Prognostic impact of surgical treatment for high-grade neuroendocrine carcinoma of the lung: a multi-institutional retrospective study.

Background: High-grade neuroendocrine carcinoma (HGNEC) of the lung, which includes small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), is an aggressive form of lung cancer. Although lobectomy followed by adjuvant chemotherapy is regarded as the standard therapy for this disease, it would be an uphill struggle for HGNEC patients to receive that multidisciplinary therapy perfectly. This study aimed to examine recurrence and survival outcomes in surgically treated patients with HGNEC of the lung. Methods: The medical records of 104 HGNEC patients who underwent surgical treatment in five institutions were retrospectively analyzed. Standard treatment (ST) was defined as lobectomy, bilobectomy, or pneumonectomy with mediastinal lymph node dissection followed by adjuvant platinum-doublet chemotherapy with more than two cycles. Results: Patients in the ST group (n=31; 30%) were younger and had fewer respiratory complications than those in the non-standard treatment (NST) group (n=73; 70%). A significantly higher proportion of patients in the NST group developed ipsilateral lymph node recurrence (21% vs. 3%; P=0.035) and ipsilateral or contralateral lung recurrence (15% vs. 0%; P=0.031). Five-year overall survival (OS) was 64.2% in the ST group and 38.3% in the NST group (P=0.038). NST was independently associated with worse OS in multivariate analysis (hazard ratio, 2.044; 95% confidence interval, 1.016-4.113; P=0.045). Conclusions: Surgically treated HGNEC patients who received ST had a more favorable outcome than those who received NST. Patients who receive NST may require additional treatment.

Upregulation of glucose and amino acid transporters in micropapillary carcinoma.

Micropapillary carcinoma (MPC), a relatively rare histologic carcinoma observed in various organs, is associated with vascular invasion, nodal metastasis, and poor prognosis. MPC is different from papillary carcinoma as it has no fibrovascular core and is thus considered essentially hypovascular. MPCs are known to upregulate glucose transporter 1 (GLUT1) via the activation of a transcription factor, hypoxia-inducible factor (HIF)-1. Here we evaluated the expression of nutrient transporters in MPCs to gain a better understanding of the system used by MPCs to compensate for their intrinsic poor vascularity. We immunohistochemically evaluated 29 MPCs including breast (n=14), lung (n=8), gastrointestinal tract (n=5), and urinary tract cancers (n=2), and compared them with non-micropapillary control cancers (n=32) regarding the expression of amino acid (ASCT1, ASCT2, LAT1, and SNAT1) and glucose (GLUT1, GLUT2) transporters. Each section was scored by the staining intensity (0-3) multiplied by the occupying area (0-10), with a possible range 0-30. The average scores of the MPC and control groups were compared by Student's or Welch's t-test according to the homoscedasticity. The MPC group showed significantly higher scores for ASCT1 (p=0.007), ASCT2 (p=0.001), GLUT1 (p<0.001), and GLUT2 (p<0.001), whereas no significant scores were noted for LAT1 and SNAT1. In conclusion, MPC could be associated with the upregulation of several nutrient transporters, which may contribute to the malignant potential by supporting the survival of cancer cells.

Cushing's syndrome caused by ACTH-producing thymic typical carcinoid with local invasion and regional lymph node metastasis: a case report.

BACKGROUND: Ectopic ACTH-producing thymic carcinoid tumors are rare, but often behave aggressively with local invasion and distant metastasis. We herein report a case of ACTH-producing thymic typical carcinoid tumor with lymph node metastasis treated by surgery and postoperative radiation therapy. CASE PRESENTATION: A 61-year-old woman was admitted to be evaluated for hypoglycemia and hypokalemia. Laboratory data revealed elevation of serum cortisol and ACTH levels. Overnight administration of 8 mg dexamethasone did not suppress plasma ACTH. Chest CT demonstrated a tumor of 30 mm in diameter and enlargement of the lymph node at the anterior mediastinum. Ectopic ACTH syndrome was suspected and total thymectomy and lymph node dissection were performed. The histopathological examination indicated typical carcinoid tumor and mediastinal lymph node metastasis, and immunohistochemical staining was positive for ACTH. The plasma ACTH level decreased immediately after surgery. She received postoperative radiation therapy of 60 Gy. CONCLUSION: Ectopic ACTH-producing thymic typical carcinoid tumors are rare, and it is important to consider this disease and perform appropriate treatment.

Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma.

AIMS: Podoplanin expression in cancer-associated fibroblasts (CAFs) has been proposed as an unfavourable indicator in squamous cell carcinoma of the lung, but little is known about its clinical significance in early-stage lung adenocarcinoma. We evaluated the prognostic impact of podoplanin expression in patients with pathological stage (p-stage) IA lung adenocarcinoma as categorised by the 8th edition of the tumour-node-metastasis classification for lung cancer. METHODS AND RESULTS: Immunohistochemical analyses using anti-podoplanin antibody were performed on resected specimens from 158 patients with p-stage IA lung adenocarcinoma. When more than 10% of cancer cells or CAFs showed immunoreactivity with podoplanin, the specimens were classified as podoplanin-positive. Podoplanin-positive status in cancer cells (n = 8) was not correlated with clinicopathological factors or with patient prognosis. Podoplanin-positive status in CAFs (n = 41) was correlated significantly with poorer tumour differentiation (P < 0.001), the presence of lymphatic invasion (P < 0.001) and high-grade (solid and/or micropapillary) components constituting ≥1% of the entire tumour (P < 0.001). The log-rank test showed that podoplanin-positive status in CAFs was associated significantly with shorter disease-free survival (DFS) (P < 0.001) and disease-specific survival (P = 0.015). In Cox's multivariate analysis, podoplanin-positive status in CAFs had the most significant effect on shorter DFS [hazard ratio (HR) = 4.411, P = 0.004], followed by the presence of high-grade components (HR = 3.581, P = 0.013). CONCLUSIONS: Podoplanin expression in CAFs could be an independent predictor of increased risk of recurrence in patients with p-stage IA lung adenocarcinoma.

Initial Results of Robotic Surgery for Primary Lung Cancer: Feasibility, Safety and Learning Curve.

BACKGROUND: At the end of 2016, robot-assisted thoracoscopic surgery (RATS) was still not covered by Japanese national health insurance. Therefore, few institutions in Japan perform RATS and even fewer have reported procedures as they occurred earlier. So, we decided to focus on the initial results of RATS for primary lung cancer. METHODS: We retrospectively reviewed 44 patients who underwent RATS for primary lung cancer from January 2011 to August 2016. After mastering the initial procedure, we introduced a completely portal robotic pulmonary resection procedure using a carbon dioxide insufflation system. Cases were divided into 2 groups: the early period (20 cases) and the later period (24 cases). RESULTS: There was no case of conversion to video-assisted thoracoscopic surgery or thoracotomy. In the 44 cases of primary lung cancer, median operating time was 239.5 min, console time was 179 min, blood loss was 10 mL, drainage period was 2 days, morbidity of Grade 2 or more (Clavien-Dindo classification) was 18.2%, morbidity of Grade 3 or more was only 4.6%, and there was no 30-day mortality. Median operating and console times were significantly shorter in the later period (215 min and 159.5 min, respectively) than in the initial period (300.5 min and 228 min, respectively). Median blood loss was significantly lower in the later period (5 mL) than in the initial period (50 mL). Five-year overall and disease-free survival rates were 100% and 88.9%, respectively. CONCLUSION: RATS for primary lung cancer is feasible and safe, has a faster learning curve, and provides satisfactory. Studies with longer follow-ups and larger numbers of cases are necessary.

Subcellular Localization of Maspin Correlates with Histone Deacetylase 1 Expression in Human Breast Cancer.

