Teppei Nishii

Unique mutation, accelerated mTOR signaling and angiogenesis in the pulmonary cysts of Birt-Hogg-Dubé syndrome.

Birt‐Hogg‐Dubé syndrome (BHD) is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors and pulmonary cysts with repeated pneumothorax. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is known to be involved in the signaling of mammalian target of rapamycin (mTOR). We investigated the lung of a BHD patient who presented with a unique mutation. A 33‐year‐old woman visited our hospital due to repeated pneumothorax. Histopathologic study of the resected lung demonstrated multiple epithelial cysts. An increase of blood vessels was observed in the vicinity of subpleural cysts. Genomic DNA analysis revealed heterozygous mutation at the 3′ end of intron 5 of the FLCN gene. Total mRNA and protein were extracted from the resected lung tissue. RT‐PCR and sequence analysis demonstrated the production of exon 6‐skipped FLCN mRNA. In Western blotting, the band intensities of phospho‐mTOR, phospho‐S6, phospho‐Akt, hypoxia‐inducible factor (HIF)‐1α and vascular endothelial growth factor (VEGF) were increased in the BHD lung compared with normal lungs. Histopathologic analysis demonstrated strong immunostainings of mTOR signaling molecules in cyst‐lining cells. Collective data indicates that dysregulation of mTOR signaling facilitates S6‐mediated protein synthesis and HIF‐1α‐mediated angiogenesis, which may contribute to the development of pulmonary cysts in this disorder.

Comparison between CT tumor size and pathological tumor size in frozen section examinations of lung adenocarcinoma

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.

Correlations Between the EGFR Mutation Status and Clinicopathological Features of Clinical Stage I Lung Adenocarcinoma.

Abstract 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.

Case of solitary pulmonary capillary hemangioma: Pathological features based on frozen section analysis

Solitary pulmonary capillary hemangioma (SPCH) is a rare benign lung tumor that must be distinguished from small and early lung cancers. Here, we report a case of SPCH for which we performed frozen section diagnosis. The patient was a 55‐year‐old Japanese woman. Five years before the operation, mixed ground‐glass opacity was detected by computed tomography in the left posterior basal segment of the lower lobe (S10). Because the interior tumor density of the ground‐glass opacity increased slightly, video‐assisted thoracic surgery wedge resection was performed. Frozen section diagnosis revealed a benign tumor without proliferation of atypical epithelial cells. The tumor had narrow alveolar lumens, thickened alveolar septa and a clear boundary separating it from normal lung tissue. The proliferated lumens varied in size and were lined with single layers of flat cells. After the operation, immunohistochemical staining of a paraffin section revealed that the thickened alveolar septa resulted from the proliferation of capillary vessels, the flat cells of which were positive for CD31 and CD34 and negative for podoplanin; the tumor was diagnosed as SPCH. Here, we discuss the pathological features of SPCH on frozen sections with reference to this case and review previous related reports.

Well-Differentiated Extraskeletal Osteosarcoma Arising from the Retroperitoneum That Recurred as Anaplastic Spindle Cell Sarcoma

Extraskeletal osteosarcoma is an uncommon high-grade malignant soft tissue sarcoma. Well-differentiated extraskeletal osteosarcoma is thought to have a better prognosis than classical extraskeletal osteosarcoma, but dedifferentiation after recurrence has also been reported. We present a case of a primary retroperitoneal extraskeletal osteosarcoma in a 62-year-old Japanese woman. Abdominal CT revealed a large mass with diffuse calcification in the right retroperitoneal space and tumor resection was performed. The histopathological diagnosis was well-differentiated retroperitoneal extraskeletal osteosarcoma. She was followed up by CT every 6 months without adjuvant radiotherapy and chemotherapy for 31 months until anaplastic high-grade spindle cell sarcoma recurred in the retroperitoneum. Our case is the seventh reported description of well-differentiated extraskeletal sarcoma, and the first to arise in the retroperitoneum and recur as an entirely dedifferentiated spindle cell sarcoma.

Lung cancer associated with an azygos lobe successfully treated with video-assisted thoracoscopic surgery

Primary lung cancer associated with an azygos lobe is extremely rare. Herein, we report the case of a 64‐year‐old woman with lung adenocarcinoma arising in the right upper lobe with an azygos lobe. The patient underwent a right upper lobectomy and lymph node dissection with video‐assisted thoracoscopic surgery. Video‐assisted thoracoscopic surgery lobectomy for lung cancer of this variant has yet to be reported. We demonstrate the intraoperative findings and the resected pulmonary lobe. This is the first case of primary lung cancer associated with the azygos lobe treated by lobectomy with video‐assisted thoracoscopic surgery.

