGFR, are likely to progress to nonmucinous bronchioloalveolar carcinomas.

Mutation of the epidermal growth factor receptor gene in the development of adenocarcinoma of the lung.

Recently, a mutation of the epidermal growth factor receptor (EGFR) gene has been reported to be implicated in the development of pulmonary adenocarcinoma. However, the involvement of the mutation in atypical adenomatous hyperplasia (AAH) and multiple adenocarcinomas still remains unclear. We herein examined the EGFR mutations in 9 AAH and 31 adenocarcinoma lesions obtained from 30 Japanese patients. Nine patients had synchronous or metachronous multiple adenocarcinomas and/or AAH. Mutations in exons 18-21 of EGFR gene were analysed using polymerase chain reaction and direct sequence methods. EGFR mutations were detected in 4 (44%) of 9 AAH and in 7 (23%) of 31 adenocarcinomas. A gefitinib-resistant point mutation (T790M) in exon 20 without gefitinib treatment was detected in 1 AAH and 1 adenocarcinoma. The patient with T790M mutated AAH, which also had an exon 19 mutation of D761Y, had synchronous adenocarcinoma, which had only an exon 19 mutation of D761Y. The other exon 19 mutations were all in-frame deletions. In the two patients with synchronous AAH and adenocarcinoma, AAH had mutations at exon 19 although adenocarcinoma did not have any mutations. In the patient with synchronous 2 adenocarcinomas, each had different mutations (exons 19 and 21). In two patients with double adenocarcinomas, 1 adenocarcinoma harbored exon 21 mutations, while the other demonstrated no mutations. Although EGFR mutations appeared to be partially associated with the early steps of adenocarcinoma development, such mutations may possibly occur randomly even in multiple lesions in a single patient.

Molecular alterations in atypical adenomatous hyperplasia occurring in benign and cancer-bearing lungs.

Atypical adenomatous hyperplasia (AAH) is considered to be a precursor lesion of the lung adenocarcinoma. Several genetic abnormalities have been reported in AAH associated with adenocarcinoma, but little is known about AAH associated with benign lung lesions. To address this we compared the molecular characteristics of AAH present in benign conditions to those coexisting with carcinoma. Seven cases of AAH from resected non-neoplastic lungs (AAH-B) and 12 cases from lungs resected for primary lung carcinoma (AAH-M) were analyzed for loss of heterozygosity (LOH) using 21 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes on chromosomes 3p, 5q, 7p, 9p, 10q, and 17p. Direct DNA sequencing for K-ras mutation was also performed. There was a broad range of LOH in both groups. No LOH was identified in 3 cases (25%) of AAH-M, but all cases of AAH-B showed LOH (P=0.26). Six cases (50%) of AAH-M and 3 cases (43%) of AAH-B showed loss at 1 marker (P=0.99). LOH at 2 or more markers was identified in 3 (25%) cases of AAH-M and 4 (57%) cases of AAH-B (P=0.32). LOH was most frequently detected on chromosomes 3p and 10q in both groups. The difference in overall fractional allelic loss between the 2 groups did not reach statistical significance. K-ras mutations were not identified in either group. Our results showed a significant overlap in LOH patterns between AAH with or without coexistent lung malignancy. Therefore, AAH may represent a smoking induced low-grade neoplastic lesion that may be a precursor lesion of only a subset of invasive lung adenocarcinoma.

Genetic relationship among atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and adenocarcinoma of the lung.

Atypical adenomatous hyperplasia (AAH) has been recently defined by WHO as a small lesion, not exceeding 5mm in major axis, composed of slightly enlarged alveolar septa lined by pneumocytes with plump, atypical nuclei. AAH is frequently found in tissue surrounding lung adenocarcinoma and is considered a precursor of this subtype of lung cancer by many Authors. However, the genetic relationship between adenocarcinoma and the associated foci of AAH is not well defined. In particular, it is not clear whether multiple foci of AAH and of adenocarcinoma in the same patients are clonally related to each other or represent independent neoplastic foci. To clarify if AAH and the associated cancer are clonally related, we evaluated the genetic distance between these two lesions in 16 patients, using direct sequencing of mitochondrial DNA (D-loop region). Furthermore, LOH analysis for 7 microsatellites (D3S1478 at 3p21, D3S1300 at 3p14.2, D9S942 at 9p21, D5S346 at 5q21, D17S261 at 17p13.1, D18S46 at 18q21, D19S246 at 19q13.2) was also performed. Our results indicate that, in at least 9 out of 13 informative cases (69.2%), AAH and the associated cancer were not clonally related as they showed a different mutation pattern in the mitochondrial D-loop region. These findings were also in agreement with the LOH data which showed losses in different loci in at least three cases. On the contrary an identical LOH pattern between BAC and AAH was found in one case. Similar but not identical LOH pattern between AAH and related tumors was found in other three cases. Therefore, our results suggest that AAH and the associated cancer are genetically independent in agreement with the concept of cancerization field. Less frequently AAH foci could represent an early spread of cells from the main tumor, rather than a precursor lesion.

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.

[Surgical therapy for impalpable small lung lesion; confirmation method by means of combining computed tomography (CT)-guided marking with soft X-ray radiography].

OBJECTIVE: We examined the usefulness of soft X-ray radiography of the specimen which was obtained by the lung wedge biopsy. PATIENTS AND METHODS: From September 2002 to September 2005, we entered the 10 cases (5 men and 5 women) which were consisted of 15 lesions. We performed lung wedge biopsy after computed tomography (CT)-guided lung marking, and then confirmed the lesion in the specimen by means of soft X-ray radiography. RESULTS: We could confirm impalpable small lung lesions in all cases. CONCLUSION: The confirmation method of impalpable small lung lesion that combined CT-guided lung marking with soft X-ray radiography was very useful.

A clinicopathological study of resected pulmonary nodules with focal pure ground-glass opacity.

OBJECTIVE: Pulmonary lesions with focal ground-glass opacity (GGO) have been detected increasingly by low-dose helical computed tomography (CT). However, the strategy of treatment for focal pure GGO lesions is still undecided. This study evaluates clinicopathological characteristics of resected pulmonary nodules with focal pure ground-glass opacity. METHODS: Between January 1997 and December 2005, 26 patients (35 lesions) with pure GGO lesions underwent pulmonary resection. The data on patient age, lesion size, pathology, carcinoembryonic antigen (CEA) level and palpability of the tumor in the resected specimen were evaluated. RESULTS: The histological diagnosis was bronchioloalveolar carcinoma (BAC) in 10 patients (12 lesions), atypical adenomatous hyperplasia (AAH) in 15 patients (22 lesions), and focal scar in 1 patient (1 lesion). There were no significant differences in age, sex, tumor size, and CEA level between the patients with BAC, AAH, and focal scar. However, the lesions >10mm in size were all BAC. Palpability of the tumor in the resected specimen was significantly more frequent in BAC cases than in AAH cases (p<0.01). For BAC, lobectomy was performed for four lesions, and limited resection for eight. None of the BACs showed lymphatic or vascular invasion upon pathological examination. At the median follow-up point of 44 months (range: 4-84 months), no recurrences were observed. CONCLUSIONS: BAC and AAH cannot be discriminated by their size. In the resected specimen, BAC lesions are more frequently palpable than AAH lesions. Thoracoscopic surgery is recommended for focal pure GGO after repeated CT even if the GGO lesion is small. Partial resection is a sufficient treatment for pure GGO.