BACKGROUND/AIM: Maspin is known to be a tumor suppressor protein. Its nuclear localization and endogenous inhibition of histone deacetylase 1 (HDAC1) are considered crucial for its tumor suppressor activity. However, it remains unclear whether subcellular localization of maspin correlates with HDAC1 expression level in human breast cancer. PATIENTS AND METHODS: Immunohistochemical analyses were performed on 164 resected specimens of invasive breast carcinoma using antibodies for maspin and HDAC1. Subcellular localization of maspin protein and HDAC1 mRNA expression level in two human breast cancer cell lines (MCF7, MDA-MB-231) and mammary epithelial cell line (MCF10) were analyzed by immunofluorescence and quantitative polymerase chain reaction, respectively. RESULTS: The frequency of cytoplasmic-only, pancellular (combined nuclear and cytoplasm) and no staining of maspin were 31%, 14.0% and 55%, respectively. The cytoplasmic-only subgroup showed significantly higher histological grade (p=0.004), negative progesterone receptor status (p=0.003) and shorter disease-free survival compared to the pancellular subgroup (p=0.043). High HDAC1 expression was observed in 60% of cases and was significantly correlated with cytoplasmic-only staining compared to pancellular (p<0.001) or no staining (p=0.004). Immunofluorescence analysis revealed that maspin protein was localized mainly in the cytoplasm in MCF7 and MDA-MB-231 cells, while in both the nucleus and cytoplasm in MCF10A cells. HDAC1 mRNA levels were significantly up-regulated in MCF7 and MDA-MB-231 cells compared to MCF10A cells (p<0.001). CONCLUSION: High HDAC1 expression may contribute to the aggressiveness of human breast cancer with cytoplasmic-only expression of maspin.

Prognostic Factors for Post Recurrence Survival in Resected Pathological Stage I Non-small Cell Lung Cancer.

Background: Recurrence of lung cancer after surgical resection is a major obstacle in the cure and long-term survival of patients and has become the most common cause of death. However, prognostic factors and efficacy of therapy after recurrence remain controversial. We evaluated the prognostic factors of post recurrence survival (PRS) in patients of resected stage I non-small cell lung cancer (NSCLC). Methods: Of the 551 patients who underwent surgery for stage I NSCLC between 2005 and 2013, we reviewed 89 (16.2%) patients who had recurrence. We examined PRS using the Kaplan-Meier method and multivariate Cox regression analyses. Results: The median follow-up period after recurrence was 21.0 months. The median recurrence free interval (RFI) was 16.8 months. The 1-year PRS and 3-year PRS were 65.6% and 44.7%, respectively. Multivariate analysis revealed that size of primary lesion > 25 mm (P = 0.048), RFI ≤ 17 months (P = 0.048) and no treatment for recurrence (P < 0.001) were independent poor-prognosis factors of PRS. We further examined PRS in 66 patients who underwent any post recurrence therapy. For the patients who underwent treatment after recurrence, bone metastasis (P = 0.025) and treatment without epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) (P = 0.049) were independent poor prognostic factors. Conclusion: PRS may be associated with characteristics of a recurrent lesion, including the biology of the recurrent tumor, RFI, recurrent site, the treatment for recurrence, rather than characteristics of primary lesion. Although further validation is needed, this information is important for the design of clinical trials for post-recurrence therapy.

Podoplanin Expression in Cancer-associated Fibroblasts Predicts Poor Prognosis in Patients with Squamous Cell Carcinoma of the Lung.

