Identification of a rare MET variant in three siblings with extramammary Paget disease.

Extramammary Paget disease (EMPD) is an intraepithelial adenocarcinoma that primarily affects the genital and axillary areas in older individuals. A limited number of paired patients with familial EMPD (i.e. parent-offspring, siblings) have been reported but the genetics have not yet been adequately studied. We report, to the best of our knowledge, the first familial cases of patients with EMPD involving three affected siblings. The tumour-only multigene panel testing using surgical specimens revealed a heterozygous c.2997A>C (p.Glu999Asp) nonsynonymous variant in the proto-oncogene MET (NM_000245.4) in the three affected siblings. The germline multigene panel testing using peripheral blood lymphocytes revealed the same missense MET variant in all five family members who were tested, including two asymptomatic offspring (51 and 37 years of age). The MET variant we identified could be involved in EMPD carcinogenesis. Further genomic analyses of patients with familial EMPD are warranted to validate the pathogenic relevance of MET variants in EMPD development.

Histological differences in cancer cells, stroma, and luminal spaces strongly correlate with in vivo MRI-detectability of prostate cancer.

The current study aimed to investigate the plausible histopathological factors that affect the detectability of prostate cancers on multiparametric magnetic resonance imaging (MP-MRI). This retrospective study included 59 consecutive patients who had undergone MP-MRI and subsequent radical prostatectomy. The cases were standardized according to the tumor size ranging from 10 to 20 mm on the final pathological diagnosis. Histopathological review and semi-automated imaging analysis were performed to evaluate the relative area fractions of the histological components, including cancer cells, stroma, and luminal spaces. Among the 59 prostatectomy specimens, no case showed two or more foci of cancer that matched the size criteria. Of the 59 lesions, 35 were MRI-detectable [Prostate Imaging Reporting and Data System (PIRADS) score of 3 or greater] and 24 were MRI-undetectable (PIRADS score of 2 or less). No significant differences were observed in Gleason Grade Group, percentage of Gleason pattern 4, and predominant subtype of Gleason pattern 4 between MRI-detectable and MRI-undetectable cancers. On the other hand, significantly higher mean area fraction of cancer cells (60.9% vs. 42.7%, P < 0.0001) and lower mean area fractions of stroma (33.8% vs. 45.1%, P = 0.00089) and luminal spaces (5.2% vs. 12.2%, P < 0.0001) were observed in MRI-detectable cancers than in MRI-undetectable cancers. In a multivariable analysis performed upon exclusion of area fraction of stroma due to its multicollinearity with that of cancer cells, area fractions of cancer cells (P = 0.0031) and luminal space (P = 0.0035) demonstrated strong positive and negative correlation with MRI-detectability, respectively. Changes in cancer cells, stroma, and luminal spaces, rather than conventional histological parameters, could be considered one of the best predictors to clinical, in vivo MRI-detectability of prostate cancer.

Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis with detection of myeloperoxidase and phospholipase A2 receptor in membranous nephropathy-lesions: report of two patients with microscopic polyangiitis.

BACKGROUND: Podocyte phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic adult membranous nephropathy (MN). Histological PLA2R staining in the renal tissue has proven to be useful for the detection of idiopathic MN. However, glomerular PLA2R deposits have also been recently observed in several patients with secondary MN, such as hepatitis B virus-associated, hepatitis C virus-associated, and neoplasm-associated MN. Certain inflammatory environments have been suggested to lead to abnormal expression of PLA2R epitopes, with the resulting production of PLA2R autoantibodies. CASE PRESENTATION: We report two patients diagnosed with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis with MN-lesions, in whom ANCA titers for myeloperoxidase (MPO) were persistently positive. The first patient was a 52-years-old man who presented with interstitial pneumonitis. Microscopic hematuria and proteinuria were found when the interstitial pneumonitis became more severe. Renal biopsy findings yielded a diagnosis of ANCA-associated glomerulonephritis (mixed class) with MN-lesions. The second patient was a 63-years-old woman who had been treated for relapsing polychondritis. Her renal tissue showed evidence of focal ANCA-associated glomerulonephritis with MN-lesions. Interestingly, both MPO and PLA2R were detected in the glomerular subepithelial deposits of both patients. Immunoglobulin G (IgG) 1 and IgG2 were positive in the glomeruli of patient 2, and all subclasses of IgGs were positive in patient 1. CONCLUSION: The present cases suggest that ANCA-associated glomerulonephritis could expose PLA2R, leading to the development of MN-lesions.

