Kyohei Masai

Expression of squamous cell carcinoma markers and adenocarcinoma markers in primary pulmonary neuroendocrine carcinomas.

Recent clinical trials have revealed that accurate histologic typing of non–small cell lung cancer is essential. Until now, squamous cell carcinoma (SQC) and adenocarcinoma (ADC) markers have not been thoroughly analyzed for pulmonary neuroendocrine carcinomas (NECs). We analyzed the expression of 8 markers [p63, cytokeratin (CK) 5/6, SOX2, CK7, desmocollin 3, thyroid transcription factor-1 (8G7G3/1 and SPT24), and napsin A] in 224 NECs. SOX2 (76.2%) had the greatest expression for NECs. CK5/6 (1.4%), desmocollin 3 (0.5%), and napsin A (0%) were expressed less or not at all in NECs. Although our investigated markers have been reported useful for differentiating between SQC and ADC, some of them were also present in a portion of pulmonary NECs. In our study, CK5/6 and desmocollin 3 were highly specific markers for SQC, and napsin A was highly specific for ADC. These markers are recommended for diagnosis of poorly differentiated non–small cell lung cancer.

P40 is the best marker for diagnosing pulmonary squamous cell carcinoma: Comparison with p63, cytokeratin 5/6, desmocollin-3, and Sox2

Histologic distinction among non–small cell lung carcinomas, particularly between squamous cell carcinoma (SQC) and adenocarcinoma (ADC), has become more important. Recently, a p40 antibody was suggested to be a highly specific marker for SQC. We evaluated p40 expression and compared it with the expression of other SQC markers in 580 primary lung carcinomas, including 158 SQCs, 156 ADCs, 50 carcinoid tomors, 107 large cell neuroendocrine carcinomas, 68 small cell lung carcinomas, and 41 malignant mesotheliomas. Detailed histologic distributions of p40-positive cases were as follows: 153 (96.8%) of 158 SQCs, 7 (4.6%) of 152 ADCs, 0 (0%) of 50 carcinoid tomors, 4 (3.6%) of 107 large cell neuroendocrine carcinomas, 1 (1.5%) of 68 small cell lung carcinomas, and 1 (2.4%) of 41 mesotheliomas. p40 staining yields high sensitivity as well as high specificity for distinguishing SQC from ADC, neuroendocrine carcinomas, and malignant mesothelioma.

Prognostic Impact of Margin Distance and Tumor Spread Through Air Spaces in Limited Resection for Primary Lung Cancer

Objectives The aim of this study was to investigate the relationship between clinicopathological prognostic factors, including surgical margin distance and tumor spread through air spaces (STAS), and recurrence after limited resection for primary lung cancer. Methods We identified 508 cases of limited resection (12.8%) and examined their clinicopathological features. Using Cox regression analysis, we examined the significant prognostic factors for recurrence of limited resection. Finally, we conducted a histopathological evaluation of tumor STAS. Results Multivariate Cox analysis showed that the risk for local recurrence was significantly associated with STAS (hazard ratio = 12.24, p = 0.001) and a tumor margin less than 1.0 cm (hazard ratio = 6.36, p = 0.02). However, the presence of tumor STAS was not significantly associated with distant recurrence (p = 0.98). This lack of association of STAS with distant recurrence may be due to the small number of distant recurrences. In all, 76 cases (15.0%) (60 adenocarcinomas, nine squamous cell carcinomas, and seven others) were positive for STAS. The morphological STAS patterns were 12 single cells, 45 small cell clusters, and 19 large nests. There was no significant relationship between the recurrence rate and morphological STAS pattern. The STAS‐positive group was associated with the presence of micropapillary (p = 0.002) and/or solid components (p = 0.008) in patients with adenocarcinoma and with lymphovascular and pleural invasion (p < 0.001). Conclusions The presence of STAS and tumor margins less than 1.0 cm are significant risk factors for local recurrence in early‐stage lung cancer after limited resection. Thus, the presence of tumor STAS might be a pathological prognostic factor for patients with lung cancer who have undergone limited resection. However, the pathological and molecular significance of STAS remain to be clarified.

Clinicopathological, Immunohistochemical, and Genetic Features of Primary Lung Adenocarcinoma Occurring in the Setting of Usual Interstitial Pneumonia Pattern

