A case of hepatoid adenocarcinoma of the lung harboring KRAS G12C responded favorably to sotorasib.

Hepatoid adenocarcinoma of the lung is a rare variant of adenocarcinoma. We describe a case of hepatoid adenocarcinoma of the lung that harbored KRAS G12C and responded favorably to sotorasib. A man in his 70s was found to have an abnormality on his chest X-ray. He underwent right middle lobectomy, and a pathological examination of the surgical specimen showed conventional invasive adenocarcinoma with highly focal hepatoid adenocarcinoma. He received chemoradiotherapy and concurrent radiation, followed by durvalumab for postoperative recurrence. After three doses of durvalumab, he reported feeling short of breath. A computed tomography scan showed emerging broad consolidation in the right lower lobe. Transbronchial lung biopsy specimens from the consolidation showed hepatoid adenocarcinoma harboring KRAS G12C mutation. Therefore, he was started on sotorasib 960 mg daily. Eight days later, a computed tomography scan showed that the area of consolidation had reduced in size. Progressive disease was detected after 42 days of treatment with sotorasib. The patient died 1 month after cessation of sotorasib and 3 months after postoperative recurrence. We have encountered what we believe to be the first case of hepatoid adenocarcinoma of the lung with KRAS G12C mutation that responded favorably to treatment with sotorasib.

Laparoscopic Radical Total Gastrectomy and Pancreatosplenectomy for Synchronous Cancer of the Stomach and Pancreas.

The safety of laparoscopic surgery for advanced gastric and pancreatic cancers has been established individually, but there is little evidence for synchronous cancers. In this case, a 59-year-old man with a history of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) treatment for diffuse large B-cell lymphoma underwent laparoscopic surgery for a suspected pancreatic invasion of advanced gastric cancer. Pathology revealed double cancer of the stomach and pancreas. Laparoscopic total gastrectomy and distal pancreatectomy were successfully performed. The patient had a pancreatic leak on postoperative day seven but was discharged from the hospital on postoperative day 21. This case suggests the possibility of expanding the indications for laparoscopic surgery for similar cancers in the future. Additionally, the anatomical reticulum can be resected as a single mass using laparoscopy alone.

[A case of primary central nervous system lymphoma of the sellar region presented with panhypopituitarism].

The patient is a 41-year-old woman. She presented with vomiting and lightheadedness, and blood tests showed a generalized decrease in pituitary hormones and hyperprolactinemia. A head MRI showed increased signal intensity lesions on FLAIR image in the pituitary stalk, corpus callosum, periventricular area of the fourth ventricle, and superior cerebellar peduncle. The lesions were homogeneously enhanced, and a brain biopsy confirmed the diagnosis of primary diffuse large B-cell lymphoma of the central nervous system, and chemotherapy was started. Although the suprasellar region is a rare site for primary central nervous system lymphoma (PCNSL), it should be diagnosed early by biopsy.

Carboplatin and weekly paclitaxel in combination with bevacizumab for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias: A feasibility study.

BACKGROUND: Idiopathic interstitial pneumonias are an independent risk factor of lung cancer, and a chemotherapy-induced acute exacerbation is the most common lethal complication in Japanese patients. The safety and efficacy of carboplatin and weekly paclitaxel for the treatment of non-small cell lung cancer with idiopathic interstitial pneumonias has been previously reported in prospective studies. However, carboplatin + paclitaxel with bevacizumab is currently the standard therapy. We conducted a multicenter, phase II study to confirm the safety and efficacy of carboplatin + weekly paclitaxel + bevacizumab for the treatment of patients with lung cancer complicated by idiopathic interstitial pneumonias. METHODS: Chemotherapy-naïve patients with advanced-stage or patients with post-operative recurrent non-squamous non-small cell lung cancer complicated by idiopathic interstitial pneumonias were enrolled. Patients received carboplatin (area under the curve: 5.0) and bevacizumab (15 mg/kg) on day 1 and paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 4-week cycle. RESULTS: Seventeen patients less than the predetermined number were enrolled and received a median of four treatment cycles (range: 1-6). One patient (5.9%; 95% confidence interval: 0.1-28.7%) had acute exacerbation of interstitial pneumonia related to the study treatment which improved after corticosteroid treatment. The overall response rate was 52.9%. The median progression-free survival, median survival time, and 1-year survival were 5.7 months, 12.9 months, and 52.9%, respectively. CONCLUSION: The addition of bevacizumab to carboplatin and weekly paclitaxel might be safe and effective for the treatment of advanced non-small cell lung cancer complicated by idiopathic interstitial pneumonias. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000008189.

