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Background: The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non-small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD-L1) expression., Methods: We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center., Results: This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p < 0.001). In both AD and NFAD, EGFR mutation was the most frequent gene alteration, followed by KRAS mutation. The frequency of EGFR mutations was significantly higher in AD than in NFAD. PD-L1 expression was significantly higher in NFAD than in AD (p < 0.001)., Conclusion: This study shows a clear difference between AD and NFAD in terms of cancer progression, pathological features of the main tumor, genetic characteristics, and PD-L1 expression., (© 2024 The Authors. Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

We analyzed the outcomes of genetic testing to study the frequency of mutations in advanced thyroid cancer in Japan. Patients (n = 96) with unresectable or metastatic thyroid carcinoma were included for retrospective chart review. Results of gene panel testing, which was performed between May 2020 and April 2023, were analyzed. The median age of the patients was 73.5 years (range, 17-88); 59 were women, and 39 were men. Overall, 17 patients had anaplastic thyroid carcinoma (ATC), 68 had papillary thyroid carcinoma (PTC), 7 had follicular thyroid carcinoma, and 6 had poorly differentiated thyroid carcinoma (PDTC). Of the 81 patients with differentiated thyroid carcinoma (DTC) and PDTC, 88.9% were radioactive iodine-refractory, and 32.7% of all cases had previously been treated with multiple kinase inhibitors. Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion. Of PTC cases, 83.1% had BRAF mutations, 9.2% had RET fusion, and 1.5% had NTRK fusion. One case each of ATC and PTC had a tumor mutation burden of ≥10. ATC cases had a significantly higher prevalence of TP53 alterations than the other cases (82.3% vs. 11.8%), whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and 64.7% in the other cases, albeit without a significant difference. In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic alterations linked to therapeutic agents. Active gene panel testing is required to increase treatment options.

Cribriform pattern and intraductal carcinoma of the prostate (IDC-P) are widely accepted as poor prognostic factors in prostate cancer. However, it remains unclear to what extent the presence of these morphological features in prostate biopsy specimens, as diagnosed by hematoxylin-eosin-stained specimens only, affects the clinicopathological impact. In this study, we summarized the characteristics of the cribriform pattern and IDC-P in 850 prostate biopsy cases. The results showed a statistically significant increase in the incidence of cribriform pattern and IDC-P as grade group (GG) increased (especially in cases ≥ GG4, Chi-square test P < 0.001). The independent risk factors for cribriform pattern and IDC-P in biopsy specimens in the multivariate logistic regression analysis were the former GG, presence of IDC-P, lesion length of the highest GG core, latter GG, presence of the cribriform pattern, number of biopsies obtained, and number of highest GG core. Overall, 125 cases in which radical prostatectomy was conducted after biopsy were selected for further analysis. Multivariate logistic regression analysis using biopsy and surgical specimens confirmed that the presence of the cribriform pattern and IDC-P in biopsy specimens were independent risk factors for lymph node metastasis (odds ratios [95% confidence interval] were 6.54 [1.15-37.05] for the cribriform pattern and 23.71 [1.74-322.42] for IDC-P). The presence of the cribriform pattern and/or IDC-P in a biopsy specimen was a significant factor, even if only partially present, indicating lymph node metastasis. However, further validation is required to predict poor prognostic factors more accurately., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prostate biopsy is essential in diagnosing prostate cancer. The Prostate Imaging-Reporting and Data System (PI-RADS) and magnetic resonance imaging (MRI)-transrectal ultrasound fusion-guided biopsy are also useful for diagnosis. However, the burden of implementing and maintaining these techniques should be considered. Therefore, we investigated the significance of non-standardized pre-biopsy MRI abnormalities (conditions not in accordance with PI-RADS) and subsequent targeted biopsy. We collected clinicopathological data, including the presence or absence of MRI abnormalities, through biopsies from January 2017 to February 2022 at the Kanagawa Cancer Center and performed statistical analyses. We enrolled in 1086 cases: MRI abnormalities were observed in 861 cases (79.3%). In these 861 cases, the adenocarcinoma detection rate, number of positive cores, and length of the highest Grade Group (GG) lesions were significantly higher. In the multivariate analysis, MRI abnormalities were the most significant factor for detecting adenocarcinoma of ≥GG 2 (odds ratio: 4.52, 95% confidence interval: 3.08-6.63). Targeted biopsy showed a higher percentage of positive cores with ≥GG2 and longer highest GG lesion lengths than systematic biopsy. Furthermore, the highest GG was upgraded in 109 of 788 cases by targeted biopsy. However, several adenocarcinomas (125/788; 15.9%) could not be detected using only targeted biopsy. Non-standardized MRI abnormalities are powerful predictors of cancer and grading. Targeted biopsies based on MRI abnormalities provide several benefits. Owing to the relatively low implementation hurdle, these biopsies may serve as a bridge until the ideal approaches are popularized if the limitations are well understood., Competing Interests: Declarations of interest None., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Differentiating small cell neuroendocrine (NE) carcinoma (SCNC) of the prostate from adenocarcinoma with NE differentiation based on morphological features alone sometimes can be challenging. Given that treatment strategies vary depending on histological type, an accurate diagnosis is critical. This study aimed to identify the accurate diagnostic factors for SCNC of the prostate. Furthermore, the possibility of novel treatment strategies through genetic analysis was also investigated. Prostate biopsies conducted in our hospital between January 2017 and May 2020 were included. Consequently, seven cases of SCNC and four cases of adenocarcinoma with NE differentiation were identified. No significant differences in the serum neuron-specific enolase, pro-gastrin-releasing peptide, and prostate-specific antigen (PSA) levels were observed between both tumors. The Ki-67 labeling index was significantly higher, and PSA immunoreactivity tended to be lower in SCNC. Although the morphology was undetectable, genetic analysis confirmed several mutations, including those of PIK3CA and TP53. The fact that morphological findings are not apparent indicates that genetic investigation rather than only morphological findings would be important in the future. In conclusion, given the heterogeneity of serum NE markers in SCNC, diagnosis based on these markers alone is challenging. A high Ki-67 labeling index and low PSA immunoreactivity may be useful for diagnosis, but p53 immunoreactivity is insufficient in distinguishing. Although further studies are required to interpret the results of the genetic analysis involving ALK, PIK3CA, and TP53 mutations, the results of our genetic analysis suggest that PIK3CA mutations in SCNC of the prostate may provide a novel therapeutic strategy., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Aim: With the advent of the molecular-targeted therapy, rapid progress has been made in the treatment of advanced or recurrent non-small-cell lung cancer (NSCLC). Although surgical complete resection remains the standard and most promising treatment, the clinical significance of epidermal growth factor receptor (EGFR) gene mutations in early-stage NSCLC remains uncertain., Methods: We investigated the prognostic value of EGFR mutations in surgically resected pathological stage I NSCLC. A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method., Results: Mutations of EGFR were detected in 185 of the 388 patients (47.7%). EGFR mutations were more frequently found in women (110 of 185, 59.5%), adenocarcinoma (183 of 185, 98.9%), patients with no vascular invasion (139 of 185, 75.1%) and nonsmokers (106 of 185, 57.3%). In patients with pathological stage I adenocarcinoma, both overall survival (OS) and disease-free survival (DFS) were significantly higher in patients with EGFR mutation than in those with wild-type EGFR. Furthermore, patients with exon 21 mutation have better DFS than those with exon 19 mutation in stage IB adenocarcinoma. Cox's proportional hazard model indicated that EGFR status was an independent variable for predicting the OS and DFS in patients with pathological stage IB adenocarcinoma., Conclusion: Our results suggest that EGFR mutations might be a prognostic factor in patients with pathological stage I lung adenocarcinoma., (© 2016 John Wiley & Sons Australia, Ltd.)