BACKGROUND/AIM: Podoplanin is a candidate cancer stem cell marker in squamous cell carcinoma (SCC). Several studies have reported the prognostic value of podoplanin expression in tumor cells in lung SCC but few have focused on its expression in cancer-associated fibroblasts (CAFs). The aim of this study was to analyze the prognostic significance of podoplanin expression, with special reference to the expression pattern in both tumor cells and CAFs. PATIENTS AND METHODS: Immunohistochemical analyses using anti-podoplanin antibody were performed on 126 resected specimens of lung SCC. When more than 10% of tumor cells or CAFs showed immunoreactivity with podoplanin levels as strong as those of the positive controls, the specimens were classified as a podoplanin-positive. RESULTS: Podoplanin-positive status in tumor cells (n=54) was correlated with a lower incidence of lymphatic invasion (p=0.031) but there were no significant differences in disease-free survival (DFS) and disease-specific survival (DSS) by the log-rank test. Podoplanin-positive status in CAFs (n=41) was correlated with more advanced stage (p=0.008), higher frequency of pleural invasion (p=0.002) and both shorter DFS (p=0.006) and DSS (p=0.006). In Cox's multivariate analysis, podoplanin-positive status in CAFs was an independent negative prognostic factor for DFS (p=0.027) and DSS (p=0.027). CONCLUSION: Podoplanin expression in CAFs might be an independent unfavorable prognostic indicator in patients with lung SCC, irrespective of the expression status of tumor cells.

Simplified comorbidity score for elderly patients undergoing thoracoscopic surgery for lung cancer.

PURPOSE: We investigated the efficiency of the Simplified Comorbidity Score (SCS) for predicting postoperative complications and prognosis in elderly patients undergoing video-assisted thoracoscopic surgery (VATS) for lung cancer. METHODS: We reviewed 216 patients aged 75 years or older, who underwent pulmonary resection by VATS for lung cancer between January, 2005 and December, 2012. The SCS assigns different scores to patients' comorbidities; namely, smoking (n = 7); diabetes mellitus (n = 5); renal insufficiency (n = 4); and respiratory, neoplastic, and cardiovascular comorbidities or alcoholism (n = 1 each). Patients were divided into a high SCS group (SCS ≥ 9; n = 154) and a low SCS group (<9; n = 62), for a comparative analysis of differences in perioperative factors and prognoses. RESULTS: Limited resection was more frequent in the high SCS group (58 %) than in the low SCS group (40 %; P = 0.02). Postoperative complications were more frequent in the high SCS group (45 %) than in the low SCS group (15 %; P < 0.01). A logistic regression analysis revealed that a high SCS was significantly predictive of postoperative complications (odds ratio 2.7; P = 0.02). The 5-year overall survival rate was 79 % for the low SCS group and 52 % for the high SCS group (P < 0.01). CONCLUSIONS: The SCS can predict the likelihood of postoperative complications and prognosis of elderly patients with VATS-treated lung cancers.

Prognostic Significance of Solid and Micropapillary Components in Invasive Lung Adenocarcinomas Measuring ≤3 cm.

BACKGROUND/AIM: We aimed to analyze the clinical impact of solid and micropapillary components in a series of Japanese patients resected for ≤3 cm lung adenocarcinoma. PATIENTS AND METHODS: A total of 115 patients with ≤3 cm lung adenocarcinomas were reviewed and classified according to the American Thoracic Society and the European Respiratory Society classification. The presence of solid (S+) or micropapillary component (MP+) was defined when the component constituted ≥1% of the entire tumor. The impact of these components on disease-free (DFS) and disease-specific (DSS) survival was analyzed. RESULTS: Thirty (26.1%) cases with S+ and 27 (23.5%) with MP+ were identified, and multivariate analysis indicated that S+ status significantly reduced the duration of DFS and DSS. In 86 patients of acinar- and papillary-predominant subgroups, S+ and/or MP+ had the most significant effect on DFS and DSS by multivariate analysis. CONCLUSION: S+ and/or MP+ status predict worse prognosis in patients with acinar- and papillary-predominant lung adenocarcinoma.

[Circulatory disturbance of middle lobe by bending of lobar pedicle after right upper lobectomy].

A 66-year-old man was diagnosed as lung cancer. We performed right upper lobectomy and lymphnode dissection. On the 1st postoperative day, a chest radiograph showed an opacification in the right upper lung field. Computed tomography (CT) showed a stenosis of the middle lobe bronchus and infiltrative shadow of the middle lobe on the 3rd postoperative day. Fiber optic bronchoscopic examination also revealed a bend and stenosis of the middle lobe bronchus, but tortion was not demonstrated. On the 6th postoperative day, chest radiographic findings was worsened. Torsion of the middle lobe was suspected, and rethoracotomy was performed on the 7th postoperative day. The right middle lobe was not rotated, but the lobar pedicle bend toward cranial. The middle lobe was highly congested necessitating lobectomy.