Human intestinal spirochetosis: right-side preference in the large intestine.

Human intestinal spirochetosis (HIS) is a colorectal bacterial infection, and its clinicopathologic features remain unclear. The aim of this study was to examine its characteristics. We histologically reviewed paraffin-embedded section slides made in 2001, 2006, and 2011 at a single institution in Japan. Cases histologically exhibiting a distinct fringe formation were considered to have HIS. Information was obtained from pathology request forms. We identified 85 HIS cases among 4930 patients (7 cases [0.5%) in 2001, 29 [1.7%] in 2006, and 49 [2.8%] in 2011]. Gastrointestinal symptoms were observed in 7.1% of HIS cases. Human intestinal spirochetosis was more frequent in the right-side large intestine than in the left side. Among 224 samples from HIS cases, conventional (tubular, tubulovillous, and villous) adenomas were found in 148 samples. These adenomas were more frequent in the right side than in the left side, although neither their size nor morphology differed between the sides. Histopathologic evaluation suggested a year-upon-year increasing prevalence of HIS in Japan. A small number exhibited gastrointestinal symptoms. Both histologic sign of HIS and conventional adenomas were more frequent in the right-side large intestine. Therefore, a right-side preference may be a characteristic of HIS.

Passenger lymphocyte syndrome with hemophagocytic syndrome after peripheral blood stem-cell transplantation from an HLA-matched full biological sibling: case report.

Massive hemolysis due to passenger lymphocyte syndrome (PLS) is rare after peripheral blood stem-cell (PBSC) transplantation with a minor ABO mismatch. We present, in a 16-year-old boy (group A Rh+), PLS with hemophagocytic syndrome (HPS) after PBSC transplantation from his HLA (human leukocyte antigens)-matched biological sister (group O Rh+). Mild-to-moderate hemolysis was evident from day +11 to day +15 after transplantation. HPS was diagnosed by bone marrow examination on day +16, while antibodies against the recipient's red blood cell antigens were detected on days +15 and +27. This hemolysis may have been due to PLS with HPS. Therefore, measurement of antibodies may provide a useful hallmark of immune hemolysis.

Pneumothorax as a rare presentation of bronchial schwannoma.

Tracheobronchial schwannomas are rare diseases. Common signs and symptoms of this tumor include cough, wheezing, and dyspnea. In contrast, pneumothorax is an exceptional presentation. This study reports the first case of bronchial schwannoma presenting with pneumothorax. A 79-year-old woman was diagnosed with pneumothorax by chest radiography. Chest computed tomography unexpectedly revealed a tumor occluding the right main bronchus. Following the pathological diagnosis of bronchial schwannoma, the patient underwent thoracoscopic tumor enucleation. The airway lumens are consequently secured postoperatively. We reviewed the literature and discussed the mechanisms and treatment options for bronchial benign tumor-associated pneumothorax. Pneumothorax should be aware of a rare presentation of non-malignant tracheobronchial tumors.

Expression of P2X4R mRNA and protein in rats with hypobaric hypoxia-induced pulmonary hypertension.