Objectives: We studied whether histologic subtype according to the new IASLC/ATS/ERS adenocarcinoma classification influences the extent of resection in patients with pathological stage IA lung adenocarcinoma., Methods: Data on 288 patients with pathological stage IA lung adenocarcinoma were analyzed retrospectively. Recurrence-free survival (RFS) rates were compared according to clinicopathological characteristics, including predominant histologic subtype and extent of resection., Results: Median follow-up was 38.9 months. Lobectomy was performed in 146 patients, and sublobar resection in 142 patients. When recurrence was compared among the low-grade group (adenocarcinoma in situ, AIS; minimally invasive adenocarcinoma, MIA), intermediate-grade group (lepidic, acinar, and papillary) and high-grade group (solid and micropapillary), the RFS rate decreased as the grade increased (p = 0.037). There was no recurrence in the low-grade or lepidic predominant groups. The recurrence pattern did not differ according to the type of resection or histological subtype. Even in the intermediate- and high-grade groups, the extent of resection was not significantly related to the RFS rate (p = 0.622, p = 0.516). The results were unchanged after adjusting for independent risk factors. The concordance rate between clinical and pathological stage IA was good in low (98.6%) and intermediate grade (84.6%) and poor in high grade (41.2%)., Conclusions: AIS, MIA, and lepidic predominant may be curable by any type of complete resection. Even in invasive subtypes, lobectomy does not offer a recurrence-free advantage over sublobar resection. However, in the high-grade group, less than half of clinical stage IA was actually pathological stage IA. Physicians should exercise caution whenever sublobar resection is planned.

Pulmonary enteric adenocarcinoma (PEA) is a rare variant of pulmonary adenocarcinoma; it is sometimes difficult to discriminate between PEA and metastatic colorectal carcinoma (MCRC) because of their morphological and immunohistochemical resemblance. Here, we conducted clinicopathological, immunohistochemical, and mutational analyses of PEA with special focus on its differentiation from MCRC. We comparatively analyzed 8 surgically resected PEA tumors (7 patients) and 20 cases of MCRC. Patients were aged 43-77 years (average age, 64.1 years); 5 of 7 patients were men. Tumor sizes ranged from 1.5 to 11.5 cm (average size, 4.8 cm). The follow-up period was 1-65 months; 4 patients are alive without recurrence, 2 are alive with recurrence, and 1 patient died of idiopathic pulmonary fibrosis. Six of the tumors were pure PEA; one PEA tumor had a small mucinous adenocarcinoma component; another had a squamous cell carcinoma component. Immunohistochemically, the positive rates of PEA for each antibody were as follows: CK7, 88% (7/8); CK20, 88% (7/8); TTF-1, 13% (1/8); β-catenin, 0% (0/8, strong nuclear expression); and SATB2, 13% (1/8). The positive rates of MCRC for these antibodies were 10%, 95%, 5%, 55%, and 100%, respectively. Genetic analysis of KRAS, EGFR, and BRAF showed the G12V mutation in exon 2 of KRAS in 1 PEA. The present study's findings indicate that β-catenin and SATB2 are useful immunohistochemical markers for differentiating between PEA and MCRC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Advanced unresectable pulmonary adenocarcinoma with the epidermal growth factor receptor (EGFR) exon 21 L858R point mutation (Ex21) is associated with a poor prognosis. However, for early-stage resectable adenocarcinoma, Ex21 tumors have a lower-grade malignancy than exon 19 deleted (Ex19) tumors. We therefore investigated the effect of EGFR mutations on the prognosis in patients with completely resected pN1-N2 adenocarcinoma., Methods: Five-year disease-free survival (DFS) and overall survival (OS) were analyzed in 202 pN1-N2 pulmonary adenocarcinoma patients, 100 of whom had EGFR mutations, comprising Ex21 in 41 (20.3%), Ex19 in 55 (27.2%), and Ex18 in 4 (2%)., Results: Patients with and without EGFR mutations had similar DFS (26.2% vs 24.6%, respectively; p = 0.280) and OS (64.9% vs 54.2%, respectively; p = 0.564). Patients with Ex19 tumors had significantly better DFS (38.8% vs 11.8%, p = 0.001) and tended to have better OS (78.3% vs 48.3%, p = 0.123) than those with Ex21 tumors. For pN1, patients with Ex19 tumors had a longer disease-free interval (54.0 vs 22.3 months, p = 0.003) and median survival time (81.0 vs 50.6 months, p = 0.022) than those with Ex21 tumors. For pN2, patients with Ex19 tumors had longer disease-free interval than those with Ex21 tumors (43.6 vs 30.1 months, p = 0.109). Multivariate analysis showed Ex21 was a prognosticator of poor DFS (hazard ratio, 2.25; 95% confidence interval, 1.21 to 4.20)., Conclusions: For pN1-N2 pulmonary adenocarcinoma, Ex21 mutation was associated with poorer prognosis than Ex19 mutation. Thus, EGFR mutation status should be considered when predicting prognosis., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

A 72-year-old man was admitted to our hospital department in September 2014 because of a positive fecal occult blood test.Colonoscopy showed a type 2 tumor in half of the AV 15 cm rectosigmoid colon.Histology of the biopsy indicated a moderately differentiated adenocarcinoma, and the RAS gene test found wild type.On CT examination, there were multiple liver lung metastases and a 30mm diameter tumor with pancreatic duct extension to the pancreatic body.A PET-CT examination had a high SUVmax at the same site.Because of the location of the tumor EUS-FNA was not used.However, the possibility of pancreatic body cancer could not be denied after the CT examination.Treatment by radical resection was impossible because of the spread of the cancer so we selected chemotherapy.Undeniable pancreatic metastasis of rectal cancer, pancreatic cancer was used as a prognostic factor as double cancer of rectal cancer and pancreatic cancer, from that UGT1A1 test side effects appearance was a low-risk decision, was selected FOLFIRINOX in the treatment regimen.After 25 cycles, the pancreatic body tumor and liver metastases and also the primary tumor were reduced, the multiple lung metastases disappeared, and disease control was good.Side effects were diarrhea on the day of administration of irinotecan, but this was controllable by administering oral loperamide when starting the infusion.Grade 3 or more peripheral neuropathy has not developed, and this regimen is continuing.Pancreatic cancer is a solid cancer with a poor prognosis; if you do not reach the tissue diagnosis of metastatic pancreatic cancer, was a case in which no choice but to select a regimen to carcinoma of the prognostic.

Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.

Background: Palpation is the most important means of locating lung tumors and resecting them with sufficient margins. This study aimed to predict the palpability of pulmonary lesions using high-resolution computed tomography., Methods: Eighty-six pulmonary lesions were palpated in fresh resected lung specimens from July 2013 to March 2014. The following parameters were compared between 10 impalpable and 76 palpable lesions: maximum tumor size in pulmonary and bone window level settings, consolidation tumor size in pulmonary window level setting, and pleural-tumor distance. In 54 adenocarcinomas, the lepidic component and fibrosis foci rates were compared between the two groups., Results: Tumor size in bone window level setting and the consolidation tumor size were significantly smaller in the impalpable group (both p < 0.001), and an operational cutoff of 5 mm was identified by receiver-operating characteristic analysis (sensitivity/specificity was 90.0%/94.7% and 90.0%/86.9%, respectively). Pulmonary lesions were impalpable with 87.5% probability when the tumor size in bone window level setting was ≤ 5 mm and the pleural-tumor distance was ≥ 5 mm, and with 85.7% probability when the consolidation tumor size was ≤ 5 mm and the pleural-tumor distance was ≥ 5 mm. Lepidic component and fibrosis foci rates of impalpable/palpable lesions were 96.0%/52.8% and 4.0%/24.7%, respectively (both p < 0.001)., Conclusions: Tumor size in bone window level setting or a consolidation tumor size ≤ 5 mm and pleural-tumor distance ≥ 5 mm are simple criteria that are potentially useful indicators for preoperative marking to locate small-sized lepidic-predominant adenocarcinomas with few fibrotic foci., (© The Author(s) 2015.)

