Tomoharu Yoshiya

Role of lymphatic invasion in the prognosis of patients with clinical node-negative and pathologic node-positive lung adenocarcinoma

OBJECTIVE Some patients with clinical T1 N0 M0 lung adenocarcinoma have pathologic lymph node metastasis. However, neither the precise prognosis nor the factors predictive of the prognosis of such patients have yet been identified. METHODS Our study included 609 patients with clinical T1 N0 M0 lung adenocarcinoma; 568 (93.3%) pathologic node negative [pN(-)] and 41 (6.7%) pathologic node positive [pN(+)] patients, diagnosed after complete surgical resection. The association between prognosis and pathologic findings was analyzed retrospectively. RESULTS pN(+) patients had a significantly lower lepidic growth component ratio (10% vs 50%), a higher lymphatic invasion (LI) rate (68% vs 11%), vessel invasion rate (59% vs 14%), and visceral pleural invasion rate (29% vs 9%), compared with pN(-) patients (all Ps < .001). Surprisingly, 13 of 41 (32%) pN(+) patients showed no LI. In pN(-) patients, a multivariate analysis of recurrence-free survival revealed that lower lepidic growth component ratio, and lymphatic, vessel, and pleural invasion were significantly correlated with a poor prognosis (P = .008, .045, .031, and .024). However, in pN(+) patients, the multivariate analysis of recurrence-free survival showed that only LI was a significant independent prognostic factor (P = .037). The 5-year recurrence-free survival rates were as follows: 91.2% for pN(-)/LI(-) patients, 68.2% for pN(-)/LI(+) patients, 63.5% for pN(+)/LI(-) patients, and 41.9% for pN(+)/LI(+) patients. LI status stratified the prognosis not only in patients with no nodal metastasis but also in those with metastasis. CONCLUSIONS LI, which is not always present in node-positive adenocarcinoma, is an important prognostic variable in patients with node involvement.

Prediction for prognosis of resected pT1a-1bN0M0 adenocarcinoma based on tumor size and histological status: relationship of TNM and IASLC/ATS/ERS classifications.

OBJECTIVES This study aimed to estimate the relationship between 7th TNM classification and IASLC/ATS/ERS classification with regard to tumor size and pathological status and to determine the utility of these classifications for predicting prognosis in resected node-negative adenocarcinoma with tumor size ≤2.0 cm and >2.0-3.0 cm. MATERIALS AND METHODS We reviewed 321 pN0M0 lung adenocarcinoma cases resected at Hiroshima University Hospital from January 1991 to December 2010. Histological differences between T1a and T1b based on the IASLC/ATS/ERS classification were estimated and followed by evaluation of overall survival (OS) and recurrence-free interval (RFI) based on differences in tumor size and histological features. RESULTS We found 188 cases of pT1a-1bN0M0 (135 T1a, 53 T1b). Pathological T1a tumors included significantly more adenocarcinoma in situ (AIS) cases and minimally invasive adenocarcinoma (MIA) cases than T1b tumors (60.7% vs 18.8%, respectively; p<0.0001), while more invasive adenocarcinoma cases were included in pT1b. By considering the two classifications simultaneously, the 5-year OS rates of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 97.5%, 87.5%, 95.8%, and 86.8%, respectively. The 5-year RFIs of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 100%, 100%, 91.3%, and 72.5%, respectively. T1a AIS/MIA and T1b AIS/MIA could be separated as good prognostic cases with a 100% RFI. Multivariate analysis indicated that only T1b invasive adenocarcinoma was an independent factor for predicting recurrence (p=0.001). CONCLUSION Compared to a single classification, combining TNM and IASLC/ATS/ERS classifications could provide more detail information concerning disease recurrence. AIS and MIA should be handled equally, regardless of tumor size, because their non-/less invasive status is more useful for predicting prognosis than their tumor size classification. In contrast, the T descriptors based on TNM classification are important for predicting prognosis in invasive adenocarcinoma.

Prognostic value of the new IASLC/ATS/ERS classification of clinical stage IA lung adenocarcinoma

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.