Introduction: An association between usual interstitial pneumonia (UIP) and carcinogenesis has been well established. However, few detailed analyses have investigated the clinicopathological, immunohistochemical, and genetic features of patients with primary lung adenocarcinoma (ADC) with UIP (UIP‐ADC). Methods: We identified 44 patients with ADC in the setting of UIP (the UIP‐ADC group) (1.9%) from 2309 patients with primary ADC and compared clinicopathological, immunohistochemical, and genetic features between the UIP‐ADC group and patients with ADC without UIP (the non–UIP‐ADC group). Results: Clinicopathological features of UIP‐ADC included an older age at occurrence; male predominance; smoking history; predilection for the lower lobe; large tumor size; high incidence of lymph vessel invasion, pleural invasion, and lymph node metastasis; and poor survival rate. However, the cause of death of patients with UIP‐ADC was largely influenced by respiratory complications. Histologically, patients in the UIP‐ADC group could be stratified according to invasive mucinous‐predominant subtype. Genetically, patients in the UIP‐ADC group had lower EGFR and higher KRAS mutation rates compared with patients in the non–UIP‐ADC group. Conclusions: UIP‐ADC was associated with a poor prognosis owing to the high frequency of perioperative complications rather than the malignancy of the tumor itself. There was a high prevalence of the invasive mucinous‐predominant subtype in cases of UIP‐ADC. UIP‐ADC also had a low prevalence of EGFR mutations and a high prevalence of KRAS mutations. These findings suggest that UIP‐ADC should be distinct from non–UIP‐ADC.

Cytokeratin 19 expression in primary thoracic tumors and lymph node metastases

BACKGROUND The use of one-step nucleic acid amplification (OSNA), which allows for the rapid intraoperative detection of lymph node (LN) metastasis, is becoming more widely accepted in breast cancer. To provide basic data for the development of this method for lung tumors, we conducted a large-scale investigation of cytokeratin (CK) 19 expression in thoracic tumors. PATIENTS AND METHODS We examined CK19 expression in specimens from a total of 801 surgically resected samples of primary lung adenocarcinoma (ADC), squamous cell carcinoma (SQC), large-cell carcinoma (LCC), pleomorphic carcinoma (PC), large cell neuroendocrine carcinoma (LCNEC), small cell carcinoma (SCC), and carcinoid tumor (CT) as well as pleural malignant mesothelioma and lung metastatic deposits from breast cancer using tissue microarrays (TMAs) and whole sections. We also compared the CK19 expression status between primary sites and LN metastatic deposits. RESULTS The overall rate of CK19 expression as observed on TMAs and whole sections in the 801 analyzed cases was 88.0%. CK19 expression was detected in 94.6% of ADCs, 93.6% of SQCs, 54.5% of LCCs, 54.8% of PCs, 77.4% of LCNECs, 31.8% of SCCs, 34.0% of CTs, and 92.9% of malignant mesotheliomas. Expression of CK19 was also detected in 90.9% of lung metastatic deposits from breast carcinomas. CK19 expression was maintained between CK19-positive primary sites and the corresponding LN metastatic deposits. Of note, a portion of CK19-negative primary tumors showed upregulation of CK19 protein expression in LN metastases. CONCLUSIONS Most thoracic tumors, except for PCs, CTs, and SCCs, were positive for CK19. We also found that CK19 expression was maintained between CK19-positive primary tumors and the corresponding LN metastatic deposits. These results may be useful in the development of the OSNA method for the intraoperative detection of LN metastasis in non-small cell lung cancer (NSCLC).

Clinical and pathological characteristics of EGFR mutation in operable early-stage lung adenocarcinoma

OBJECTIVES Over the past decade, the biological and clinical characteristics of lung cancer with epidermal growth factor receptor (EGFR) mutation have been well studied. However, most studies have focused on advanced inoperable cancer, and not on resected early-stage lung adenocarcinoma. We aimed to elucidate the differences in the clinicopathological characteristics and postoperative prognosis according to the EGFR mutation status in early-stage lung adenocarcinoma. MATERIALS AND METHODS We retrospectively collected clinical and pathological data from 369 patients with pathological stage I or II lung adenocarcinoma who underwent complete resection. Clinicopathological characteristics and postoperative prognosis were compared depending on the EGFR mutation status, using the Chi-squared test and the log-rank test, respectively. RESULTS AND CONCLUSION Of the 369 patients, 160 (43.3%) had EGFR mutation, of which 64 (40.0%) were exon 19 deletion (Del-19) and 90 (56.3%) were exon 21 point mutation L858R. Although there was no difference in overall survival (OS) between patients with and without EGFR mutation (p=0.086), tumors with EGFR mutation were associated with a lower consolidation to tumor ratio (CTR) (p <0.001) and a higher incidence of a lepidic growth pattern by pathological evaluation (p <0.001) compared to those without EGFR mutation. Among tumors with EGFR mutation, there was no difference in OS (p=0.140) between Del-19 and L858R. Tumors with L858R were associated with a lower CTR (p=0.046), and tended to have a higher incidence of a lepidic growth pattern by pathological evaluation (p=0.073) compared to those with Del-19. In conclusion, although EGFR mutation status was not a prognostic indicator after surgery in early-stage lung adenocarcinoma, L858R and Del-19 had different radiological and pathological features.

Pleuroscopic punch biopsy using insulated-tip diathermic knife-2 for the diagnosis of desmoplastic malignant mesothelioma.