In June 2010, a 73-year old man diagnosed with sigmoid colon cancer underwent laparoscopic sigmoidectomy. The histopathological diagnosis was tub2, pSS, n (-), stageⅡ.Vascular invasion was present; however, at the patient's request, no adjuvant chemotherapy was administered.Computed tomography (CT) performed at the outpatient follow-up 4 years and 6 months after the surgery revealed a para-aortic lymph node metastasis in the caudal aspect of the left renal artery branch point. No other definite mass shadows were detected. Positron emission (PET)-CT revealed high tracer accumulation (SUVmax) not only in the CT-identified lymph node, but also near the site of the anastomosis in the bowel. Considering that no tracer accumulation was detected at any other sites and the patient's compliance with medication and scheduled visits was poor, surgical resection rather than chemotherapy was adopted as the treatment strategy. No metastases other than at the sites identified by the diagnostic imaging were found during the surgery. Since the findings on palpation did not rule out the possibility that the nodule near the anastomotic site was present inside the intestinal tract, lymph node dissection, resection of the intestinal tract including the anastomotic site, and re-anastomosis were performed. The most likely diagnosis based on the histopathological findings was dissemination for both the adenocarcinoma and the nodule near the anastomotic site. At present, the patient is being treated with adjuvant chemotherapy. In the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines for the Treatment of Colorectal Cancer, the recommended therapeutic intervention is surgical resection of hematogenous metastases; however, no treatment is specified for lymph node metastases. In general, chemotherapy is administered for distant metastases. However, we have found no reports of cases in which a complete remission has been achieved. There are reports of improvement of survival by surgical resection in cases with solitary lymph node metastasis or isolated dissemination of colorectal cancer. These observations suggest that surgical therapy may have contributed to the improved prognosis in the present case.

Objectives: We analyzed and validated the prognostic utility of the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) for clinical stage IA lung adenocarcinoma (ADC) classification of adenocarcinoma (ADC)., Methods: We retrospectively reviewed 347 patients with clinical stage IA nonmucinous ADC, who had undergone complete resection. The histological subtype was classified according to the predominant subtype, as proposed by the new IASLC/ATS/ERS ADC classification., Results: The histopathological subtypes, defined according to the new IASLC/ATS/ERS ADC classification, were ADC in situ (AIS) in 56 patients (16.1%), minimally invasive ADC (MIA) in 15 (4.3%), lepidic-predominant ADC in 109 (31.4%), papillary-predominant ADC in 70 (20.2%), acinar-predominant ADC in 61 (17.6%), solid-predominant ADC in 30 (8.6%), and micropapillary-predominant ADC in 6 (1.7%). The 5-year disease-free survival (DFS) rate was 100% for both AIS and MIA. All cases of recurrence involved invasive ADC. The 5-year DFS for lepidic-predominant ADC was 99.0%; acinar-predominant ADC, 82.4%; papillary-predominant ADC, 80.8%; solid-predominant ADC, 73.6%; and micropapillary-predominant ADC, 33.3%. The predominant subtype of ADC was significantly correlated with DFS (P<0.0001). Multivariate analysis indicated that the pathological stage was an independent predictor of DFS (P=0.031). Other independent predictors of increased risk of recurrence were the presence of vascular or lymphatic invasion (HR=4.96, P=0.001), and a pathological stage more advanced than IB (HR=2.87, P=0.010). The coincidence between the clinical stage and pathological stage was 79.8%. The stage migration was found in 53.3% of solid-predominat ADC and in 83.3% of micropapillary-predominant ADC., Conclusion: The new IASLC/ATS/ERS ADC classification has prognostic value in predicting the recurrence and survival of patients with clinical stage IA ADC. The frequency of stage migration was found in more than half of solid and micropapillary predominant ADCs., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Advanced lung cancers with epidermal growth factor receptor (EGFR) exon 19 deletions (Ex19s) and EGFR exon 21 L858R point mutations (Ex21s) exhibit different clinical behavior. However, these differences are unclear in resectable primary lung tumors.The clinicopathological features of 88 (20.9%) Ex19, 124 (29.4%) Ex21, and 198 (46.9%) EGFR wild-type (Wt) clinical stage I primary adenocarcinomas resected between January 1, 2012 and October 31, 2014 were compared by using Chi-square tests, residual error analysis, analysis of variance, and Tukey tests.Ex21 lesions occurred more frequently in women and never-smokers and had a higher tumor disappearance rate (TDR: 59.6% vs 43.9%; P < 0.001) and lower maximum standardized uptake value (maxSUV: 2.0 vs 3.5; P < 0.01) than Wt lesions; Ex19 lesions had intermediate values (52.8% and 2.6). There was a low frequency of vascular invasion in Ex21 lesions (12.1%; P < 0.05) and a high frequency in Wt lesions (22.7%; P < 0.05). Most Ex19 lesions were intermediate-grade adenocarcinoma (lepidic, acinar, and papillary predominant: 73.9%; P < 0.05). Wt and Ex21 lesions were predominately high-grade (micropapillary or solid predominant, mucinous variant) and low-grade (adenocarcinoma in situ and minimally invasive adenocarcinoma) adenocarcinoma, respectively. Wt lesions had smaller lepidic components (42.1% vs 56.3%; P < 0.001) and larger papillary and solid components (papillary: 15.5% vs 9.0%; P < 0.05; solid: 13.2% vs 3.2%; P < 0.001) than Ex21 lesions. Most Ex19 lesions had intermediate component rates.Most Ex21 lesions were low-grade adenocarcinoma with lepidic growth patterns. Wt high-grade adenocarcinomas included solid and papillary components with vascular invasion. Ex19 lesions were intermediate grade between Ex21 and Wt.

We report a case of metachronous multiple lung adenocarcinoma at the cut-end, diagnosed 4 years after sublobar resection for adenocarcinoma in situ (AIS), on the basis of discordance of epidermal growth factor receptor (EGFR) mutation status between the first and second tumor. The patient was an 81-year-old Japanese man, whose chest computer tomography (CT) scan showed mixed ground-glass opacity in the right upper lobe of the lung. Wedge resection was performed and a diagnosis of AIS, non-mucinous (18 × 14 mm), with a margin of 6 mm, was made. A tumor at the cut-end was seen on a CT scan 4 years later, and abnormal uptake was identified by fluorine-18 fluorodeoxyglucose-positron emission tomography. Right upper lobectomy and lymph node dissection were performed and the tumor was diagnosed as invasive adenocarcinoma, acinar predominant. Discordance of EGFR mutation status between the first tumor, harboring exon 19 deletion, and the second tumor, having an L858R point mutation in exon 21, revealed that the second tumor was metachronous multiple lung cancer. This case demonstrates the necessity of comparing EGFR mutation status between the first tumor and the second tumor at the cut-end.

