Hajime Otsuka

Histopathologic Features of the Tumor Budding in Adenocarcinoma of the Lung: Tumor Budding As an Index to Predict the Potential Aggressiveness

Introduction: The term tumor budding has been applied to single cells or small clusters of up to four cells within the stromal tissue at the invasive margin of colorectal cancers. This morphologic feature is increasingly being recognized as an adverse prognostic factor. The purpose of this study was to evaluate the clinicopathologic significance of tumor budding in adenocarcinomas of the lung. Methods: We investigated the relationship between tumor budding and clinicopathologic parameters of adenocarcinomas of the lung and the prognostic significance of tumor budding by reviewing the cases of 201 consecutive patients who had undergone complete resection of adenocarcinoma of the lung measuring 30 mm or less in diameter. We examined immunohistochemical profile of budding cells (BCs) by immunohistochemical staining with 14 antibodies. Results: Tumor budding was observed in 78 (43.1%) of the 181 cases with invasive adenocarcinoma. The presence of tumor budding was significantly associated with lymph node metastasis (p = 0.005), pathologic stage (p < 0.001), vascular invasion (p = 0.003), lymphatic invasion (p = 0.009), and pleural invasion (p = 0.029). Examination of the relation between the presence of tumor budding and the predominant histologic subtype revealed that the predominant papillary subtype was significantly associated with the presence of tumor budding (p = 0.0023), whereas the predominant bronchioloalveolar carcinoma subtype was significantly associated with the absence of tumor budding (p < 0.001). The overall 5-year survival rates of the group with budding and the group without budding was 67.5% and 88.3%, respectively, and difference was significant (p = 0.0057). Compared with cancer cells forming nests, BCs displayed reduced expression of cellular adhesion molecule, E-cadherin, and β-catenin (p < 0.05 and p < 0.05, respectively) and increased expression of laminin5-γ2 (p < 0.05). However, BCs displayed reduced expression of differentiation marker, surfactant protein A (p < 0.05). Multivariate analysis revealed that tumor budding was significant independent prognostic factor of the small-sized adenocarcinoma of the lung. Conclusions: Our data showed that tumor budding in adenocarcinoma of the lung is a distinct morphologic feature that has biologic and prognostic significance.

Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation.

Background: Germline alterations in the proapoptotic protein Bcl-2–like 11 (BIM) can have a crucial role in tumor response to treatment. To determine the clinical utility of detecting BIM deletion polymorphism in non–small-cell lung cancer positive for epidermal growth factor receptor (EGFR) mutation, we examined outcomes of patients with and without BIM alterations. Methods: We studied 70 patients with EGFR mutation-positive non–small-cell lung cancer who were treated with an EGFR tyrosine kinase inhibitor between January 2008 and January 2013. BIM deletion was analyzed by polymerase chain reaction in 58 samples of peripheral blood and 24 formalin-fixed paraffin-embedded slides of surgical specimens (20 of lung tissue and four of brain tissue); both blood and tissue specimens were available for 12 patients. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM deletion. Results: BIM deletion was present in 13 of 70 patients (18.6%). There were no significant differences between patients with and without BIM deletion in clinical characteristics, rate of response to EGFR tyrosine kinase inhibitor, or incidence of adverse events. Patients with BIM deletion had significantly shorter progression-free survival (PFS) than those without BIM deletion (median, 227 versus 533 days; p < 0.001). Multivariate Cox regression analysis showed that BIM deletion was an independent indicator of shorter PFS (hazard ratio, 3.99; 95% confidence interval, 1.864–8.547; p < 0.001). Conclusions: Polymerase chain reaction successfully detected BIM deletion in samples of peripheral blood and formalin-fixed paraffin-embedded slides of surgical specimens. BIM deletion was the most important independent prognostic factor in shorter PFS.

Treatment options for patients with large cell neuroendocrine carcinoma of the lung.

Large cell neuroendocrine carcinoma (LCNEC) of the lung is categorized as a variant of large cell carcinomas, and LCNEC tumors display biological behaviors resembling those of small cell lung carcinomas and features of high-grade neuroendocrine tumors. Because patients with LCNEC have a poor prognosis, surgery alone is not sufficient. Multimodality therapies, including adjuvant chemotherapy, appear promising for improved prognosis in patients with LCNEC. In this review article, we discuss treatment options for patients with LCNEC of the lung.

Ciliated Muconodular Papillary Tumor of the Lung: A Newly Defined Low-grade Malignant Tumor with CT Findings Reminiscent of Adenocarcinoma

A ciliated muconodular papillary tumor has been reported to be a peripheral low-grade malignant tumor, consisting of ciliated columnar cells and goblet cells with basaloid cell proliferation. Although ciliated muconodular papillary tumors have not yet been classified according to the World Health Organization classification, they can pose diagnostic and therapeutic problems. Here we report a resected case of ciliated muconodular papillary tumor with computed tomography findings reminiscent of adenocarcinoma, showing a small irregular nodule adjacent to the intersegment pulmonary vein. There was no uptake of F-18 fluorodeoxyglucose positron emission tomography. The patient underwent surgical resection, and a lobectomy was performed because intraoperative needle biopsy suggested neoplastic proliferation. No EGFR mutations were detected. No recurrence was noted during 24-month follow-up after lobectomy.