BACKGROUND: The experimental pulmonary hypertension that develops in hypobaric hypoxia is characterized by structural remodeling of the heart. The P2X4 receptor (P2X4R) controls vascular tone and vessel remodeling in several blood vessels, and it has emerged as a key factor in the enhancement of cardiovascular performance. METHODS AND RESULTS: To study the possible effects of hypobaric hypoxia on the P2X4R-synthesis system, 150 male Wistar rats were housed in a chamber at the equivalent of the 5,500 m altitude level for 21 days. After 14 days' exposure to hypobaric hypoxia, pulmonary arterial pressure (PAP) was significantly increased. In the right ventricle (RV) of the heart, P2X4R expression was significantly increased on days 1 and 14 (mRNA) and on days 7 and 21 (protein) of hypobaric hypoxic exposure. Immunohistochemical staining for P2X4R protein became more intense in RV in the late phase of exposure. These changes in P2X4R synthesis in RV occurred alongside the increase in PAP. In addition, P2X1R and P2Y2R mRNA levels in the RV were significantly increased on days 1, 14, and 21, and day 5, respectively, of exposure. The level of P2X1R protein in the RV was significantly increased on day 21 of exposure. CONCLUSIONS: Conceivably, P2 receptors, including P2X4R and P2X1R, might play roles in modulating the RV hypertrophy that occurs due to pulmonary hypertension in hypobaric hypoxia.

Glucose-regulated protein 78 expression in urothelial carcinoma of the upper urinary tract.

OBJECTIVE: To examine glucose-regulated protein 78 (GRP78; a major molecular chaperone at the endoplasmic reticulum, strongly expressed in several tumours) expression in urothelial carcinoma (UC) of the upper urinary tract (UUT) and to evaluate the diagnostic and progressive importance of GRP78 expression in UC-UUT. PATIENTS AND METHODS: We investigated GRP78 expression (using immunohistochemistry) in 126 UC-UUTs to assess its relevance to progression. GRP78 overexpression was recognised in 23 (18.3%) of tumour samples. RESULTS: There was no association between GRP78 overexpression and clinicopathological findings, except for an association with low grade in invasive tumours. GRP78 overexpression significantly improved the disease-free survival rate in all patients (according to univariate and multivariate analyses), but did not alter the overall survival rate. CONCLUSION: The detection of GRP78 overexpression would appear to provide valuable information for the prognosis of UC-UUT.

Nonviral retrograde gene transfer of human hepatocyte growth factor improves neuropathic pain-related phenomena in rats.

Peripheral nerve injury occasionally causes chronic neuropathic pain with hyperalgesia and allodynia. However, its treatment is difficult. Here, we used a chronic constriction injury (CCI) model in rats to investigate the effects on experimental neuropathic pain of the human hepatocyte growth factor (HGF) gene delivered into the nervous system by retrograde axonal transport following its repeated intramuscular transfer, using liposomes containing the hemagglutinating virus of Japan (HVJ). CCI (control) rats exhibited marked mechanical allodynia and thermal hyperalgesia, and decreased blood flow in sciatic nerve and hind paw. All these changes were significantly reversed by HGF gene transfer. In the sciatic nerve in HGF-treated rats, the size-frequency distributions for myelinated and unmyelinated axons each showed a rightward shift, the number of myelinated axons >5 microm in diameter was significantly increased, and the mean diameter of unmyelinated axons was significantly increased (versus CCI rats). Levels of P2X3, P2X4, and P2Y1 receptor mRNAs, and of interleukin-6 (IL-6) and activating transcription factor 3 (ATF3) mRNAs, were elevated in the ipsilateral dorsal root ganglia and/or sciatic nerve by CCI, and these levels were decreased by HGF gene transfer. These results may point toward a potential new treatment strategy for chronic neuropathic pain in this model.

Lymphohistiocytoid mesothelioma of the pleura.

Lymphohistiocytoid mesothelioma (LHM), reported to be a rare variant of sarcomatoid mesothelioma, is challenging to differentiate from non-Hodgkin's lymphoma due to marked lymphocytic infiltration. To aid accurate recognition of LHM, we examined immunohistochemical, in situ hybridization (ISH) of Epstein-Barr virus RNA (EBER-1) mRNA, fluorescence ISH (FISH) for homozygous deletion of 9p21, and asbestos analysis in four cases (three men and 1 woman). Three patients died, while Case 4 was still alive 19 months after extrapleural pneumonectomy. Histologically, these cases were characterized by heavy lymphocytic infiltration. All neoplastic cells were positive for calretinin, AE1/AE3, and epithelial membrane antigen, but negative for CEA. EBER1 factor was negative. FISH analysis demonstrated homozygous deletion of the 9p21 locus in three of the four cases. In Case 1: (i) autopsy findings showed mesothelioma primarily located in the right parietal pleura, but metastasized into the left lung and abdominal organs; (ii) the histological findings at autopsy indicated sarcomatoid mesothelioma; and (iii) we found asbestos bodies and fibers in extracts from lung tissue (Cases 1 & 4) using digestion with bleaching fluid. LHM, an infrequent variant of sarcomatoid mesothelioma, displayed homozygous deletion of the 9p21 locus (three of four cases), and has a relatively favorable prognosis for the sarcomatoid type.