Objective: Our previous trial for small ground-glass opacity nodule on high-resolution computed tomography suggested all these cancers might have been radically managed with limited resection. Good correlation between radiologic and pathologic findings in early lung adenocarcinomas has been reported. We aimed to confirm limited resection efficacy as radical surgery in patients with high-resolution computed tomography-indicated minimally invasive lung cancer. The purpose of this interim analysis is to report the details of the patient and nodule characteristics, intraoperative cytology capability as a negative margin indicator, and patient outcome with the median follow-up period of 7 years and 4 months., Methods: Enrollment required patients with a tumor ≤2 cm, diagnosed or suspected as a cT1N0M0 carcinoma in the lung periphery and depicted on high-resolution computed tomography as a sub-solid nodule with tumor disappearance ratio ≥0.5. We performed a wedge or segmental resection as appropriate. The primary endpoint is 10 year local recurrence-free survival rate., Results: This study started in November 2003, and 101 patients were enrolled as of November 2009. Of them, 95 were eligible for analysis. There were 38 men and 57 women, aged 30-75, averaging 62 years. Tumor sizes ranged from 7 to 20 mm on computed tomography, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 24 type C tumors, one malignant lymphoma and 5 non-cancerous lesions. All cancers showed no vessel invasion. With a median follow-up period of 88 months, there have been no recurrences., Conclusion: So far, high-resolution computed tomography appears to predict non- or minimally invasive ground-glass opacity lung cancers with high reliability, warranting limited resection as curative surgery in this cohort., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Surgical treatment has become the mainstay of treatment for multiple primary lung cancers. In particular, the prevalence of synchronous primary lung adenocarcinomas (SPLA) has recently increased, but few studies have evaluated surgical outcomes of patients with SPLA. We reviewed the clinicopathologic features and surgical outcomes of SPLA to identify factors related to survival., Methods: Data on 2,041 consecutive patients with primary non-small cell carcinoma who underwent surgical resection in our hospital from 1995 through 2009 were retrospectively analyzed., Results: The SPLA was pathologically diagnosed in 93 patients, including 26 with bilateral tumors. The rates of overall survival and recurrence-free survival at 5 years were 87.0% and 81.8%, respectively. There was no surgical mortality at 30 days. On univariate analysis, lymph node metastasis (p = 0.0000), nonlepidic predominant histologic subtype (p = 0.0018), and a solid appearance of the largest tumor on computed tomography (p = 0.0088) were significantly related to poor overall survival. On multivariate analysis, bilateral distribution of tumors (p = 0.031), lymph node metastasis (p = 0.004), and sublobar resection (p = 0.042) were independent predictors of poor survival., Conclusions: Surgery has good outcomes and should be aggressively performed for patients with SPLA. The evaluation of lymph node status has an important role in deciding whether surgery is indicated. Bilateral tumors are a predictor of poor outcomes, requiring that caution be exercised. Lobectomy has a high cure rate and should be performed whenever possible. However, sublobar resection should be considered for patients likely to have poor residual lung function postoperatively., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

We report the case of a solitary pulmonary tumor, which was diagnosed as recurrent early gastric cancer by detailed pathological examinations. A 59-year old man initially underwent total gastrectomy for gastric adenocarcinoma located at the esophago-gastric junction. A pathological examination indicated a papillary adenocarcinoma (pap ) that had invaded the submucosal layer (sm²), but had not metastasized to the regional lymph nodes (n0). The final diagnosis was P0H0M0T1bN0, Stage IA. Chest computed tomography (CT) 30 months after primary surgery indicated a solitary tumor with a diameter of 9 mm at S3 of the left lung. A positron emission tomography (PET)-CT scan showed an accumulation of ¹⁸F-fluordeoxy-glucose (FDG18) at the same location. Lung cancer was suspected and the patient was given a left upper lobectomy. The resected tumor was diagnosed as gastric cancer metastatic adenocarcinoma by permanent pathological examination. The tumors showed similar histology and immuno histochemical findings for CK7, CK20, TTF-1, SP-A, CDX-2, and HER2 . Early gastric cancer is an almost curable disease and recurrence is very rare. We report the details of this case and review the literature.

Objective: We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE., Materials and Methods: We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests., Results: FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors., Conclusion: FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

Purpose: The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer., Experimental Design: We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.-617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients' overall survival., Results: Patients harboring wild-type (WT) homozygous (c.-617C/C), SNP heterozygous (c.-617C/A), and SNP homozygous (c.-617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.-617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.-617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021)., Conclusion: SNP homozygous (c.-617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.

Introduction: Nuclear grading involves an evaluation of the size and shape of nuclei and the percentage of tumor cells that are in the mitotic phase. To estimate the degree of aggressiveness, this approach has been applied to various types of carcinomas, such as breast carcinoma and pulmonary adenocarcinoma (Nakazato et al.). In the present study, we estimated and evaluated the interobserver variability of nuclear grading in primary pulmonary adenocarcinomas., Methods: We selected 122 primary pulmonary adenocarcinomas measuring 2 cm or less in diameter. Eight pathologists independently evaluated the nuclear factors, using the nuclear grading system reported previously by Nakazato et al. The same pathologists also used both the international multidisciplinary classification of pulmonary adenocarcinoma (2011 International Association for the Study of Lung Cancer classification) and Noguchi's classification, and assessed the extent of the lepidic pattern in the largest cut surface of the tumor. Interobserver agreement was evaluated using the κ statistic. The disease-free survival curves of the patients were obtained using the Kaplan-Meier method and analyzed with the log-rank test., Results: The mean (±SD) κ values for the two histological classifications, the extent of the lepidic pattern, and nuclear grading were 0.46 ± 0.09, 0.48 ± 0.09, 0.45 ± 0.16, and 0.58 ± 0.09, respectively. The cases judged as negative on the basis of nuclear grading showed a significantly better prognosis (5-year disease-free survival rate; 91.8% ± 2.7) than the positive cases did (68.6% ± 3.1)., Conclusion: : Nuclear grading is practical for prognostic evaluation of pulmonary adenocarcinoma. The interobserver agreement for nuclear grading is significantly higher than for histological classifications and the extent of the lepidic pattern. Nuclear grading is a reliable prognostic indicator for small adenocarcinomas.