Total pancreatectomy with remnant stomach preservation in a patient with a history of proximal gastrectomy and interposed jejunal reconstruction with right gastroepiploic conduit preservation: a case report.

BACKGROUND: Pancreatic head resection following proximal gastrectomy jeopardizes the blood flow of the remnant stomach owing to right gastroepiploic conduit sacrifice, thereby necessitating total gastrectomy. However, owing to its high invasiveness, concomitant remnant total gastrectomy with pancreatectomy should be avoided as much as possible. Herein, we describe our experience of total pancreatectomy with right gastroepiploic conduit preservation in a patient with a history of proximal gastrectomy and reconstruction by jejunum interposition. CASE PRESENTATION: A 78-year-old woman with a history of gastric cancer was followed up at our institute for multiple intraductal papillary mucinous neoplasm, and main pancreatic duct stricture in the pancreatic head was newly detected. The cystic lesion was extended to the pancreatic body. Proximal gastrectomy and reconstruction by jejunal interposition were previously performed, and the mesenteric stalk of the interposed jejunum was approached through the retrocolic route. We planned total pancreatectomy with right gastroepiploic conduit preservation. Following adhesiolysis, the interposed jejunum and its mesentery lying in front of the pancreas were isolated. The arterial arcade from the common hepatic artery to the right gastroepiploic artery was detached from the pancreas. Furthermore, the right gastroepiploic vein was isolated from the pancreas. The pancreatic body and tail were pulled up in front of the remnant stomach, and the splenic artery and vein were resected. The pancreatic body and tail were pulled out to the right side, and the pancreatic head was divided from the pancreatic nerve plexus to the portal vein. The jejunal limb for entero-biliary anastomosis was passed through the hole behind the superior mesenteric artery and vein, and gastrointestinal anastomosis using the antecolic route and Braun anastomosis were performed. CONCLUSIONS: To avoid remnant total gastrectomy, right gastroepiploic conduit preservation is an optional procedure for pancreatic head resection in patients who have undergone proximal gastrectomy with reconstruction by jejunal interposition.

Pancreatic acinar cell carcinoma with pleomorphic and spindle cells: An autopsy-proven case.

Pancreatic acinar cell carcinomas are glandular and have amphophilic/eosinophilic cytoplasm, presenting acinar, solid, and trabecular structures. Unusual histological features of acinar cell carcinoma are known, such as oncocytic, pleomorphic, spindle, and clear cell variants, but their clinical significance has not been well described. A man in his 70s was referred to our hospital because of elevated serum pancreatic enzymes. Contrast-enhanced abdominal computed tomography revealed slight swelling of the pancreatic head and suspension of the main pancreatic duct in the pancreatic body. He died only 14 days after admission. Gross findings at autopsy showed an ill-defined tumor located in the pancreatic head, involving the gastric and duodenal walls. Peritoneal dissemination, liver metastases, and lymph node metastases were also observed. Microscopically, tumor cells had moderate-to-severe nuclear atypia and amphophilic cytoplasm showing pleomorphism, and diffusely proliferated in solid pattern without lumina, were admixed with spindle cells. Immunohistochemically, tumor cells including pleomorphic and spindle cells were positive for B-cell lymphoma/leukemia 10 and trypsin. Consequently, the diagnosis was pancreatic acinar cell carcinoma with pleomorphic and spindle cells. We encountered a rare variant of pancreatic acinar cell carcinoma with pleomorphic and spindle cells. Clinically, our case showed rapid progression.

[HUMIDIFIER LUNG WITH ORGANIZING PNEUMONIA DETECTED BY BRONCHOSCOPY: A CASE REPORT].

A 58-year-old man presented with dyspnea on exertion and diffuse ground-glass opacities with mosaicism on chest computed tomography in April 201X. A transbronchial lung biopsy revealed organizing pneumonia and lymphocytic infiltration, and steroids were administered. During steroid tapering, the shortness of breath and ground-glass opacities recurred, and a transbronchial lung re-biopsy revealed organizing pneumonia without a granuloma again. Based on the clinical history, imaging features, and amount of humidifier usage, hypersensitivity pneumonitis caused by a humidifier was suspected. The inhalation challenge test was considered positive, and the diagnosis was confirmed. There have been some reports of unidentified granuloma in patients with humidifier lungs. Therefore, this case suggests that humidifier lung should be considered as a possibility even if pathological examination does not reveal granulomas and inflammatory changes such as organizing pneumonia are the only findings.