Prognostic value of EGFR mutations in surgically resected pathological stage I lung adenocarcinoma

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.

Lung adenocarcinoma with Lambert–Eaton myasthenic syndrome indicated by voltage-gated calcium channel: a case report

IntroductionLambert–Eaton myasthenic syndrome is a rare disorder and it is known as a paraneoplastic neurological syndrome. Small cell lung cancer often accompanies this syndrome. Lambert–Eaton myasthenic syndrome associated with lung adenocarcinoma is extremely rare; there are only a few reported cases worldwide.Case presentationA 75-year-old Japanese man with a past history of chronic rheumatoid arthritis and Sjögren syndrome was diagnosed with Lambert–Eaton myasthenic syndrome by electromyography and serum anti-P/Q-type voltage-gated calcium channel antibody level preceding the diagnosis of lung cancer. A chest computed tomography to screen for malignant lesions revealed an abnormal shadow in the lung. Although a histopathological examination by bronchoscopic study could not reveal the malignancy, lung cancer was mostly suspected after the results of a chest computed tomography and [18F]-fluorodeoxyglucose positron emission tomography. An intraoperative diagnosis based on the frozen section obtained by tumor biopsy was adenocarcinoma so the patient underwent a lobectomy of the right lower lobe and lymph node dissection with video-assisted thoracoscopic surgery. The permanent pathological examination was the same as the frozen diagnosis (pT2aN1M0: Stage IIa: TNM staging 7th edition). Immunohistochemistry revealed that most of the cancer cells were positive for P/Q-type voltage-gated calcium channel.ConclusionsOur case is a rare combination of Lambert–Eaton myasthenic syndrome associated with lung adenocarcinoma, rheumatoid arthritis and Sjögren syndrome, and to the best of our knowledge it is the first report that indicates the presence of voltage-gated calcium channel in lung adenocarcinoma by immunostaining.

Video-assisted thoracoscopic surgery for pulmonary arteriovenous malformations: report of five cases

We experienced five cases of pulmonary arteriovenous malformations (PAVMs) that were successfully treated by video-assisted thoracoscopic surgery. Four malformations were treated by local wedge resection and one was treated by segmentectomy. Criteria for patient selection for surgery were peripheral and solitary lesions, with feeding arteries larger than 3 mm. Postoperative hospital stays were 1–7 days (median, 2 days). All patients showed unchanged or increased values of PaO2 in arterial blood after operation. No major postoperative complication occurred in any patient, but a persistent air leak for 5 days occurred in the one patient who was treated by segmentectomy. No growth of accessory vessels or untreated malformations were seen in any patient throughout the follow-up period of 14–54 months. Thoracoscopic surgical resection for well-selected patients provides a high certainty of eliminating fistulae and was associated with lower morbidity, lower mortality, and shorter hospital stays.

Detection of tumor spread through airspaces by airway secretion cytology from resected lung cancer specimens

It currently remains unclear whether tumor spread through airspaces (STAS) actually exist in vivo or are an artifact. The morphologies of STAS and tumor cell clusters in airway secretions collected from the segmental or lobar bronchus of resected lung adenocarcinomas and squamous cell carcinomas were compared among 48 patients. The EGFR status of tumor cell clusters in airway secretions was also compared with that of the main tumor in EGFR mutant adenocarcinomas. Tumor cell clusters were observed in the airway secretion cytology of ten patients (20.8%), and eight patients were adenocarcinoma (20.0% of adenocarcinoma). The morphology of STAS closely resembled that of tumor cell clusters detected in airway secretion cytology. The positive rates of airway secretion cytology were 83.3%, 100%, and 50% in papillary adenocarcinoma, micropapillary adenocarcinoma, and invasive mucinous adenocarcinoma, respectively. Among three EGFR mutant adenocarcinomas, the EGFR mutation subtypes of the main tumors in FFPE sections and tumor cell clusters in airway secretions were identical. These indicate that STAS may be detected in the airway secretion cytology. STAS is common in papillary or micropapillary adenocarcinoma and may spread as far as the segmental or lobar bronchus at the time of surgery.