We report a rare case of lung adenocarcinoma in which micropapillary components were considered to cause stump recurrence. A woman in her fifties was diagnosed with lung cancer in the right middle lobe with invasion to the upper lobe, which was treated by a right middle lobectomy together with upper lobe partial resection. The cancer was pathologically diagnosed as adenocarcinoma and had a free surgical margin. There was no recurrence during the following 5 years and 8 months, and thus periodical surveillance, including computed tomography, was stopped. However, 2 years and 7 months after this, she was discovered to have an abnormal shadow on chest radiography, and a thorough examination revealed a 3-cm-sized tumor involving the previous surgical margin. Therefore, she underwent right upper lobectomy. We pathologically re-evaluated the first tumor and found that it was an adenocarcinoma with a micropapillary component in the periphery, 6mm away from the surgical margin. In addition, a few tiny clusters of tumor cells were found to be floating within the alveolar spaces near the margin. The first and second tumors showed almost the same histological mixture of components of adenocarcinoma and the same EGFR mutation. From these results, we concluded the second tumor was a stump recurrence originating from the first tumor resection. This case illustrates the importance of careful pathological investigation when an autosuture instrument is used for a partial resection in a case of lung adenocarcinoma with micropapillary components. In such cases, it is particularly important to clarify if micropapillary components are floating near a stump., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Aim: To analyse the correlation between computed tomography (CT) findings of small lung adenocarcinomas and the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma., Materials and Methods: A retrospective review of 300 lung adenocarcinoma lesions (size ≤20 mm) after surgical resection in 295 consecutive patients was performed. Tumours were defined as air-containing type if the ratio of the maximum dimension of the tumour on mediastinal windows to the maximum dimension of the tumour on lung windows was ≤50%, and as solid-density type if the ratio was >50%. The incidence between CT findings (air bronchogram, vascular involvement, pleural tags, notches, and spiculation) and pathological findings were investigated., Results: Of the 142 air-containing lesions, 114 were adenocarcinoma in situ (AIS), 28 were minimally invasive adenocarcinoma (MIA), and none of the lesions were invasive adenocarcinoma. Of the 158 solid-density lesions, 30 were AIS, 24 were MIA, and 104 were invasive adenocarcinoma. Notches and pleural tags were commonly observed in cases of invasive adenocarcinoma (p < 0.05)., Conclusions: In the air-containing type of small lung adenocarcinomas, AIS and MIA were observed but no cases of invasive adenocarcinoma were found. The presence of notches and pleural tags were a significant factor in invasive adenocarcinoma., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to have prognostic value. We previously reported the correlation between SUVmax and pathological invasive area, and determined an SUVmax cut-off value of 2.15 for predicting the recurrence potential of an invasive area of diameter 5mm. Here, we evaluate the validity of FDG-PET for prediction of recurrence in pathological stage IA lung adenocarcinoma., Methods: From February 2006 to May 2008, 100 patients with pathological stage IA lung adenocarcinoma underwent complete resection at our hospital. Tumors were classified as air-type or solid-type based on thin-section computed tomography (TS-CT) findings and the influence of TS-CT classification, SUVmax, and clinicopathologic features were evaluated in terms of the incidence of recurrence., Results: Unlike air-type adenocarcinomas, recurrent disease was detected in 8 of 62 solid-type adenocarcinomas. SUVmax and diameter of invasive area were significantly correlated with recurrence and a shorter time to recurrence. All 8 recurrent cases had pathological invasive area >5mm. All except one case of recurrence were solid-type adenocarcinomas with SUVmax≥2.15. Three-year disease-free survival rates were 100% in air-type adenocarcinomas, 97.1% in solid-type adenocarcinomas with SUVmax<2.15, and 74.1% in solid-type adenocarcinoma with SUVmax≥2.15., Conclusion: Combined evaluation of TS-CT classification and SUVmax had significant value in predicting recurrence in stage IA lung adenocarcinoma, reflecting the aggressiveness of primary lung adenocarcinoma. Prediction of tumor aggressiveness could contribute to decision-making regarding the choice of surgical procedure and treatment after surgery., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R+T790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA.

Objective: We divided pulmonary adenocarcinoma of ≤ 20 mm into air-containing and solid-density types based on a percentage reduction of the maximum tumor diameter in the mediastinal window image compared to the area in the lung window image on thin-section (TS) CT of ≥ 50% (air-containing type) and <50% (solid-density type). No relapse occurred in patients with air-containing type. The prognosis of solid-density type may be poor even when the tumor size is 20mm or smaller. We investigated whether CT findings for these tumors could serve as prognostic factors., Methods: The subjects were 105 patients with solid-density type pulmonary adenocarcinoma that was identified on TSCT and found to have a diameter of 20mm or smaller after surgical resection during the period from April 1997 to November 2004. Notches, air bronchogram, pleural retraction, spiculation, venous involvement, and ground glass opacity were examined on TSCT, and their associations with pathological findings (i.e., pleural invasion, lymphatic permeation, vascular invasion, lymph node metastasis, and Noguchi's classification) and relapse were investigated using chi-square test and Cox proportional hazards model., Results: The incidence of relapse was significantly higher in cases with notches. The incidence of notches increased with tumor growth and notches were frequent in Noguchi type D tumors, reflecting poorly differentiated adenocarcinoma. Lymphatic permeation and type D cases were independent factors associated with a poor prognosis using Cox proportional hazards model., Conclusions: TSCT findings may be useful for prediction of the prognosis of solid-density type pulmonary adenocarcinoma., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Pulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM., Methods: Autopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases., Results: Six autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF), five showed positive reactivity for vascular endothelial growth factor (VEGF), and three showed positive reactivity for osteopontin (OPN)., Conclusions: In the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric carcinoma indicating PTTM shows a higher TF-positive rate than typical gastric carcinoma. However, it remains still obscuring whether gastric carcinoma indicating PTTM shows a higher VEGF or OPN-positive rate as determined by immunohistochemistry.

Study Objectives: Previously, we reported that small pulmonary adenocarcinomas (tumor diameter 20 mm or less) could be classified according to attenuation on thin-section CT (TS-CT) images as either 'air-containing type' or 'solid-density type' (Lung Cancer 2002;36:49-57). Air-containing type was defined as having areas where TOM (tumor opacity on mediastinal window images) was half or less than half the size of those noted on lung window images. Solid-density type was defined as having areas where TOM was greater than half the size of those noted on lung window images. Our findings indicated that there was no microscopic evidence of metastasis with air-type nor any relapses nor deaths, after resection. By contrast, patients with solid-density types demonstrated a poor prognosis. At this time, the histopathological characteristics of areas of TOM have not been fully investigated. The purpose of this study is to define the correlations between TOM and histopathological findings of small lung adenocarcinomas., Method: We retrospectively reviewed the records and CT scans of 134 patients, who had undergone surgical resection of peripheral adenocarcninomas. All tumor diameters were 20 mm or less in size. All 134 patients had undergone TS-CT prior to surgery. TS-CT Images were acquired by a model X-Vigor/Real or an Aquillion CT scanner (Toshiba Medical Systems). Thin-section images of tumors were obtained at 135 kVp at 250 mAs with 1-2 mm section thicknesses. All images were photographed using mediastinal (level, 40 HU; width, 400 HU) and lung (level, -600 HU; width, 1600 HU) window settings. We researched the histopathological components corresponding to the areas of TOM., Results: Areas of TOM demonstrated five possible histopathological findings; (1) collapse (C), (2) collapse with bronchioloalveolarcell carcinoma (CwB), (3) adenocarcinoma cells (Cells), (4) fibroblasts (F), and (5) mucus (M). Areas of TOM in air-containing type adenocarcinomas (52 cases) demonstrated predominantly C and/or CwB (C/CwB type, 44 cases). Areas of TOM in solid-density type adenocarcinomas (82 cases), in comparison, demonstrated predominantly Cells and/or Cells/F (Cell/F type, 67 cases). We noted a statistically significant difference between the histopathological findings of the areas of TOM of air-containing type and solid-density type tumors. The 39 cases of Cell/F type adenocarcinomas revealed microscopic evidence of metastasis (pleural involvement, vascular invasion, lymphatic permeation, or lymphnode metastasis). Whereas, no C/CwB type adenocarcinomas cases revealed any microscopic metastasis. The prognosis of C/CwB type after resection is better than for Cell/F type., Conclusion: We found that air-containing type adenocarcinomas demonstrated C/CwB type, and that solid-density type adenocarcinomas demonstrated Cell/F type. The histopathological findings of small pulmonary adenocarcinomas could be classified into three groups: C/CwB type, Cell/F type and M type. The prognosis of C/CwB type is better than for Cell/F type. Our results indicate that there are clear correlations between the areas of TOM and the histopathological components of small pulmonary adenocarcinomas. Therefore TS-CT findings are a useful aid in determining the best surgical methods., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small-cell lung cancer. The clinicopathological features of EML4-ALK-positive adenocarcinoma are reported to include its high incidence in young, non-smoking patients, tumors that show distinct solid or acinar growth patterns with or without signet-ring cell histology, and its mutually exclusive occurrence with mutations in EGFR and KRAS. However, the clinical findings have not been well described. Here, we report a case of EML4-ALK-positive lung adenocarcinoma that showed multiple metachronous lesions on the pleura and pulmonary field, suspected to be a recurrence of lung adenocarcinoma after a 20-year disease-free interval. The slow clinical course may be characteristic of EML4-ALK-positive lung adenocarcinoma. Therefore, long-term observation of patients with EML4-ALK-positive lung adenocarcinomas is required after surgery., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is commonly used to distinguish benign from malignant lesion. Recently, maximum standardized uptake value (SUVmax) on FDG-PET has found to have prognostic value. We examined the relationship between SUVmax and proliferative activities as indicated by maximum diameter of tumor opacity on mediastinal-window images (TOM), Ki-67 index, and diameter of the pathological invasive area in lung adenocarcinomas 5mm was determined as 2.15 by ROC analysis, with sensitivity of 88.3% and specificity of 84.6%., Conclusions: SUVmax correlated significantly with Ki-67 index and diameter of the pathological invasive area. The present results suggest the potential role of FDG-PET in predicting adenocarcinomas with invasive characteristics., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: We reported that adenocarcinomas with a bubblelike appearance (BLA) appear similar to old inflammation (J Comput Assist Tomogr 2009;33:42-48). The histopathological, clinical, and biological characteristics of adenocarcinomas with BLA need more investigation., Methods: We retrospectively reviewed the records of 26 patients who had undergone surgical resection between 1993 and 2008. We analyzed correlations between thin-section computed tomographic (TS-CT), histopathological, and clinical findings. We analyzed epidermal growth factor receptor and K-ras gene mutations., Results: The TS-CT findings are unique with one pattern that was the same in all the 26 cases: (1) polygonal with straight and concave margins, (2) slight peripheral ground-glass opacity areas, (3) 3 or more dilated air bronchograms, and (4) clear pleural indentations. The histopathological findings were identical with our TS-CT findings. The mean tumor doubling time was 1165 days. Epidermal growth factor receptor mutations were observed in 17 cases. There were no K-ras mutations. After resection, the 5-year survival rate is 100%., Conclusion: The adenocarcinomas with BLA have unique TS-CT, histopathological, and clinical findings.