Poorly differentiated adenocarcinoma with signet-ring cell carcinoma of the extrahepatic bile duct in a 42-year-old Japanese female: a case report.

Poorly differentiated adenocarcinoma without papilla or tubule formation of the extrahepatic bile duct is rare. Here we present a case (a 42-year-old Japanese woman) without either pancreatobiliary maljunction or liver disease. The patient had obstructive jaundice. Imaging studies revealed a bile duct tumor obstructing the common bile duct and invading the surrounding tissues. Pathologic examination revealed a dense periductal growth of poorly differentiated adenocarcinoma containing signet-ring cells, but without papilla or tubule formation in the extrahepatic bile duct. The tumor cells directly invaded the pancreatic parenchyma and the portal vein. In the extrahepatic bile duct, poorly differentiated adenocarcinoma may be established as a distinct clinicopathologic entity if the tumors are characterized by: 1) the absence of papilla or tubule formation, 2) Asian preponderance, 3) occurrence at a younger age than is usual for patients with biliary cancers, and 4) an aggressive mural invasiveness.

Sarcoidosis-associated hepatocellular carcinoma.

Sarcoidosis is a systemic granulomatous inflammation of unknown etiology, and seems to involve the liver parenchyma in most cases. However, sarcoidosis-associated hepatocellular carcinoma is rare. We report here a case in which a hepatocellular carcinoma occurred within the liver, which was probably involved as a result of systemic sarcoidosis. A 57-year-old Japanese man had been followed up for 2 years because of diabetic nephropathy and sarcoidosis. On admission for pneumonia, imaging studies revealed an unexpected hepatic tumor. Histology revealed a hepatocellular carcinoma accompanied by T-lymphocytic infiltration and marked granulomatous inflammation, which was surrounding some tumor nodules. The background liver parenchyma exhibited a moderate degree of fibrosis with granulomatous inflammation. The patient had no other apparent liver disease such as viral hepatitis, steatohepatitis, or primary biliary cirrhosis. Therefore, in the present case, sarcoidosis may be considered the probable background etiology for hepatocarcinogenesis.

Histologic characteristics of human intestinal spirochetosis in operatively resected specimens.

Human intestinal spirochetosis (HIS), one of the zoonoses, is caused by colonization by Brachyspira species bacteria within the large intestine. Histologic diagnosis of HIS is usually established by finding "fringes" on the colonic surface epithelium in biopsy specimens. However, its histologic characteristics, especially beneath the colonic mucosa, have not been elucidated. The present study was designed to examine the histologic characteristics of HIS in operatively resected specimens. We reviewed operatively resected (colectomy or appendectomy) specimens obtained in six consecutive years at a single medical center. HIS was diagnosed histologically by finding "fringes". Immunohistochemical study using anti-Treponema pallidum antibody, which cross-reacts with Brachyspira, was additionally performed. A total of 848 (M:F = 477:371; median age, 59 years; 12-94 years) colectomy and/or appendectomy cases were examined, and the seven cases (0.8%) diagnosed as having HIS were all male (1.5% of male cases). Four HIS cases (0.8% of 508 colectomy cases (1.4% of 285 male-cases)) were colectomy cases with cancers, and the other three (0.9% of 340 appendectomy cases (1.6% of 192 male-cases)) were appendectomy cases for acute appendicitis. Our study revealed (1) a heterogeneous distribution of diagnostically important "fringes" within the large intestine, (2) an ileal presence of Brachyspira, (3) superficial location of HIS-related findings among anatomical wall layers, and (4) the presence of Brachyspira or its derivatives within macrophages in the lamina propria and immune apparatus (lymphoid follicles in superficial wall structures (lamina propria or submucosa) and lymph nodes). Investigation using operatively resected specimens might help elucidate the characteristics of HIS. Brachyspira may have immunogenicity in humans.