Desmoplastic malignant mesothelioma (DMM) is a rare subtype of malignant pleural mesothelioma (MPM) and is often difficult to distinguish from pleural fibrosis and reactive mesothelial hyperplasia, especially if the biopsy samples are small. We performed full-thickness pleural biopsy on a lesion suspected to be DMM using an insulated-tip diathermic knife-2 (IT knife-2) during flex-rigid pleuroscopy. IT knife-2 is a novel electrosurgical device for endoscopic submucosal dissection in the early gastrointestinal cancer. It consists of a needle knife with 3 short blades at the distal end attached to an insulated ceramic tip. A 54-year-old man presenting with chest wall mass and thickened pleura, in whom a computed tomography-guided percutaneous needle aspiration had remained negative, underwent flex-rigid pleuroscopy for definitive diagnosis. While applying electric current, we used the IT knife-2 to incise the pleura in a circular shape just above the endothoracic fascia. The incised pleura was removed by forceps and examined pathologically. The microscopic examination was compatible with DMM. We discovered that pleuroscopic punch biopsy using IT knife-2 can diagnose DMM. Use of IT knife-2 during flex-rigid pleuroscopy can obtain sufficient samples from densely thickened pleura, which is difficult to diagnose with small biopsies.

A Proposal for Definition of Minimally Invasive Adenocarcinoma of the Lung Regardless of Tumor Size

BACKGROUND Based on the current World Health Organization classification, adenocarcinoma with a predominantly lepidic pattern larger than 3.0 cm in diameter is considered to be invasive adenocarcinoma, specifically lepidic adenocarcinoma, even if it shows pathologic invasion of 0.5 cm or less. However, we sometimes encounter lepidic adenocarcinomas larger than 3.0 cm with a good prognosis as well as minimally invasive adenocarcinoma. METHODS Of 4,606 resected primary lung cancers at our institute between 1998 and 2011, this study focused on 18 lepidic adenocarcinomas with invasion of 0.5 cm or less. Clinicopathologic characteristics, including epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement status, and prognosis were evaluated. RESULTS The median maximum pathologic tumor diameter was 3.4 cm (range, 3.1 to 4.7 cm) and the median maximum diameter of the invasive area within the tumor was 0.4 cm (range, 0 to 0.5 cm). No lymph node metastasis, vascular invasion, lymphatic permeation, or pleural invasion was pathologically confirmed in any of the 18 cases. Although epidermal growth factor receptor mutation was detected in 13 cases (72%), none of the patients showed anaplastic lymphoma kinase rearrangement. Recurrence was not observed in any of the 18 patients. The 5-year overall and cancer-specific survival rates were 94.4% and 100%, respectively. CONCLUSIONS Lepidic adenocarcinoma with invasion of 0.5 cm or less had a good prognosis. Adenocarcinoma with a predominantly lepidic pattern and invasion of 0.5 cm or less can be regarded as minimally invasive adenocarcinoma even if the tumor is larger than 3.0 cm in diameter.

Clinicopathological features of colloid adenocarcinoma of the lung: A report of six cases.

Colloid adenocarcinoma of the lung (CA) is a rare neoplasm that is associated with abundant mucin, which destroys alveoli. We evaluated the clinicopathological features of CA.

Clinical Features of Ground Glass Opacity–Dominant Lung Cancer Exceeding 3.0 cm in the Whole Tumor Size

BACKGROUND Ground glass opacity (GGO)-dominant lung adenocarcinoma sized 3.0 cm or less in the whole tumor size is widely known to have an excellent prognosis and is regarded as early lung cancer. However, the characteristics and prognosis of lung cancer showing GGO exceeding 3.0 cm remains unclear. METHODS From 2002 through 2012, we reviewed 3,735 lung cancers that underwent complete resection at our institution. We identified 160 lung cancers (4.3%) showing GGO exceeding 3.0 cm on thin-section computed tomography and divided them into three types by the consolidation/tumor ratio (CTR) using cutoff values of 0.25 and 0.5. We compared the characteristics and prognosis among these types. RESULTS Type A (CTR, 0 to ≤0.25), type B (CTR, >0.25 to ≤0.5), and type C (CTR, >0.5 to <1.0) were found in 16 (10%), 37 (23%), and 107 lesions (67%), respectively. No lymph node metastasis was found in types A and B. Recurrence was not observed in types A and B. The 5-year overall survival and disease-free survival rates were both 100% in type A, both 97.2% in type B, and 88.4% and 66.7% in type C, respectively. Patients with type C had a significantly worse prognosis than those with the other types with respect to overall survival and disease-free survival. CONCLUSIONS A patient with GGO-dominant lung cancer exceeding 3.0 cm can be considered to be in a group of patients with nodal-negative disease and an excellent prognosis.