Pulmonary pleomorphic carcinoma arising in mixed squamous and glandular papilloma: A case report.

Solitary pulmonary papillomas (SPPs) are rare lung neoplasms. Histologically, SPP is classified into three subtypes, and mixed squamous and glandular papilloma (MP) is the rarest subtype. Although SPPs are considered benign tumors, there have been several reports on the synchronous malignant transformation in SPPs. An 82-year-old asymptomatic man was referred to our hospital for further examination of a 2.2 cm-sized left lung tumor. Pathology of bronchoscopic specimens showed the possibility of pulmonary papilloma but did not reveal any malignancy. The patient complained of bloody sputum during the eighth month after the initial visit. The size of the lesion had increased to 4.3 cm. These data suggested the existence of malignancy, and the patient underwent an operation. Histologically, the tumor was composed of fibrovascular cores and papillomatous fronds lined by pseudostratified columnar cells and mucin-filled goblet cells. Keratinizing squamous epithelium was also observed. Overall, the diagnosis of MP was obtained by fundamental histology. In addition, a solid part beneath mild atypical squamous epithelia, which was composed of malignant-appearing squamous cells and spindle-shaped atypical cells, was observed. The spindle portion was positive for cytokeratin AE1/AE3 and vimentin, and focally positive for alpha-smooth muscle actin (αSMA). The final diagnosis was pulmonary pleomorphic carcinoma (PPC) arising in the MP. Only two cases have been reported for atypical spindle tumor cells that are found in MP or bronchiolar adenoma/ciliated muconodular papillary tumor (BA/CMPT), which has histologically similar features to MP. This is the second case report of PPC arising in MP.

A Th1-like CD4+ T-cell Cluster That Predicts Disease-free Survival in Early-stage Lung Cancer.

Perioperative immune checkpoint inhibitors have been shown to improve prognosis in early-stage lung cancer. However, no biomarkers are known to indicate the requirement for treatment. This study aimed to identify T-cell clusters responsible for antitumor immunity in patients with early-stage lung cancer. Preoperative blood samples from 50 consecutive patients with lung cancer who were diagnosed as operable and underwent complete resection were analyzed by mass cytometry. Patients were divided into two groups: no recurrence at a minimum observation period of 851 days (median observation period: 1,031.5 days) and recurrence by the last observation date. Mass cytometry and single-cell RNA sequencing analysis of lymph nodes (LN) and tumor-infiltrating T cells were also performed. CCR4-CCR6+ Th7R showed discriminative ability between recurrence and non-recurrence patients with lung cancer. Patients with more than 3.04% Th7R showed significantly favorable disease-free survival. Th7R was a major component of CD4+ T cells in tumor microenvironments and LNs adjacent to lung cancer tissues and was the only cluster that decreased in peripheral blood after the removal of cancer tissues, suggesting that Th7R was primed and proliferated in tumor-draining LNs in the presence of cancer tissues. Th7R had the kinetics that antitumor T cells should have, as indicated by the cancer immunity cycle; thus, peripheral blood Th7R could represent the potency of tumor immunity by reflecting priming and proliferation in tumor-draining LNs and Th7R in the tumor microenvironment. Prediction using peripheral Th7R before surgery could allow the selection of patients who require perioperative drug therapy and optimize therapeutic interventions with clinical implications. Significance: Peripheral Th7R, a Th1-like CD4+ T-cell cluster reflecting priming status in draining LNs and immune status in the tumor microenvironment, predicts disease-free survival after complete resection and has significant clinical relevance in selecting appropriate therapeutic interventions in patients with early-stage lung cancer.

Prognostic significance of lymph node dissection for lung cancer surgery: a narrative review.