Negative prognostic influence of micropapillary pattern in stage IA lung adenocarcinoma

OBJECTIVES There is uncertainty as to which factors determine the aggressiveness of lung adenocarcinoma with a micropapillary pattern (MPP). The present study aimed to clarify the influence of a MPP on the malignant aggressiveness of clinical stage IA lung adenocarcinoma. METHODS We retrospectively examined 347 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection. We defined MPP-positive as accounting for ≥5% of the entire tumour. RESULTS Forty-eight (14%) and 299 (86%) patients were MPP-positive and negative, respectively. Lymphatic (P = 0.003) and vessel (P = 0.029) invasion as well as lymph node metastasis (P = 0.002) were more frequent in the MPP-positive than negative group. Five-year disease-free survival (DFS) rates were significantly lower in the MPP-positive than negative group (69.7 vs 89.3%, P < 0.001). Multivariate analysis for DFS showed that MPP (P = 0.048), lymphatic invasion (P = 0.003) and vessel invasion (P = 0.002) were independent poor prognostic factors. In addition, higher proportions (<5%, 5-30% and ≥30%) of MPP were associated with a poorer prognosis (89.3, 76.0, and 48.1%, respectively; P < 0.001). The prognosis of patients with MPP-positive tumours and negative tumours harbouring lepidic and solid predominant growth patents did not differ (100 vs 96.8%, P = 0.564; 66.7 vs 62.5%, P = 0.791, respectively). On the other hand, the prognosis tended to be poorer for patients with papillary predominant MPP-positive tumours than for those with negative tumours (62.5 vs 82.5%, P = 0.075). CONCLUSIONS MPP has an effect on tumour malignancy and patients with tumours harbouring a higher ratio of MPP or papillary predominant subtypes have worse survival.

Role of Positron Emission Tomography/Computed Tomography Findings for Adjuvant Chemotherapy Indications in Stage T1b-2aN0M0 Lung Adenocarcinoma

BACKGROUND This study aimed to determine the significance of the maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) images on postoperative adjuvant chemotherapy for lung adenocarcinoma. METHODS We assessed recurrence-free interval (RFI) and overall survival (OS) based on SUVmax values derived from preoperative FDG-PET/CT images in 174 consecutive patients with completely resected pathologic stage T1b-2aN0M0 lung adenocarcinoma. RESULTS Ninety patients received adjuvant chemotherapy and 84 did not. Adjuvant chemotherapy conferred benefits on RFI and OS when compared with observation (p=0.007 and p=0.004, respectively). Multivariate Cox regression analyses revealed SUVmax as an independent prognostic factor for RFI. RFI and OS were significantly longer for patients who received adjuvant chemotherapy compared with those who did not in the group with SUVmax greater than or equal to 2.6 (p<0.001 and p<0.001, respectively). However, RFI and OS did not differ significantly between such patients in the group with SUVmax less than 2.6 (p=0.421 and p=0.452, respectively). CONCLUSIONS Preoperative SUVmax determined from FDG-PET/CT images reflected the effect of adjuvant chemotherapy after complete resection in patients with pathologic stage T1b-2aN0M0 lung adenocarcinoma. Indications for postoperative adjuvant chemotherapy among patients with lung adenocarcinoma might be more precisely determined using SUVmax derived from FDG-PET/CT images together with tumor size.

The Difference in Maximum Standardized Uptake Value among Lung Adenocarcinomas Located at the Upper and Lower Zone on PET/CT

Background: Findings on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) are surrogate markers of malignancy in lung adenocarcinoma. Breathing during PET/CT can substantially reduce the maximum standardized uptake value (maxSUV) of lung tumors when they are located at the lower zone (LZ). Objectives: We assessed whether lung cancer location influences the malignancy predicted by maxSUV. Methods: 608 patients with clinical stage IA lung adenocarcinoma had been preoperatively examined by PET/CT and high-resolution computed tomography (HRCT). We evaluated the clinicopathological characteristics of these patients and the accuracy of precognition obtained by maxSUV between the upper zone (UZ, n = 395) and the LZ (n = 213). maxSUV was also analyzed for matched pairs between the two groups. Results: The mean maxSUV in the LZ group was significantly lower than that in the UZ group (1.98 ± 1.73 vs. 2.44 ± 2.43, respectively; p = 0.0145). The receiver operating characteristics curve of maxSUV for predicting high-grade malignancy (lymphatic, vascular, pleural invasion, or lymph node metastasis) was larger for the UZ group than for the LZ group [0.89, 95% confidence interval (CI) 0.86-0.93, vs. 0.82, 95% CI 0.76-0.88]. Analysis for maxSUV of 213 pairs matched for the solid component size on HRCT, pathological characteristics, and gender revealed that maxSUV in the LZ group was significantly lower than that in the UZ group (1.98 ± 1.73 vs. 2.47 ± 2.39, respectively; p < 0.001). Conclusions: maxSUV of a tumor in the LZ group is apparently lower than the value which reflects the potential malignancy of a tumor. We have to carefully consider these facts when selecting the appropriate surgical procedure for lung cancer with PET/CT and HRCT.