Phosphoglyceride crystal deposition disease requiring differential diagnosis from malignant tumors and confirmed by Raman spectroscopy: A case report.

BACKGROUND: Phosphoglyceride crystal deposition disease (PCDD) is a rare acquired disease in which phospholipid crystals deposit in bone and soft tissue long after surgery, trauma, or repeated injections. CASE SUMMARY: A 60-year-old-woman was referred to our department because of multiple abdominal masses after open splenectomy for idiopathic thrombocytopenic purpura 29 years earlier. All the masses showed marked fluorodeoxyglucose (FDG) uptake on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and were strongly suspected to be malignant tumors. Surgical biopsies were performed, and the abdominal masses were found to be aligned vertically, three in a row, along the tissue layers cut in the patient's previous surgery. Pathological finding of the specimens showed foreign body granuloma consisting of histiocytes and multinucleated giant cells accumulating around needle-like crystals. The crystals were confirmed as phosphoglyceride by Raman spectroscopy, and PCDD was diagnosed. To our knowledge, this is the first report of PCDD diagnosed by Raman spectroscopy. CONCLUSION: We made a definitive diagnosis of PCDD in a patient with multiple tumors showing marked FDG uptake on 18F-FDG-PET by incisional biopsy and compo- sition analysis using Raman spectroscopy, a method that has not previously been reported for the diagnosis of PCDD.

Predictive biomarkers for response to immune checkpoint inhibitors in lung cancer: PD-L1 and beyond.

Immune checkpoint inhibitor (ICI) therapies, including the programmed cell death protein 1 (PD-1) axis blockade, are considered a major oncological breakthrough of the early twenty-first century and have led to remarkable response rates and survival in a subset of patients with non-small cell lung cancer (NSCLC). However, the available therapies work only for one in five unselected, advanced NSCLC patients; thus, patient selection needs to be performed with the use of efficient biomarkers. Although imperfect, programmed death-ligand 1 (PD-L1) expression by immunohistochemistry (IHC) on tumor cells and/or immune cells has been established as a predictive biomarker for response to the PD-1 axis blockade. There remain several pre-analytical, analytical, and post-analytical issues, however, before implementing a PD-L1 IHC assay(s) in the pathology laboratory. In addition, given the lack of robust sensitivity and specificity of PD-L1 IHC for predicting response to ICIs, other biomarkers including tumor mutation burden (TMB) are under investigation. In this review, issues associated with PD-L1 IHC and TMB estimations will be discussed, and other promising biomarkers for predicting response to ICIs will be briefly introduced.

Characteristics of non-small-cell lung cancer with interstitial pneumonia: variation in cancer location, histopathology, and frequency of postoperative acute exacerbations in interstitial pneumonia.

BACKGROUND: Non-small-cell lung cancer (NSCLC) has been reported to develop in patients with interstitial pneumonia (IP); however, clinical, radiological, and pathological features remain to be elucidated. METHODS: We retrieved the records of 120 consecutive NSCLC patients associated with IP who underwent surgery at Toranomon Hospital between June 2011 and May 2017. We classified the patients into three groups according to NSCLC location using high-resolution computed tomography: group A, within a fibrotic shadow and/or at the interface of a fibrotic shadow and normal lung; group B, within emphysematous tissue and/or at the interface of emphysematous tissue and normal lung; and group C, within normal lung. In 64 patients, programmed death ligand-1 (PD-L1) status was assessed with immunohistostaining. RESULTS: Most of the patients (89; 70%) were classified as group A. This group tended to have squamous cell carcinoma with the usual interstitial pneumonia (UIP). These cancers were located mainly in the lower lobes and seven of the eight postoperative acute exacerbations (pAE) of IP developed in this group. NSCLC in the group B were mainly squamous cell carcinomas located in the upper lobes. No patient with PD-L1 negative was classified into group B. None of the patients in group C showed UIP. and most of the cancers were adenocarcinoma. The frequency of epidermal growth factor receptor mutation-positive NSCLC was the highest in this group. CONCLUSIONS: The three groups each showed characteristic features in terms of tumor location, histopathology, PD-L1 expression, and frequency of pAEof IP.

Safety of bronchoscopy in patients with malignant hematologic disorders.