Background and Objective: Theoretically, systematic lymph node dissection (SLND) in lung cancer surgery is a technique that leaves less cancer cells behind and is speculated to improve the prognosis, but its prognostic significance still remains controversial. In addition, the social environment surrounding lymph node dissection has changed with the advent of limited surgery for peripheral small-sized lung cancer and emergence of immune check inhibitor (ICI). Therefore, we reconsidered the role of lymph node dissection. Methods: By referring to past reports, we reviewed the process leading up to the establishment of SLND in lung cancer surgery. We compared five randomized prospective comparative studies on SLND and lymph node sampling (LNS) in lung cancer surgery. Key Content and Findings: Of the five randomized prospective comparative studies, two reported an improvement in overall survival (OS) with SLND, but the remaining three reported no significant difference in OS between SLND and LNS. One out of the five reports revealed a significant increase in complications with SLND. For peripheral non-small cell lung cancer (NSCLC) cases with tumor diameter ≤2 cm and consolidation-to-tumor ratio >0.5 segmentectomy was found to significantly improve the hazard ratio of OS, when compared to a lobectomy. However, the proportion of SLND and lobe-specific lymph node dissection (L-SLND) in each group seems to be unclear. In segmentectomy, the dissection of intersegmental lymph nodes tends to be lenient, and therefore it seems necessary to examine the significance of lymph node dissection in segmentectomy. ICIs are already showing excellent effects, and it may be necessary to examine how they will be affected by removal of regional lymph nodes where cancer-specific cytotoxic T lymphocytes (CTLs) are concentrated. SLND is essential for accurate staging, but ideally-in a host with no cancer cells in the lymph node or a host with cancer cells having a high sensitivity to ICI-it might be better to leave the regional lymph node. Conclusions: SLND may not be the right choice in all cases. A time may come when the extent of lymph node dissection is determined individually for each case. Future verification results are awaited.

Tumor immunity is related to 18 F-FDG uptake in thymic epithelial tumor.

BACKGROUND: 2-deoxy-2-[fluorine-18] fluoro-d-glucose (18 F-FDG) positron emission tomography (18 F-FDG-PET) is a convenient modality to assess the metabolic activity within tumor cells. However, there is no consensus regarding the relationship between 18 F-FDG uptake and the immune environment in thymic epithelial tumors (TETs). We conducted a clinicopathological study to elucidate the relationship between 18 F-FDG uptake and programmed death ligands 1 and 2 (PD-L1/PD-L2) expression in patients with TETs. METHODS: A total of 108 patients with histologically confirmed TETs classified as thymomas or thymic carcinomas who underwent surgical resection or biopsy or needle biopsy and 18 F-FDG PET before any treatment between August 2007 and March 2020 were enrolled in this study. Tumor specimens underwent immunohistochemical staining for PD-L1, PD-L2, GLUT1, HIF-1α, VEGFR2, VEGF-C, and ß2 adrenergic receptor. RESULTS: High uptakes of SUVmax , SUVmean , MTV, and TLG were identified in 28 (25.9%), 61 (56.5%), 55 (50.9%), and 55 (50.9%) of 108 patients, respectively. High uptake of SUVmax significantly correlated with PS (performance status) of 1-2, thymic carcinoma, and advanced stage, and SUVmax on 18 F-FDG uptake displayed a close association with PD-L1 and PD-L2 expressions, but not with MTV and TLG. Our analysis revealed that SUVmax was identified as being significant relationship for positive PD-L1/PD-L2 expression. GLUT1, HIF-1α, and VEGFR2 were significantly associated with the expression of PD-L1/PD-L2 from the biological viewpoint. CONCLUSION: 18 F-FDG accumulation was closely associated with the expression of PD-L1/PD-L2, which, in turn, was correlated with glucose metabolism and hypoxia. PD-L1/PD-L2 could affect the glucose metabolism and hypoxia in thymic tumor cells.

Chylothorax associated with lymphatic reflux in a thoracic duct tributary after lung cancer surgery.