Video-Assisted Thoracoscopic Surgery for Ectopic Middle Mediastinal Thymoma in a Patient With Myasthenia Gravis

We present a rare case of middle mediastinal thymoma with myasthenia gravis. A 51-year-old man presented with right ptosis and muscle weakness, and received a diagnosis of generalized myasthenia gravis. Computed tomography of the chest showed a 20-mm nodule in the middle mediastinum, suggesting a possible ectopic thymoma. He underwent video-assisted thoracoscopic extended thymectomy and resection of the tumor. Histologic examination revealed an ectopic thymoma and ectopic thymic tissue around the tumor. One year after the operation, his condition remains well controlled solely with tacrolimus. Careful preoperative radiologic examination concerning possible ectopic thymoma outside the dissection area of the extended thymectomy is recommended.

Simultaneous bilateral spontaneous pneumothorax with congenital pleuro-pleural communication

A single pleural space can lead to serious simultaneous bilateral pneumothorax in cases of congenital or acquired pleuro-pleural communication. Here we report a 35-year-old man with bilateral pneumothorax. Chest computed tomography scans revealed a small air space between the esophagus and aorta, suggesting pleuro-pleural communication. Bilateral thoracoscopic bullectomy was performed. Repeated inspection revealed a 2-cm-long pleural window between the aorta and esophagus, which was closed with a collagen patch. Although congenital pleuro-pleural communication has been regarded as rare, as many as nine patients have been reported (if suspected cases are included). The lower middle mediastinum should be carefully inspected.

Tracheal leiomyoma resected with endobronchial electrocautery snare.

Tracheobronchial leiomyoma is a rare benign tumor, which comprises about 2% of benign tumors of the lower respiratory tract. Bronchoscopic intervention is a minimally invasive treatment, but incomplete resection or recurrence has been reported. We report a case of a 76-year-old woman with a tracheal tumor of 14 mm in diameter incidentally detected on chest computed tomography. Bronchoscopic examination revealed a smooth polypoid tumor which pedunculated from the left side of the cartilaginous tracheal wall. An endobronchial electrocautery snare with flexible bronchoscope was successfully used under general anesthesia and with intubation. The resected specimen was pathologically consistent with leiomyoma. Bronchoscopic intervention can yield successful treatment of pedunculated tracheobronchial leiomyomas, although surgical resection should also be considered in cases of broad-based or iceberg-type leiomyomas because of the risk of incomplete resection or recurrence.

Complete response of 7 years’ duration after chemoradiotherapy followed by gefitinib in a patient with intramedullary spinal cord metastasis from lung adenocarcinoma

Intramedullary spinal cord metastasis is a rare but serious complication which causes rapid progression of neurological deficits. Here we report a 35-year-old man presenting with increasing leg pain and gait disturbance, 8 months after surgery for lung adenocarcinoma. Spinal magnetic resonance imaging revealed an intramedullary tumor at the Th7/8 level. Radiotherapy at 35 Gy resulted in transient symptomatic improvement, but during chemotherapy with vinorelbine and cisplatin, symptoms worsened again. Gefitinib was then administered; the patient improved after 2 weeks and has now maintained a complete response for 7 years.

A case of chronic expanding hematoma resulting in fatal hemoptysis

An 80-year-old woman presented with a huge intrathoracic mass which had increased in size over 4 years. Computed tomography showed a thick calcified capsule and early-enhanced streaks inside the mass. Needle biopsy aspirated pure blood and fibrous connective tissue. F-18 fluorodeoxyglucose positron-emission tomography showed moderate FDG uptake at the periphery with central photon defects. Gallium-67 scintigraphy showed no abnormal uptake. On suspicion of chronic expanding hematoma, we recommended surgical resection, but the patient requested only follow-up. One year later, she was hospitalized with cardiac tamponade and subsequent massive hemoptysis. Repeated embolization was ineffective, and the patient soon succumbed.

Haemothorax following bullectomy caused by a sharp edge of the Endoloop

A 22-year old man presented with a massive haemothorax 25 days after bullectomy for a spontaneous pneumothorax. Thoracoscopic surgery revealed ongoing bleeding from the chest wall caused by a sharp edge of the Endoloop Ligature (Ethicon Endo-Surgery) used to resect the remaining small part of the lung at the earlier staple bullectomy. The point where bleeding was occurring was clipped and covered using a collagen patch coated with human fibrinogen and thrombin. The protruding sharp edge of the Endoloop was excised together with the surrounding lung tissue, using a stapler. Although prevention of this type of complication is difficult, awareness of the potential problem may help in managing such extremely rare events.