BACKGROUND: Factors affecting the safety of bronchoscopy in patients with malignant hematologic disorders have not been well described. We evaluated the safety of bronchoscopy and describe factors affecting its complication rate in such patients. METHODS: Between January 2009 and December 2018, 316 bronchoscopies in 282 patients with malignant hematologic disorders and pulmonary infiltrates were performed at our institution. The bronchoscopic procedure used and its complications were evaluated. RESULTS: The most common underlying disease was acute myeloid leukemia (134/282 patients, 47.5%). Platelet transfusion was performed the day before or the day of bronchoscopy in 42.4%, supplemental oxygen was administered before the procedure in 23.1%, and midazolam was used in 74.4%. Thirty-five bronchoscopies (11.1%) were complicated by hemoptysis and 7 patients developed pneumothorax, 4 of whom required thoracic drainage. Two patients (0.6%) were intubated within 48 h of the procedure and prolonged oxygen desaturation (> 48 h) occurred in 3.8%. Multivariate analysis showed that only use of midazolam significantly reduced the risk of prolonged oxygen desaturation (hazard ratio 0.28, 95% confidence interval 0.09-0.85, p = 0.03). Transbronchial lung biopsy significantly increased the risk of hemoptysis (hazard ratio 10.40, 95% confidence interval 4.18-25.90, p = 0.00), while use of midazolam significantly reduced the risk (hazard ratio 0.31, 95% confidence interval 0.14-0.73, p = 0.01). CONCLUSIONS: Bronchoscopy is relatively safe in patients with malignant hematologic disorders. Caution and judicious use of sedatives may improve the patient's procedural tolerance and lower complications.

IgG4-related disease in the differential diagnosis of lung nodules.

IgG4-related disease is an evolving entity of immune-mediated origin. We report a case of IgG4-related disease mimicking lung cancer with pleural dissemination. A 76-year-old male non-smoker was admitted to our hospital because of chest X-ray abnormality. Chest computed tomography scan showed a lung nodule measuring 26 × 14 mm with tiny nodules on the adjacent pleural surface. Wedge resection by video-assisted thoracoscopic surgery (VATS) was performed to aid diagnosis. Pathological findings of the nodule consisted of lymphoid follicular hyperplasia with lymphoplasmacytic infiltrate, fibrosis, and obstructive vasculitis. Focal and scattered thickening of the pleura with lymphoplasmacytic infiltrate was also observed. The IgG4/IgG ratio in the most prominent area exceeded 80%. Thus, we made a diagnosis of IgG4-related lung and pleural disease. To our knowledge, there has been no report of IgG4-related lung disease mimicking lung cancer with pleural dissemination.

Squamous cell transformation as a mechanism of acquired resistance to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma: a report of two cases.

Pathological transformation to squamous cell carcinoma after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment has been reported, but details of the transformation remain unclear. We report two cases with transformation to squamous cell carcinoma. The first case was a 61-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 19 insertion. He experienced squamous cell transformation after 28 months of erlotinib therapy. Next-generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS. The second case was a 72-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R. He experienced squamous cell transformation after nine months of erlotinib therapy. NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT. Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.

Development of a CT image case database and content-based image retrieval system for non-cancerous respiratory diseases: Method and preliminary assessment.

BACKGROUND: To evaluate the benefits of using a CT image case database (DB) with content-based image retrieval system for the diagnosis of typical non-cancerous respiratory diseases. METHODS: Using this DB, which comprised data on 191 cases covering 69 diseases, 933 imaging findings that contributed to differential diagnoses were annotated. Ten test cases were selected. Image similarity between each marked test case lesion and the lesions of the top 10 retrieved cases were assessed and classified as similar, somewhat similar, or dissimilar by two physicians in consensus. Additionally, the accuracy of five internal medicine residents' abilities to interpret CT findings and provide disease diagnoses with and without the proposed system was evaluated by image interpretation experiments involving five test cases. The rates of concordance between the subjects' interpretations and the correct answers prepared in advance by two specialists in consensus were converted into scores. RESULTS: The mean (± SD) of image similarity among the 10 test cases was as follows: 5.1 ± 2.7 (similar), 2.9 ± 1.0 (somewhat similar), and 2.0 ± 2.4 (dissimilar). Using the proposed system, the subjects' mean score for the correct interpretation of CT findings improved from 15.1 to 28.2 points (p = 0.131) and for the correct disease diagnoses, from 9.3 to 28.2 points (p = 0.034). CONCLUSIONS: Although this was a preliminary small-scale assessment, the results suggest that this system may contribute to an improved interpretation of CT findings and differential diagnosis of non-cancerous respiratory diseases, which are difficult to diagnose for inexperienced physicians.