Introduction: In our limited resection trial of pulmonary peripheral ground-glass opacity (GGO) lesions from 1998 to 2002, limited resection of Noguchi type A and B carcinomas seemed to have a positive outcome. However, recently three of the 24 patients, with mixed GGO lesions intraoperatively diagnosed as type B, developed a solid lesion at the cut-end scar., Methods: Medical records and radiology and pathology findings of the three patients were reviewed. We also analyzed epidermal growth factor receptor gene mutations when possible., Results: Radiologically, these three second tumors were clearly cut-end scar area recurrences. However, other pathologic and mutation findings suggest metachronous primary cancers developed in Case 1, cut-end recurrence in Case 2, and needle biopsy implantation in Case 3. It is difficult to definitively conclude whether the second tumors were recurrences or metachronous primaries., Conclusions: These second tumors have convinced us that our initial caution in concluding GGO lesions can be cured by limited resection was very appropriate. The recurrences definitely indicate that continuing follow-up attention for more than 5 years is needed after limited resection even for GGO bronchioloalveolar carcinomas.

The ability to resist anoikis is critical for carcinoma cells to metastasize. Although several lung adenocarcinoma cell lines were shown to repress anoikis through the activation of Src, it remains unknown whether Src actually plays a crucial role in anoikis resistance in lung adenocarcinoma tissues. We examined 20 human lung adenocarcinoma tissues with lymphatic permeation and nine cell lines to investigate whether intralymphatic floating carcinoma cells in the tissues, used as an in vivo model of anoikis resistance, actually suppressed anoikis and whether cell lines in suspension culture, an in vitro model of anoikis resistance, survived through Src activation. We observed that the intralymphatic carcinoma cells aggregated tightly to form nests expressing E-cadherin and phosphorylated Src (p-Src). The apoptotic indices of these cells were comparable to those of extracellular matrix adhesive cells in all tissues, indicating that the intralymphatic cells actually evaded anoikis. Next, we found that the nine cell lines in suspension aggregated loosely (five cell lines) or tightly (four cell lines), and all cells resisted anoikis. Upon detachment, four cell lines (LC-KJ, HCC827, H1650, and H1975) formed compact spheroids that expressed E-cadherin and p-Src. The spheroids were similar to intralymphatic tumour nests and were thus considered to be a suitable model of the nests. The spheroids of the four cell lines underwent apoptosis after treatment with the Src/Abl/Kit inhibitor PP1 or Src/Abl inhibitor bosutinib. On the other hand, the Abl/Kit inhibitor imatinib did not affect cell growth or apoptosis in the four types of spheroids. These results indicate that Src, but not Abl or Kit, plays an essential role in the development of anoikis resistance in lung adenocarcinomas.

Diagnostic criteria to identify small lung adenocarcinomas that relapse after resection have yet to be established. For this purpose, we developed a mathematical logistic model in the present study. We collected data for patients with lung adenocarcinoma of 2 cm or less in size: the original cohort comprised 28 men and 25 women and the validation cohort comprised 11 men. By entering five clinicopathological factors (vascular invasion, lymphatic permeation, histological subtype, papillary carcinoma component, and smoking status) into the logistic model, we calculated a predictive function for relapse after surgery. The obtained predictive function accurately classified the patients into a recurrence or non-recurrence group: the overall accuracy of the predictive model for recurrence established from the male patients in the original cohort was 86%. Our predictive model is, however, currently limited to male patients only, because the original cohort included only one female patient with relapse. By applying the logistic model to the validation cohort, six patients were classified into a recurrence group and the other five into a non-recurrence group: four of the six patients in a recurrence group had relapsed, while all five patients in the non-recurrence group were well during their follow-up periods. Although the predictive ability of the logistic model did not reach a statistical significance (P=0.0606), nine of the 11 (82%) patients in the validation cohort were correctly classified. Consequently, using a logistic predictive model consisting of the five clinicopathological factors might enable us to predict the recurrence of resected small-sized lung adenocarcinomas in male patients.

Objective: To study the initial findings of lung adenocarcinoma revealed by computed tomography (CT) scanning and observe tumor progression and elucidate appropriate follow-up schedule of tumor diagnosis via CT findings of suspected lung adenocarcinoma., Method: We studied 59 patients who had undergone CT scanning twice or more at intervals of 3 months or longer before surgery. We evaluated the initial CT findings as well as all subsequent changes. The rate of tumor growth was estimated by tumor volume doubling time, using the original method of Schwartz. The histological classifications were evaluated according to the criteria of Noguchi et al (Cancer 1995;75:2844-2852)., Result: The initial appearances of lung adenocarcinoma were divided into 4 types: (1) ground-glass opacity-like lesions, (2) bubble-like appearance, (3) small nodules, and (4) scar-like lesions. Ground-glass opacity-like lesions tended to increase in size over the years, with solid parts appearing in some lesions during follow-up examinations. Bubble-like appearance displayed characteristic CT findings and tended to increase over the years from the time of initial diagnosis, and we therefore tended to consider them as old inflammatory lesions. Small nodules tended to increase in size over the months more rapidly than in other types. Scar-like lesions tended to exist mainly in the lungs already damaged by lung fibrosis and/or emphysema and therefore were difficult to detect on initial CT scans., Conclusion: We categorized 4 types of initial findings of lung adenocarcinomas detected by CT. We determined that each type of lesion had its own unique characteristic growth patterns and required varying follow-up periods.