Chyle leaks are attributed to damage to the thoracic duct itself or its tributaries during surgery. Chylothorax after lung cancer surgery can occur due to damaged thoracic duct tributaries; however, little is known of the mechanism involved. A 71-year-old female underwent a left upper lobectomy with hilar and mediastinal lymphadenectomy for a 1.8-cm primary squamous cell carcinoma, and developed a chylothorax a day later. Catheter lymphangiography revealed high-flow chyle leaks from a damaged thoracic duct tributary, known as a bronchomediastinal lymph trunk, due to a lymphatic reflex from the thoracic duct. Subsequently, catheter embolization of the tributary repaired the chylothorax. The potential for persistent chylothorax after lung cancer surgery and successful lymphatic intervention should be noted.

Pulmonary high-grade fetal adenocarcinoma associated with cystic airspace: A case report.

Lung cancers associated with cystic airspaces have a life-threatening risk of a missed or delayed diagnosis. Here, we report a case of pulmonary high-grade fetal adenocarcinoma, a rare lung carcinoma associated with cystic airspaces, as confirmed by computed tomography (CT) scan. A 73-year-old asymptomatic male with a 52-pack a year smoking habit was referred to our hospital. Lung CT showed a thin-walled cystic space with exophytic and endophytic solid nodules along the cyst wall. After surgery, histological analysis of a resected lung specimen revealed a pure high-grade fetal adenocarcinoma probably associated with emphysematous bullae in pulmonary emphysema, suggesting smoking contributed to this pure form, as well as the emphysema. In conclusion, when treating elderly men with a smoking history, physicians need to carefully examine the walls of cystic airspaces on CT for fetal adenocarcinoma. KEY POINTS: Significant findings of the study •Pulmonary high-grade fetal adenocarcinoma may be associated with emphysematous bullae manifesting as cystic air spaces as shown by computed tomography. What this study adds •When scanning by computed tomography, physicians should carefully examine the pulmonary cystic airspace walls in elderly men with a smoking history.

Primary pulmonary synovial sarcoma with calcification: A case report.

The lung is the organ most commonly affected by primary synovial sarcoma. Intratumoral calcification is less common in this organ versus soft tissue. Meanwhile, the presence of calcification in a lung nodule reduces the risk of lung cancer. Here, we report a case of pulmonary synovial sarcoma which manifested as a nodule with calcification, depicted on computed tomography (CT). A 52-year-old asymptomatic male was referred to Saitama Medical University International Medical Center and CT revealed a well-defined nodule (1.8 cm), with punctate and eccentric calcification in the right lower lobe. Enhanced CT and 18F-fluorodeoxyglucose positron-emission tomography suggested a malignant tumor, and surgery was performed. Histology provided a preliminary diagnosis of monophasic spindle-cell synovial sarcoma with hyalinized collagen bands and calcifications. Genetically, the presence of the SYT-SSX2 fusion gene was consistent with the features of this disease. We conclude that primary pulmonary synovial sarcoma should be listed as a differential diagnosis for solitary pulmonary nodules with calcification.

[Surgical Outcome of Sublobar Resection in High-risk Patients with Non-small Cell Lung Cancer].

OBJECTIVES: Pulmonary lobectomy is the standard surgical procedure for resectable non-small cell lung cancer (NSCLC), while sublobar resection is an important surgical alternative for high-risk patients with comorbidities. We evaluated the treatment outcome and prognostic factors of sublobar resection in high-risk patients with NSCLC. METHODS: Eighty three high-risk patients who underwent compromised sublobar resection for clinical-N0 NSCLC with a solid appearance were retrospectively reviewed. A total of 47 wedge resections and 36 segmentectomies performed. RESULTS: Poor pulmonary function and synchronous or metachronous multiple lung cancer were found in 56.7% and 20.5% of patients respectively, all requiring sublobar resection. There were 21 instances of tumor recurrence and 24 deaths during a mean follow-up of 1,500 days. There was no local recurrence in the segmentectomy group. The 3-year recurrence free survival (RFS) and overall survival (OS) were 72.6% and 73.8% respectively. A multivariate analysis indicated that resection type and lymphatic invasion were independent prognostic factors for RFS. In the wedge resection group, a ratio of surgical margin to clinical tumor size greater than 1 (MT ratio≥1) was an independent prognostic factor for RFS( 87.1%,p=0.001). CONCLUSION: Segmentectomy leads to a favorable prognosis. MT ratio was independently associated with a longer RFS in the wedge resection group.