Efficacy of nonviral gene transfer of human hepatocyte growth factor (HGF) against ischemic-reperfusion nerve injury in rats.

Ischemic neuropathy is common in subjects with critical limb ischemia, frequently causing chronic neuropathic pain. However, neuropathic pain caused by ischemia is hard to control despite the restoration of an adequate blood flow. Here, we used a rat model of ischemic-reperfusion nerve injury (IRI) to investigate possible effects of hepatocyte growth factor (HGF) against ischemic neuropathy. Hemagglutinating virus of Japan (HVJ) liposomes containing plasmids encoded with HGF was delivered into the peripheral nervous system by retrograde axonal transport following its repeated injections into the tibialis anterior muscle in the right hindlimb. First HGF gene transfer was done immediately after IRI, and repeated at 1, 2 and 3 weeks later. Rats with IRI exhibited pronounced mechanical allodynia and thermal hyperalgesia, decreased blood flow and skin temperature, and lowered thresholds of plantar stimuli in the hind paw. These were all significantly improved by HGF gene transfer, as also were sciatic nerve conduction velocity and muscle action potential amplitudes. Histologically, HGF gene transfer resulted in a significant increase of endoneurial microvessels in sciatic and tibial nerves and promoted nerve regeneration which were confirmed by morphometric analysis. Neovascularization was observed in the contralateral side of peripheral nerves as well. In addition, IRI elevated mRNA levels of P2X3 and P2Y1 receptors, and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in sciatic nerves, dorsal root ganglia and spinal cord, and these elevated levels were inhibited by HGF gene transfer. In conclusion, HGF gene transfer is a potent candidate for treatment of acute ischemic neuropathy caused by reperfusion injury, because of robust angiogenesis and enhanced nerve regeneration.

Soluble elastin decreases in the progress of atheroma formation in human aorta.

BACKGROUND: The serum levels of soluble elastin increase in patients with aortic dissection, but its distribution and characteristics are unclear. METHODS AND RESULTS: The 173 aortic specimens were categorized into 4 groups under microscopy (non-atherosclerotic aorta, n=13; fiber-rich plaque, n=77; lipid-rich plaque, n=66; ruptured plaque, n=17). Soluble elastin was abundant within the intima of both the non-atherosclerotic aorta and fiber-rich plaque, rather than in the media, and was decreased within the intima of lipid-rich and ruptured plaques. Soluble elastin levels decreased with progress of atherosclerosis (6.0 +/-0.3 microg/mg protein in non-atherosclerotic aorta; 5.8 +/-0.2 microg/mg protein in fiber-rich plaque; 4.9 +/-0.2 microg/mg protein in lipid-rich plaque; 2.8 +/-0.4 microg/mg protein in ruptured plaque, P<0.05). As well, both matrix metalloprotease-9 activity and elastin mRNA expression showed inverse distribution against soluble elastin (r=0.437, P<0.0001; r=0.186, P<0.05, respectively). Multivariable analysis revealed a decrease in the level of soluble elastin in ruptured plaque (2.8 +/-0.4 microg/mg protein in ruptured plaque, n=18; 5.5 +/-0.2 microg/mg protein in non-ruptured plaque, n=155, P<0.01). Furthermore, western blot showed soluble elastin consists of heterogeneous molecular pattern proteins. CONCLUSIONS: Both the synthesis and degradation of elastin may be enhanced in active atherosclerotic lesions.

Malignant amelanotic melanoma of the pleura without primary skin lesion:an autopsy case report.

Melanoma metastasizing to the lungs is common, but primary pulmonary or pleural melanoma is extremely rare. We present an autopsy case of malignant melanoma of the pleura without primary skin lesion in a 49-year-old man. A mass found in the right chest was diagnosed as spindle cell sarcoma by antemortem fine-needle aspiration cytology. At autopsy, a yellow-white tumor located primarily in the right visceral pleura (diagnosed as an amelanotic melanoma) was found to have invaded into the right lung, right parietal pleura, and right diaphragm, and to have metastasized into the left lung and visceral pleura, thyroid, and left adrenal gland. No primary site was found. The tumor cells were positive for S100 and focally positive for HMB-45, but negative for other markers. Immuno-histochemical examination for S100 and HMB-45 would thus appear to be useful for the diagnosis of an amelanotic melanoma.

