Osamu Kawashima

Clinicopathological features of lung adenocarcinoma with KRAS mutations.

KRAS and epidermal growth factor receptor (EGFR) mutations are thought to play an important role in the carcinogenesis of lung adenocarcinoma. However, clinicopathological findings of KRAS mutated adenocarcinoma cases have not yet been fully clarified. The authors analyzed the relationship between the KRAS mutation and corresponding clinicopathological findings, focusing on nonmucinous and mucinous bronchioloalveolar elements.

ASC amino-acid transporter 2 (ASCT2) as a novel prognostic marker in non-small cell lung cancer.

Background:ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear.Methods:One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort.Results:ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients.Conclusions:ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.

High‐grade neuroendocrine carcinoma of the lung: Comparative clinicopathological study of large cell neuroendocrine carcinoma and small cell lung carcinoma

Large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are high‐grade neuroendocrine carcinomas. In order to clarify the similarities and differences between these cancers, 22 cases each of LCNEC and SCLC were collected and a comparative pathological study was carried out. First, their clinicopathological characteristics were confirmed, which were very similar to those previously reported. The 5 year survival rate of LCNEC and SCLC patients was 38.3% and 29.7%, respectively. The morphological characteristics of LCNEC and SCLC were then reviewed with regard to the morphology previously used to differentiate these cancers. As a result, many morphological indicators, such as tumor cell size, nuclear/cytoplasmic ratio, nuclear molding, rosette formation, prominent nucleoli and karyolysis were confirmed to be significant indicators for distinguishing LCNEC from SCLC. On comparative immunohistochemistry, LCNEC had significantly high staining scores for the expression of keratin 7 and 18, E‐ and P‐cadherins, β‐catenin, villin 1, retinoblastoma protein (pRB), c‐met and α‐enolase. These results might reflect the differentiation or deviation of LCNEC toward an epithelial nature irrespective of neuroendocrine tumor lineage. In conclusion, the present comparative study of LCNEC and SCLC defined the similarities and differences between these cancers, and showed the biologically and clinicopathologically overlapping spectrum of the tumor lineage.

The impact of residual multi-level N2 disease after induction therapy for non-small cell lung cancer

BACKGROUND The presence of residual N2 disease following induction therapy for locally advanced non-small cell lung cancer (NSCLC) has been proposed as a contraindication to surgery. However, single level N2 metastases found in the operative specimens of patients with clinical N0 NSCLC who did not receive induction therapy is associated with prolonged survival. In order to investigate whether residual single level N2 disease following induction therapy was similarly associated with prolonged survival, we conducted a retrospective review of patients with stages IIIa and IIIb NSCLC who had undergone induction therapy followed by surgery. METHODS A retrospective review was performed of the hospital records of patients with stages IIIa and IIIb NSCLC who had undergone induction therapy consisting of chemotherapy and/or radiotherapy followed by tumor resection and mediastinal lymph node dissection at 11 Japanese national referral hospitals. Survival was analyzed by the Kaplan-Meier method and prognostic factors were determined by the log-rank and Cox regression methods. RESULTS One hundred thirty-one patients underwent induction therapy of NSCLC stages IIIa (n=95) and IIIb (n=36) followed by complete tumor resection during a 12-year interval. Clinical N2 disease was present in 114 (87%) patients and N3 disease in 17 (13%) patients. Median follow up was 48 months. Eighteen patients had residual single level N2 disease and 25 patients had multiple residual N2 level metastases. The 5-year survival was 54% for patients with pathologic single level N2 disease and 11% for patients with multiple N2 level disease (P<0.01). In a multivariate analysis, only the pathologic N status significantly influenced survival. CONCLUSION Patents who have multiple levels of N2 disease have a much worse prognosis than patients who have single level of N2.

Expression of L-type amino acid transporter 1 (LAT1) in neuroendocrine tumors of the lung.

Amino acid transport systems play an important role in cellular proliferation. L-type amino acid transporter 1 (LAT1) has been associated with tumor growth, and is highly expressed in the established tumor cell lines and primary human neoplasms. In this study, we investigated the expression of LAT1 to evaluate the malignant potential and prognostic significance in neuroendocrine (NE) tumors of the lung. Twenty-one surgically resected, large cell neuroendocrine carcinomas (LCNEC), 13 small cell lung cancers (SCLC), five atypical carcinoids (AC), and 10 typical carcinoids (TC) were enrolled in the study. LAT1 expression and Ki-67 labeling index of the NE tumors were analyzed by immunohistochemical staining. LAT1 was overexpressed in 52.4% of the LCNEC, in 46.2% of the SCLC, and in 25% of the AC. LAT1 expression in LCNEC was significantly associated with lymph node metastasis and poor outcome. Moreover, a significant correlation was found between LAT1 expression and Ki-67 in both LCNEC and SCLC. Expression of LAT1 tended to increase from low-grade to high-grade NE tumors. The present results suggest that LAT1 may play a significant role in cellular proliferation, lymph node metastasis, and poor outcome in patients with NE tumors of the lung.

A Case of Esophageal Sarcomatoid Carcinoma with Molecular Evidence of a Monoclonal Origin

A case of polypoid tumor of the esophagus consisting of a sarcomatous tumor partly covered with superficial squamous cell carcinoma is described. The sarcomatous component consisted of anaplastic spindle and pleomorphic tumor cells that mimicked malignant fibrous histiocytoma (MFH). Both the sarcomatous and carcinomatous components were positive for p53 immunohistochemically. Further molecular analysis revealed that the two components had the same somatic mutation in the p53 gene. These results suggest a monoclonal origin of this biphasic tumor.