Distinctive clinicopathological features of adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung: A retrospective study.

OBJECTIVES: The aim of this study was to investigate distinguishing clinicopathological features, in addition to histological invasiveness, in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) of the lung. MATERIALS AND METHODS: Patients with lung adenocarcinoma who underwent surgery at our hospital between 2007 and 2014 were reviewed, focusing on computed tomography (CT) images, operative procedures and clinical outcomes, histopathology, Ki-67 immunostaining, and EGFR-mutation status. EGFR mutations were examined using a peptide nucleic acid-locked nucleic acid PCR clamp method. Group comparisons were investigated by Mann-Whitney U or Fisher's exact tests. RESULTS: Of 629 patients with lung adenocarcinoma who underwent surgery, 91 (14%) of 103 AIS (n = 34) or MIA (n = 69) tumors were reviewed. The ratio of male to female patients with MIA compared to AIS was significantly higher (p < 0.02). Of 103 tumors, 99 (96%) were non-mucinous. By CT, 74% of AIS appeared as pure ground-glass nodules and 75% of MIAs as part-solid ground-glass nodules. Pathological tumor diameters and Ki-67 labeling index (LI) values were significantly greater for MIAs compared to AIS (p < 0.001 for both). A Ki-67 LI of ≥2.8% indicated the presence of an MIA rather than an AIS. EGFR mutations were more frequently detected in MIAs (33/69, 48%) than AIS (9/34, 26%; p = 0.055). The ratio of exon 19 deletions to exon 21 missense mutations in MIAs tended to be higher than those in AIS (p = 0.06). Patients did not experience a local recurrence or metastasis after AIS and MIAs were removed by wedge resection, segmentectomy or lobectomy. Five-year recurrence-free survival rates were 100%. CONCLUSION: Despite similar surgical outcomes for AIS and MIAs, we found differences in terms of gender, tumor diameters, CT findings, Ki-67 LI and a subset of EGFR mutations, highlighting the validity of classifying the two subtypes.

[Tumors of the diaphragm, diagnosis and surgical treatment].

Primary tumors of the diaphragm are very rare, and we often have difficulties in preoperative diagnosis and accurate evaluation of invasion. We experienced 3 surgical cases of tumor of diaphragm:primary mucinous adenocarcinoma, metastatic gastrointestinal stromal tumor, and mesothelioma. Besides computed tomography (CT) and conventional magnetic resonance imaging(MRI), respiratory dynamic cine magnetic resonance imaging (cine MRI) was performed. Cine MRI was acquired using steady state free precession (SSFP) sequence, and about 80 consecutive images of the same slice were taken while a patient breathed deeply. In all cases, cine MRI showed lack of tumor movement along the diaphragm during respiration. During surgery, we found that tumor was originated from diaphragm and there was no adhesion to other organs. Securing a sufficient margin, we resected tumor including the diaphragm. Since the defect of diaphragm was from 4 to 5cm in short diameter, we could close the diaphragm by direct suture. Cine MRI could provide useful information concerning discrimination between diaphragmatic and para-diaphragmatic tumor.

Primary mucinous adenocarcinoma of the posterior mediastinum.