Background: Recently, peripheral lung adenocarcinomas (PLA) measuring < or = 3 cm in greatest dimension often have been diagnosed using diagnostic radiology. The objective of the current study was to determine which cytologic factors are associated with a favorable outcome and an unfavorable outcome in patients with PLA., Methods: Imprint smears from 134 patients with PLA were examined. Sixteen cytologic factors, including necrosis, cellular distribution, overlapping of cell clusters, cluster aggregation, cluster size, cluster thickness, nuclear irregularity, nuclear size, variation in nuclear size, multinucleated cells, intranuclear inclusions, type of intranuclear inclusions, appearance of nucleoli, eosinophilic nucleoli, multinucleoli, and mitosis, were evaluated using univariate and multivariate analyses. A counting method was used to determine the prognosis for individual patients., Results: In the univariate analysis, a cluster size that measured > or = 831 microm in short dimension (P = 0.0011), moderate or severe nuclear irregularity (P = 0.0030), > or = 5 multinucleated cells per 100 tumor cells (P = 0.0047), moderate or severe variation in nuclear size (P = 0.0061), medium or large nuclear size (P = 0.0169), and > or = 1 mitotic cell per 100 tumor cells (P = 0.0412) were associated significantly with a poor outcome. In the multivariate analysis, cluster size in short dimension (P = 0.0018), multinucleated cells (P = 0.0066), and nuclear irregularity (P = 0.0310) were found to be independent prognostic factors., Conclusions: The combination of cytologic features using intraoperative imprint smears, namely, cluster sizes < or = 830 microm in short dimension, < or = 4 multinucleated cells per 100 tumor cells, and mild nuclear irregularity, may provide favorable predictive information in patients with PLA., (2004 American Cancer Society)

We previously reported that loss of heterozygosity (LOH) in tuberous sclerosis 1 (TSC1)-gene-associated region on chromosome 9q34, was frequently observed in adenocarcinoma (AC) of the lung and its putative precursor lesion, atypical adenomatous hyperplasia (AAH). Some novel tumor suppressor gene for AC of the lung may be present in this region, and the TSC1 gene located on chromosome 9q34 is one candidate. The aim of this study was to determine whether the TSC1 gene itself acts as a tumor suppressor gene in the pathogenesis of AC of the lung. DNA extracted from frozen tumor tissue was used to screen 47 ACs of the lung for the presence of mutations in 21 coding exons of the TSC1 gene. When using these bulk tissue specimens, three different types of mutations were detected in five ACs. These positive samples were then submitted to laser capture microdissection to selectively collect tumor cells, DNA extraction and finally analysis of LOH and mutations of the TSC1 gene. Mutations were detected in three ACs, and LOH was detected in another AC. No mutations or LOH was detected in the other AC. Loss of heterozygosity and mutations were not detected simultaneously in the same tumor. We concluded that the TSC1 gene itself does not act as a tumor suppressor gene in the pathogenesis of AC of the lung in accordance with classical Knudsen's two-hit hypothesis. However, the frequent LOH in AC and AAH shown in our previous studies indicate the following possibility in the etiology of AC of the lung: the presence of a novel tumor suppressor gene close to the TSC1 gene, aberrant promoter methylation, or haploid insufficiency of the TSC1 gene.

Objectives: In 2001, we proposed the criteria for combined evaluation of the serum carcinoembryonic antigen (CEA) level and the tumor shadow disappearance rate (TDR) to predict pathologic N0 (pN0) disease in pulmonary adenocarcinomas. The objective of the present study was to determine the prognosis and histologic features in small-sized pulmonary adenocarcinomas according to serum CEA level and TDR., Methods: We reviewed clinical records of 189 consecutive patients with peripheral pulmonary adenocarcinoma 3.0 cm or smaller who underwent major lung resection and systematic lymph node dissection: 50 patients with TDR 0.8 or more and normal CEA level (group I) and 139 patients with TDR <0.8 and/or elevated CEA level (group II). Among them, we investigated histologic features of 177 adenocarcinomas according to serum CEA level and TDR., Results: The 5-year survival rates were 95% for group I and 75% for group II (P = 0.002) and for pN0 patients, 97% in group I and 87% in group II (P = 0.04). In univariate analyses, TDR, preoperative serum CEA level, and the maximum tumor dimension on computed tomographic (CT) scan were significantly associated with prognosis. Multivariate analysis showed that only preoperative serum CEA level and TDR were significant independent prognostic factors, and the maximum tumor dimension was not significant. Group I patients developed no local recurrence, including lymph node metastases. In 25 group I adenocarcinomas 2.0 cm or smaller, no lymph node involvement, two lymphatic permeation, two vascular invasion, and one pleural involvement tumors were observed. These signs of local invasiveness were less frequent than the remaining adenocarcinomas. CT findings correlated well with histologic findings in small-sized adenocarcinomas., Conclusions: Combined evaluation of preoperative serum CEA level and TDR may enable us to identify minimally invasive adenocarcinomas with good prognosis. Candidates for limited lung resection without systematic lymph node dissection could be selected based on these findings.

Adenocarcinomas of the lung are characterized by morphological heterogeneity, and since carcinogenesis has been suggested to be a multistep process involving sequential accumulation of multiple genetic alterations, the morphological heterogeneity may represent a cross-sectional view of genetic alterations within individual tumors. Therefore, to elucidate whether, and which, genetic alterations accumulated in relation to morphological cancer progression, we examined 56 microdissected sites for topographical distribution of loss of heterozygosity (LOH) in 12 adenocarcinomas of the lung with bronchioloalveolar (BA) and invasive components in their primary tumors and metastases to lymph nodes. The morphological changes from noninvasive BA lesions to invasive and metastatic components were characterized by a significant rise in the prevalence of allelic losses (P<0.05). Individually, eight cases (67%) showed accumulation of genetic alterations from BA lesions to metastases. LOHs in multiple foci in one case were compared to determine whether they were shared at all tumor sites as an early event or localized in metastases as an additional event. LOHs at 5q and 17p may be crucial steps in the early phase of development to metastasis, while 18q loss may be an additional step. These findings suggested that the cancer cells in some pulmonary adenocarcinomas evolved from the BA lesions to the invasive and metastatic lesions.

Objective: If non-invasive lung carcinomas are distinguishable on computed tomography (CT), limited surgery can be indicated before operation as a radical procedure. The purpose of this study is to define high resolution CT (HRCT) findings that indicate pathologic T1N0M0 tumor without vessel invasion., Patients and Methods: We reviewed HRCT findings and pathological specimens of 98 consecutive patients underwent lobectomy or pneumonectomy with systematic hilar and mediastinal lymph node dissection from January 1996 to October 1999 for 101 pulmonary peripheral adenocarcinomas smaller than 3cm in diameter on HRCT. A total of 101 consecutive surgically resected peripheral adenocarcinomas of the lung measuring 3.0cm or less in the maximum dimension on HRCT were examined both radiologically and histologically. All CT scans ware reviewed by three chest radiologists or pulmonologists. The following parameters were measured on HRCT: the greatest diameter of tumor on found on all CT cuts (Td), the greatest diameter of consolidation found on all CT cuts (Cdmax), and the greatest diameter of consolidation found on a particular CT cut (Cd). Consolidation to tumor size ratio at respective maximum dimensions was calculated as Cdmax/Td, and consolidation to tumor size ratio on the slice image with the maximum tumor dimension was calculated as Cd/Td. One pathologist reviewed all pathological specimens to determine the size of tumor, evidence of vessel invasion, etc. without any information of HRCT, and we compared CT findings with pathological findings., Results: There was a statistically significant difference between tumors with pathologic T1N0M0 adenocarcinoma without vessel invasion (least invasive disease: LID) and tumors with lymph node involvement or vessel invasion (invasive disease: ID) in each parameter. However, only when tumors with Cdmax/Td smaller than 0.5 were selected as LID tumors, could ID tumors be eliminated from the LID group. Five-year survival rate of this population is 95.7%., Conclusion: Consolidation to tumor size ratio at respective maximum dimensions was the best predictor of non-invasive peripheral adenocarcinoma.