Primary adenoid cystic carcinoma in the lung: Report of two cases and therapeutic considerations

Primary adenoid cystic carcinoma in the lung is an uncommon disease, which is regarded as a slow growing low-grade malignancy. However, this disease has a high risk of incomplete resection because of its unique histological invasion patterns. The cases of two patients who recently underwent surgery for adenoid cystic carcinoma in the lung are reported. Both patients received postoperative radiotherapy treatment as a follow-up to a histologically incomplete resection. Both patients have survived for 51 months and 7 months, respectively, with no recurrence. Postoperative radiotherapy is an acceptable treatment of choice to control residual lesions and provides long-term survival even in cases of incomplete resection.

Adenosquamous carcinoma of the lung: surgical results as compared with squamous cell and adenocarcinoma cases

OBJECTIVES An adenosquamous carcinoma (ASC) of the lung is a relatively rare tumor. In this multi-institutional cohort study, we tested the hypothesis that an ASC exhibits more aggressive clinical behavior as compared to adenocarcinoma (AC) and squamous cell carcinoma (SC). METHODS This retrospective cohort study used a prospective database produced by the Japan National Hospital Organization Study Group for Lung Cancer over a 7-year period (operations from 1997 to 2003, follow-up data until March 2010). During that period, 4668 cases underwent an operation for various types of primary malignant lung tumors. When a sample from a tumor comprised at least 20% each of SC and AC, the case was classified as ASC. Pathologic staging was done according to the seventh edition of the International Union against Cancer (UICC) Tumor Node Matastasis (TNM) classification of malignant tumors. RESULTS We identified 114 patients with ASC (2.4%), 2993 with AC (64.2%), and 1369 with SC (29.3%). Kaplan-Meier survival curves for all stage cases, p-stage IA, IB, and IIIA tumors indicated that ASC cases had the least favorable survival. The 5-year survival rates for all stage cases were 23.3% for ASC, 58.0% for AC (p < 0.0001), and 40.8% for SC (p < 0.0001). The 5-year survival rates for p-stage IA were 42.0% for ASC, 81.8% for AC (p = 0.0005), and 63.4% for SC not significant (NS), while those for p-stage IB were 19.3%, 65.3% (p = 0.0024), and 46.8% (NS), respectively, and those for p-stage IIIA were 17.8%, 24.8% (p = 0.0154), and 18.8% (NS), respectively. There was a tendency for greater survival differences between ASC and AC in earlier tumor stages. A step-wise multivariable model demonstrated that sex, age, performance status, histology, tumor size, p-stage, operative method, and neoadjuvant/adjuvant therapy were independent prognostic factors. CONCLUSION ASC of the lung is more aggressive than AC and SC. The decreased survival of patients with ASC as compared with either of those single histology tumors suggests the need for a clinical trial of adjuvant chemotherapy that includes early-stage patients.

Primary pulmonary collision tumor including squamous cell carcinoma and T-cell lymphoma

We report a very rare occurrence of a primary collision tumor in the lung consisting of squamous cell carcinoma and T-cell lymphoma. A squamous cell carcinoma was diagnosed histologically following a transbronchial lung biopsy in a 71-year-old woman, but the other component was diagnosed histologically and immunohistochemically only on examination of the resection specimen. The malignant lymphoma was stained by the monoclonal antibody UCHL-1 (anti-D45RO) against T-lymphocytes but was not stained by the L26 (anti-CD20) antibody against B-lymphocytes. Immunostaining for CD3 was positive, confirming a T-cell lineage. Despite systemic chemotherapy, the patient died 7 months after operation, from progression of the lymphoma. Our case, which illustrates interesting attributes of collision tumors, consisted of an ordinary squamous cell carcinoma and a rare T-cell lymphoma arising in the lung, with the latter part of the combination dictating subsequent treatment and outcome.

The clinicopathological significance of preoperative serum-soluble interleukin-2 receptor concentrations in operable non-small-cell lung cancer patients

BackgroundSerum-soluble interleukin-2 receptor (IL-2R) concentrations have been found to be elevated in cancer patients. However, the importance of this finding in patients with non-small-cell lung cancer (NSCLC) has not been previously established.MethodsPreoperative serum-soluble IL-2R concentrations were determined in 65 consecutive patients with operable NSCLC. The correlation of preoperative serum-soluble IL-2R concentrations with various clinicopathological features of this cancer was evaluated to clarify the clinical significance of this parameter.ResultsAlthough serum-soluble IL-2R concentrations were not significantly higher in operable NSCLC patients than in normal controls (P=.1180), serum-soluble IL-2R concentrations were significantly higher in patients with stage IIIB or IV disease than in normal controls (P=.0001). The presence of intrapulmonary metastasis was the only clinicopathological feature that was significantly correlated to serum-soluble IL-2R concentration (P=.0004). The sensitivity of serum-soluble IL-2R concentration in identifying the presence of intrapulmonary metastasis was 87.5%; specificity was 75%.ConclusionsElevated preoperative serum-soluble IL-2R concentrations in patients with operable NSCLC reflect the occurrence of intrapulmonary metastasis. Preoperative examination of serum-soluble IL-2R concentrations may be valuable in the detection of the intrapulmonary metastasis preoperatively.