We report a rare case of primary mucinous adenocarcinoma of the posterior mediastinum. A 36-year-old man was referred to our hospital with right flank pain. Computed tomography showed a cystic mass in the posterior mediastinum, and the tumor displaced the diaphragm downward and the inferior vena cava forward. The patient underwent extirpation of the tumor. The cut surface of the resected tumor showed a unilocular cyst filled with abundant gray gelatinous fluid. Microscopically, the tumor had a fibrous capsule lined with cuboidal and columnar malignant epithelial cells with intracellular mucin accumulation and was diagnosed as a mucinous adenocarcinoma.

[Clinicopathologic analysis of small-sized non-small cell lung cancer].

We reviewed the data on 149 patients who underwent complete resection for small-sized (≤ 2 cm)peripheral non-small cell lung cancer at our institution between January 2002 and July 2010. Patients with small-sized lung cancer underwent a lobectomy in 121, segmentectomy in 13, and wedge resection in 15 cases. The overall and 5-year disease-free survivals were 89% and 82%, respectively. The 5-year disease-free survival of patients with tumors exceeding 1.5 cm was lower than that of patients with tumors 1.5 cm or smaller (p=0.01). The 5-year disease-free survival for patients without pleulal invasion was 87%, whereas it was 45% for those with pleulal invasion (p=0.004). The 5-year disease-free survival according to the serum level of carcinoembrionic antigen( CEA) were 82% for the normal group and 70% for the high group( p=0.007). Although the results were not significantly different, patients with tumors with high maximum standardized uptake value (SUV) on FDG-PET/CT showed a trend toward a lower 5-year disease-free survival rate( p=0.10). There were no recurrences in patients with ground-glass opacity (GGO) or GGO-dominant lesion including those who underwent sublober resection. Multivariate analysis showed that tumor size and pleural invasion were independent prognostic factors. Indication of sublober resection for solid-type small-sized non-small cell lung cancer (NSCLC) should be carefully determined considering tumor size, pleural involvement, serum carcinoembryonic antigen( CEA) level, and maximum SUV.

Pharmacologic preconditioning effects: prostaglandin E1 induces heat-shock proteins immediately after ischemia/reperfusion of the mouse liver.

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.

Border between N1 and N2 stations in lung carcinoma: lessons from lymph node metastatic patterns of lower lobe tumors.

OBJECTIVE: Distinction of lymph node stations is one of the most crucial topics still not entirely resolved by many lung cancer surgeons. The nodes around the junction of the hilum and mediastinum are key points at issue. We examined the spread pattern of lymph node metastases, investigated the prognosis according to the level of the involved nodes, and conclusively analyzed the border between N1 and N2 stations. METHODS: We reviewed the records of 604 consecutive patients who underwent complete resection for non-small cell lung carcinoma of the lower lobe. RESULTS: There were 390 patients (64.6%) with N0 disease, 127 (21.0%) with N1, and 87 (14.4%) with N2. Whereas 11.3% of patients with right N2 disease had skip metastases limited to the subcarinal nodes, 32.6% of patients with left N2 disease had skip metastases, of which 64.2% had involvement of N2 station nodes, except the subcarinal ones. The overall 5-year survivals of patients with N0, N1, and N2 disease were 71.0%, 50.8%, and 16.7%, respectively (N0 vs N1 P = .0001, N1 vs N2, P < .0001). Although there were no significant differences in survival according to the side of the tumor among patients with N0 or N1 disease, patients with a left N2 tumor had a worse prognosis than those with a right N2 tumor (P = .0387). The overall 5-year survivals of patients with N0, intralobar N1, hilar N1, lower mediastinal N2, and upper mediastinal N2 disease were 71.0%, 60.1%, 38.8%, 24.8%, and 0%, respectively. Significant differences were observed between intralobar N1 and hilar N1 disease ( P = .0489), hilar N1 and lower mediastinal N2 disease (P = .0158), and lower and upper mediastinal N2 disease (P = .0446). Also, the 5-year survivals of patients with involvement up to station 11, up to station 10, and up to station 7 were 41.4%, 37.9% and 37.7%, respectively (difference not significant). CONCLUSIONS: N1 and N2 diseases appeared as a combination of subgroups: intralobar N1 disease, hilar N1 disease, lower mediastinal N2 disease, and upper mediastinal N2 disease. Interestingly, the survivals of patients with involvement up to interlobar nodes (station 11), main bronchus nodes (station 10), and subcarinal nodes (station 7) were identical. These data constitute the basis for a larger investigation to develop a lymph node map in lung cancer.