Thymic metastasis of breast cancer 22 years after surgery: a case report.

We report a rare case of thymic metastasis of breast cancer. A 68-year-old woman, who had undergone surgery for cancer in her right breast and had been free of recurrence for 22 years, was noted to have an abnormal shadow on a chest X-ray at a regular medical checkup. Further workup, including chest CT, revealed a 22 × 18-mm mass in the anterior mediastinum. Fluorine-18-fluorodeoxyglucose-PET showed increased fluorine-18-fluorodeoxyglucose uptake that was highly suggestive of thymoma. Thoracoscopic thymothymectomy was performed. The tumor had invaded the pericardium, which was also resected. A small nodule was found in the right lung, and it was also resected. The intraoperative frozen-section diagnosis was breast cancer metastasis to the thymus and lung. The pathological diagnosis was luminal A solid tubular carcinoma (strongly estrogen receptor and progesterone receptor positive, HER2 negative) with an MIB-1 index of less than 5%. After surgery, the patient was treated with an aromatase inhibitor. As of August 2013, she has been free of recurrence for more than 36 months. It is extremely rare for breast cancer to metastasize to the thymus more than 20 years after surgery.

First experience of robotic extended thymectomy in Japan for myasthenia gravis with thymoma.

We performed robot (da Vinci)-assisted thoracoscopic extended thymectomy (rThx) for myasthenia gravis with thymoma. The patient was a 66-year-old woman who complained of palpebral heaviness. Robotic operation was performed in the supine position by placing four ports in the right chest wall under 10 mmHg CO(2) insufflation using three arms and one assist port. Compared with conventional video-assisted thoracic surgery (VATS), the bilateral upper horns, fat around the diaphragm, and aortopulmonary window could be resected more easily. The tumor measured 41 mm maximum diameter and was diagnosed as type AB noninvasive thymoma. The operating time was 298 min, console operating time was 203 min, and the amount of bleeding was small. The postoperative course was uneventful with no complications. This is a report of the first Japanese case of rThx for myasthenia gravis. rThx is a promising technique, and further improvement in the procedure is expected.

Mediastinal malignant lymphoma difficult to diagnose: a patient report.

We report a 58-year-old man who suffered from shortness of breath on exertion with wheezing. A chest enhanced computed tomography (CT) scan showed an irregular tumor in the middle mediastinum involving the right main pulmonary artery, vena cava superior and right main bronchus. Transbronchial lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration yielded no evidence for a pathological diagnosis of malignancy. We employed mediastinoscopy, which led to a diagnosis of lymphoid reactive change. 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan revealed a high FDG uptake in the tumor lesion. Because the CT scan and FDG-PET findings led to a marked suspicion of malignancy, we decided to attempt biopsy by a video-assisted thoracoscopic surgery (VATS) approach. Flow cytometry showed a monoclonal pattern, and the final diagnosis was mediastinal follicular lymphoma both pathologically and immunohistologically. The patient achieved a complete remission by following chemotherapy. Low-grade malignancy type of lymphoma such as follicular lymphoma that generally contains small-cell components often presents a diagnostic challenge and the VATS approach was effective for the diagnosis of such type of mediastinal lymphoma.

Thoracoscopic resections of bronchogenic cysts arising in the posterior mediastinum: a report on 3 patients.

We report 3 cases of patients with bronchogenic cyst arising in the posterior mediastinum. The patients were a 19-year-old male, a 36-year-old female and a 33-year-old female, whose cysts were detected as abnormal shadows in the chest. In 2 of them, neurogenic tumors were suspected preoperatively. We performed thoracoscopic resection for the 3 tumors. Bronchogenic cysts may occur ectopically, and the posterior mediastinum must be sufficiently recognized as a rare but possible ectopic site.