A 56-year-old woman was referred for an abnormally dense area in the right upper lung field detected at medical checkup. This shadow had been pointed out frequently since she was 38 years old, but no pathological diagnosis of lung cancer had been given. The size of the abnormal area had gradually increased over the 18 years. Since lung cancer was suspected on the basis of the radiographic findings, she underwent open lung biopsy. Pathologically, the tumor tissue showed a lepidic growth pattern on the wall of preexisting alveoli; and formation of fibrotic foci caused by the collapse of alveoli and the microscopic destruction of the elastic fiber framework were seen in the tumor. There was no vascular invasion or lymphatic infiltration in the tumor. It was diagnosed as well-differentiated nonmucinous adenocarcinoma, p-T2 N0 M0. Although this tumor was untreated for 18 years from the first detection using chest radiography, the critical invasive features were not in evidence pathologically.

Purpose: The aim of this study is to assess the histologic characteristics in cases of localized pure ground-glass opacity (LPGGO) that do not exhibit consolidation on high-resolution CT (HRCT) images., Method: Twenty surgically resected lesions from 20 consecutive cases were retrospectively investigated. Each of the 20 lesions had exhibited LPGGO on HRCT images. The HRCT images and histopathologic findings were examined for correlations., Results: The areas of LPGGO had a maximum diameter of 2.0-24 mm on the HRCT images. Histopathology of the LPGGO lesions resulted in diagnosis of fibrosis (n = 3; 15%), atypical adenomatous hyperplasia (n = 5; 25%), bronchioloalveolar carcinoma (n = 10; 50%), and adenocarcinoma with stromal invasion (n = 2; 10%). Nonaerogenous components corresponding to solid components without normal alveolar septal destruction were pathologically observed in 15 of the 20 lesions. The diameter of the nonaerogenous components varied between 0.2 and 2.0 mm., Conclusion: Because 10% of LPGGO lesions include invasive disease, patients with LPGGO should undergo pathologic examination for confirmation.

Atypical adenomatous hyperplasia (AAH) has recently been implicated as a precursor to lung adenocarcinoma. We previously reported loss of heterozygosity (LOH) in tuberous sclerosis (TSC) gene-associated regions to frequently be observed in lung adenocarcinoma with multiple AAHs. In this study, we analyzed LOH in four microsatellite loci on 9q, including the TSC1 gene-associated region, and four loci on 16p, including the TSC2 gene-associated region, in both 18 AAHs and 17 concomitant lung adenocarcinomas from 11 patients. Seven of 18 (39%) AAHs and 9 of 17 (53%) adenocarcinomas displayed LOH on 9q. Five (28%) AAHs and seven (41%) adenocarcinomas harbored LOH at loci adjacent to the TSC1 gene. Four of 18 (22%) AAHs and 6 of 17 (35%) adenocarcinomas displayed LOH on 16p. One (6%) AAH and five (29%) adenocarcinomas harbored LOH at loci adjacent to the TSC2 gene. These findings may indicate a causal relationship of LOH on 9q and 16p in a fraction of AAH lesions and adenocarcinomas of the lung. Especially, the frequencies of LOH on 9q and at the TSC1 gene-associated region were high. The TSC1 gene or another neighboring tumor suppressor gene on 9q might be involved in an early stage of the pathogenesis of lung adenocarcinoma.

We report a case of a 46-year-old man with a 7 mm lung adenocarcinoma with mediastinal nodal involvement and lymphangiosis carcinomatosa. The resected right middle lobe contained a 7 mm well-differentiated papillary adenocarcinoma and lymphatic vessels towards the hilum were severely involved. The disease was pathologically diagnosed as T1N2M0. Six months after the operation, malignant pleural effusion and multiple bone metastases developed and he died 21 months after the operation. This case indicates that even a very small-sized lung cancer, 1 cm or smaller, could be biologically highly malignant.

A low incidence of lung carcinoma has been reported in cases of prolonged use of aspirin. Cyclooxygenase (COX) 2 expression is frequently seen in adenocarcinoma of the lung, but COX-2 expression in atypical adenomatous hyperplasia (AAH), a possible precursor lesion of adenocarcinoma of the lung, is not known. COX-2 expression was immunohistochemically evaluated in a cohort of 20 cuboidal cell hyperplasias (CCH), 81 atypical adenomatous hyperplasias (AAH), 18 bronchioloalveolar carcinomas (BAC), and 88 invasive adenocarcinomas (I-Ad). The relationship between COX-2 expression and clinicopathologic factors and survival was examined. COX-2 overexpression was detected in over 80% of CCH, AAH, BAC, and I-Ad. However, overexpression was diffuse in AAH (71.6%) and BAC (66.7%). No relationship was found between COX-2 expression and clinicopathological factors or survival. COX-2 expression was most frequently detected in AAH. These findings, taken with previous reports that treatment with COX-2 inhibitor suppresses human colon carcinogenesis, suggest that inhibition of COX-2 may reduce the incidence of human adenocarcinoma of the lung.

We describe a 70-year-old man with lung cancer implantation in the chest wall following percutaneous fine needle aspiration biopsy. He underwent lobectomy after percutaneous transthoracic fine needle aspiration biopsy using a 19-gauge needle. Twenty-six months after the biopsy, he noticed a hard subcutaneous tumor at the biopsy site in the chest wall. Ribs and intercostal muscles were resected. The primary lung tumor and the chest wall tumor were histologically identical, but were not contiguous to each other. We concluded that the subcutaneous tumor was due to needle biopsy implantation. This complication is extremely rare, but open biopsy should always be considered as a possible alternative. During the procedure, care must be taken with the least chance of implantation and patients should be observed carefully after needle biopsy.

Many small adenocarcinomas can be detected as a result of recent advances in diagnostic radiology. Since the histological and biological heterogeneity of adenocarcinoma often makes it difficult to predict the outcome of operated patients, clarifying the morphological prognostic factors of the tumor is indispensable to the selection of appropriate treatment. We examined 200 cases of adenocarcinoma of the lung 3 cm or less in diameter (T1). Tumor size, tumor cell characteristics, growth pattern, characteristics of fibrosis, vessel and stromal invasion, and metastasis were evaluated to define favorable and unfavorable morphological prognostic factors by univariate and multivariate statistical analysis. There were no deaths in the 66 cases with more than a 75% of lepidic growth component defined as a region of tumor cells growing along alveolar walls and without stromal invasion, central focus of fibrosis 5 mm or less in maximum diameter, or no elastic fiber framework destruction by tumor cells. Multivariate analysis to investigate unfavorable factors revealed that vascular invasion (P<0.001) and a greater than 25% papillary growth component (P=0.043) were the most significant determinants of an unfavorable outcome. The favorable and unfavorable factors demonstrated in this study will be of great value in selecting the treatment of patients with small peripheral adenocarcinoma of the lung.