Systematic expression profiling of the mouse transcriptome using RIKEN cDNA microarrays.

The number of known mRNA transcripts in the mouse has been greatly expanded by the RIKEN Mouse Gene Encyclopedia project. Validation of their reproducible expression in a tissue is an important contribution to the study of functional genomics. In this report, we determine the expression profile of 57,931 clones on 20 mouse tissues using cDNA microarrays. Of these 57,931 clones, 22,928 clones correspond to the FANTOM2 clone set. The set represents 20,234 transcriptional units (TUs) out of 33,409 TUs in the FANTOM2 set. We identified 7206 separate clones that satisfied stringent criteria for tissue-specific expression. Gene Ontology terms were assigned for these 7206 clones, and the proportion of 'molecular function' ontology for each tissue-specific clone was examined. These data will provide insights into the function of each tissue. Tissue-specific gene expression profiles obtained using our cDNA microarrays were also compared with the data extracted from the GNF Expression Atlas based on Affymetrix microarrays. One major outcome of the RIKEN transcriptome analysis is the identification of numerous nonprotein-coding mRNAs. The expression profile was also used to obtain evidence of expression for putative noncoding RNAs. In addition, 1926 clones (70%) of 2768 clones that were categorized as "unknown EST," and 1969 (58%) clones of 3388 clones that were categorized as "unclassifiable" were also shown to be reproducibly expressed.

Identification of genes regulating colorectal carcinogenesis by using the algorithm for diagnosing malignant state method.

We studied the expression profiles of various stages of colorectal tumors (adenoma (AD), seven samples; carcinoma (CA), 16 samples) by using cDNA microarrays and developed ADMS (algorithm for diagnosing malignant state) method, selecting 335 clones characteristic of CA state. We, then, applied ADMS to 12 additional samples (five from primary lesions with metastasis and seven metastases); all 16 CAs and 12 metastatic tumors were diagnosed correctly as cancerous states. Although three of the seven ADs were diagnosed as "cancerous," the large size of two of these tumors suggested their potential malignancy. Our strategy for selecting clones characteristic of the malignant state is widely applicable to diagnosis and for predicting the stage of progression during multistep carcinogenesis. Of the 335 clones we selected, 135 were known genes. Included in the 135 genes were tumor suppressor and growth factor-related genes and were consistent with the literature. ADMS is a reliable means for identifying genes useful for the diagnosis of cancer.

Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray.

BACKGROUND: Brain metastases occur in 15% to 30% of breast cancer patients, usually as a late event. The patterns of metastases to different organs are determined by the tumor cell phenotype and interactions between the tumor cells and the organ environment. METHODS: We investigated the gene expression profile occurring in brain metastases from a breast cancer cell line. We used cDNA microarrays to compare patterns of gene expression between the mouse breast cancer cell line Jyg MC (A) and a subline that often metastasis to brain, (B). RESULTS: By Microarray analysis about 350 of 21,000 genes were significantly up-regulated in Jyg MC (B). Many candidate genes that may be associated with the establishment of brain metastasis from breast cancer were included. Interestingly, we found that the expression of astrocyte derived cytokine receptors (IL-6 receptor, TGF-beta receptor and IGF receptor) were significantly increased in Jyg MC (B) cells. These results were confirmed by RT-PCR. CONCLUSIONS: These results suggest that cytokines produced by glial cells in vivo may contribute, in a paracrine manner, to the development of brain metastases from breast cancer cells.