Increased risk of recurrence in resected EGFR-positive pN0M0 invasive lung adenocarcinoma: Recurrent risk of EGFR mutation in LAD

This study was conducted to evaluate the prognostic and recurrent impact of EGFR mutation status in resected pN0M0 lung adenocarcinoma with consideration of the histological subtype.

The differences in histological changes among pulmonary vessels divided with an energy device

OBJECTIVES Histological changes after division of the pulmonary artery (PA) and the pulmonary vein (PV) using a vessel-sealing device are not fully understood. The goal of the present study was to clarify histologically and immunohistochemically how division with the device affects the wall layers of the pulmonary vasculature. METHODS This prospective cohort study analysed outcomes of 20 patients who underwent anatomical lung resection. After a single proximal ligation, the PA and the PV (diameter 2-7 mm) were divided using a LigaSure Blunt Tip (LSB). Histological findings and thermal damage were evaluated in vascular specimens from resected lungs. RESULTS The PA has a well-developed media with rich elastic fibres and a thin adventitia, whereas the PV has a thinner media and a thicker adventitia with abundant collagen fibres. Vascular division of the PAs and PVs appeared complete to the naked eye. However, in all divided PAs, the area adjacent to the sealed zone comprised only adventitia and thin disrupted media. Additionally, thermal energy generated by the LSB resulted in a wide area of thermal necrosis over the histologically fragile region in all cases. Conversely, the wall layers of all divided PVs were completely fused without disruption. Thermal spread and disruption did not significantly differ between small (2-4 mm) and large (5-7 mm) PAs [187 (150-253) vs 236 (190-275) μm, P = 0.22; 180 (138-200) vs 210 (161-305) μm, P = 0.22]. Histological changes differed significantly between the pulmonary vessels after division using the LSB. CONCLUSIONS Surgeons should consider that dividing the pulmonary vessels with a vessel-sealing device might have more histological impact on the layers of the wall of the PA than on those of the PV, although it remains unclear whether these findings constitute a clinical risk.

Second predominant subtype predicts outcomes of intermediate-malignant invasive lung adenocarcinoma†

OBJECTIVES Acinar predominant and papillary predominant invasive adenocarcinomas are likely to be classified as intermediate-malignant types. Although these two types of adenocarcinoma are distinguished morphologically, the differences between their malignant behaviours and prognoses are not clear. The aim of this study is to provide a prognostically relevant stratification of these similar subtypes based on pathological features. METHODS We retrospectively reviewed 347 consecutive clinically N0M0 lung adenocarcinomas of ≤3 cm in diameter that were resected between April 2006 and December 2010 at two institutes. Acinar and papillary predominant adenocarcinomas were classified into acinar/papillary-lepidic type and acinar/papillary-non-lepidic type according to whether the second predominant component was a lepidic or invasive component. RESULTS Fifty-four acinar and 59 papillary predominant adenocarcinoma cases were classified as acinar/papillary-lepidic type (n = 65) or acinar/papillary-non-lepidic type (n = 48) cases. Acinar/papillary-non-lepidic type cases were accompanied by more vascular invasion (13.8% vs 31.3%, P = 0.0451) and pleural invasion (9.2% vs 25.0%, P = 0.0450) than were acinar/papillary-lepidic type cases. Five-year overall survival (OS) and recurrence-free survival (RFS) also differed significantly between these types (5-year OS: acinar/papillary-lepidic type, 96.3% vs acinar/papillary-non-lepidic type, 61.8%, hazard ratio = 6.315, P = 0.00650; 5-year RFS: acinar/papillary-lepidic type, 91.4% vs acinar/papillary-non-lepidic type, 68.8%, hazard ratio = 2.967, P = 0.0210). Multivariate analysis revealed that a second predominant component was an independent prognostic factor for RFS (acinar/papillary-non-lepidic type: hazard ratio = 3.784, 95% confidence interval 1.091–13.128, P = 0.036). CONCLUSIONS The pathological second predominant component allows intermediate-malignant adenocarcinomas to be subclassified with prognostic significance. It can be utilized when assessing postoperative risks for recurrence and when considering therapeutic strategies.

The safety and efficacy of fibrinogen and thrombin-based collagen fleece for treatment of pleural injury

Fibrinogen/thrombin-based collagen fleece (TachoSil) can be applied to repair pleural injury, however, little is known about the impact of its use on lung.