Problems in the reproducibility of classification of small lung adenocarcinoma: an international interobserver study.

AIMS: The 2015 WHO classification for lung adenocarcinoma (ACA) provides criteria for adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (INV), but differentiating these entities can be difficult. As our understanding of prognostic significance increases, inconsistent classification is problematic. This study assesses agreement within an international panel of lung pathologists and identifies factors contributing to inconsistent classification. METHODS AND RESULTS: Sixty slides of small lung ACAs were reviewed digitally by six lung pathologists in three rounds, with consensus conferences and examination of elastic stains in round 3. The panel independently reviewed each case to assess final diagnosis, invasive component size and predominant pattern. The kappa value for AIS and MIA versus INV decreased from 0.44 (round 1) to 0.30 and 0.34 (rounds 2 and 3). Interobserver agreement for invasion (AIS versus other) decreased from 0.34 (round 1) to 0.29 and 0.29 (rounds 2 and 3). The range of the measured invasive component in a single case was up to 19.2 mm among observers. Agreement was excellent in tumours with high-grade cytology and fair with low-grade cytology. CONCLUSIONS: Interobserver agreement in small lung ACAs was fair to moderate, and improved minimally with elastic stains. Poor agreement is primarily attributable to subjectivity in pattern recognition, but high-grade cytology increases agreement. More reliable methods to differentiate histological patterns may be necessary, including refinement of the definitions as well as recognition of other features (such as high-grade cytology) as a formal part of routine assessment.

Transformation of epidermal growth factor receptor T790M mutation-positive adenosquamous carcinoma of the lung to small cell carcinoma and large-cell neuroendocrine carcinoma following osimertinib therapy: an autopsy case report.

A 59-year-old man with relapsed epidermal growth factor receptor (EGFR) exon 19 deletion-positive stage IA adenosquamous carcinoma after lobectomy was treated with erlotinib and bevacizumab for 1 year followed by erlotinib alone for 1 year. Because of mediastinal and supraclavicular lymphadenopathy and a nodule on the left anterior chest wall, the patient underwent repeat biopsy from the supraclavicular lymph node. Pathological analysis demonstrated adenosquamous carcinoma harbouring EGFR exon 19 deletion and T790M mutation. Osimertinib treatment was therefore started. Six months later, the patient underwent a second-repeat biopsy from the mediastinal lymph nodes and liver metastases. Both specimens showed small cell lung carcinoma (SCLC). After chemotherapies for SCLC, he died from lung cancer. An autopsy demonstrated tumour heterogeneity, including histological types of adenosquamous, SCLC, and large-cell neuroendocrine carcinoma. Repeat biopsies at the time of disease progression are useful to choose subsequent treatment for patients with EGFR mutation-positive lung cancer.

Treatment outcome of patients with unresectable stage III non-small cell lung cancer and interstitial pneumonia.

BACKGROUND: The standard treatment for unresectable stage III non-small cell lung cancer (LC) is chemoradiation therapy (CRT); however, the optimal treatment for LC in patients with interstitial pneumonia (IP) (LC-IP) has not been determined. This study compared the clinical course of LC-IP patients to that of patients without IP (LC without IP) and determined the key factors of survival. METHODS: We retrieved the records of 52 consecutive LC patients treated at our institution between January 2011 and September 2016. The characteristics and outcomes of LC patients with and without IP were compared. Survival was analyzed using the Kaplan-Meier method and univariate and multivariate analyses of two-year survival were also conducted. RESULTS: Forty-two men and 10 women were evaluated. Eleven patients (21%) had IP as their underlying disease. Except for age, the backgrounds of LC patients with and without IP were almost identical. Among LC-IP patients, the median predicted forced vital capacity was 86% and the Gender-Age-Physiology (GAP) index was 3. None of the LC-IP patients received CRT but 32 (78%) of the LC without IP patients underwent CRT. Chemotherapy alone was the main treatment for LC-IP. The median survival times were 485 and 1271 days in LC patients with and without IP, respectively (p=0.419). Multivariate analysis of survival longer than two years revealed CRT as the only predictive factor. CONCLUSIONS: CRT was the only predictive factor for longer survival in LC patients; however, no LC-IP patients received CRT, possibly because of the underlying IP.