Cell-to-cell variation of chromosomal number in the adult testicular germ cell tumors: a comparison of chromosomal instability among histological components and its putative role in tumor progression.

By allelotyping analysis, we previously reported a putative progression pathway from germ cell neoplasia in situ (GCNIS) to seminoma, then to embryonal carcinoma in mixed-type testicular germ cell tumors (TGCTs), and detected that loss of heterozygosity events in seminoma components in mixed tumors were more frequent than those in pure seminomas. To elucidate a role of chromosomal instability in the progression of non-seminomatous germ cell tumor (NSGCT), we performed fluorescence in situ hybridization with centromeric probes for chromosomes 1, 7, 8, 12, 17, and X on a cohort of 52 TGCT cases with 103 histologically distinct components: 39 GCNIS lesions (16 and 23 in tumors with and without NSGCT components, respectively), 39 seminomas (27 as pure seminomas and 12 in mixed tumors), and 25 embryonal carcinomas. On a total component basis, both the mean copy number per tumor cell nucleus and the deviations from the modal number of all chromosomes examined significantly increased from GCNIS to seminoma, then to embryonal carcinoma with few exceptions. Seminoma components in mixed tumors showed a significantly greater extent of chromosomal instability in chromosomes 8 and 12 than pure seminomas, whereas no statistically significant difference was observed between GCNIS lesions with and without NSGCT components. These results suggest that not only aneuploidy, but also the cell-to-cell variation of chromosomal number is a sensitive indicator of chromosomal instability and would be implicated in the progression of NSGCT.

Seminoma component of mixed testicular germ cell tumor shows a higher incidence of loss of heterozygosity than pure-type seminoma.

Using analysis of allelic loss (loss of heterozygosity [LOH]), we previously reported a putative progression pathway from germ cell neoplasia in situ (GCNIS) to seminoma and then to embryonal carcinoma in mixed-type testicular germ cell tumors. To identify the genetic backgrounds related to the progression of nonseminomatous germ cell tumor, patterns of LOH were studied in seminoma components in mixed tumors (18 cases), pure seminomas (20 cases), and coexisting GCNIS lesions. Each tumor was assessed for LOH at 22 polymorphic loci located on 12 chromosomal arms: 3q, 5q, 6p, 9p, 10q, 11p, 12p, 12q, 13q, 17p, 17q, and 18q. For all informative loci, the frequency of LOH in seminoma components in mixed tumors was significantly higher than that in pure seminomas (32% [96/302 loci] versus 19% [60/323 loci], P < .0001). The frequency of LOH in GCNIS lesions was not significantly different between the 2 tumor groups. The frequencies of LOH at chromosomes 6p and 10q were significantly higher in seminoma components in mixed tumors than in pure seminomas (P = .020 and P = .0041, respectively). Immunohistochemical analysis demonstrated a close association between the allelic status of the 10q23 locus and levels of phosphatase and tensin homolog deleted from chromosome 10 protein expression in seminoma (P = .00051). These data indicate that the seminoma, which has a potential to progress to nonseminomatous germ cell tumor, already exhibits several genetic changes including allelic losses of 6p and 10q, unlike pure seminoma.

Left ventricular noncompaction with pulmonary capillary hemangiomatosis-like lesions: case report.

Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by prominent left ventricular trabeculae and deep intertrabecular recesses. Pulmonary capillary hemangiomatosis (PCH) is a rare disease that causes uncontrollable proliferation of pulmonary capillaries. We experienced a 52-year-old man who was diagnosed with LVNC about 8 years previously who subsequently died of heart failure. The major autopsy findings were enlargement of the heart with prominent trabeculations and deep intertrabecular recesses in the apical and middle regions of the left ventricular wall. The mean ratio of noncompacted to compacted layers was 2.4. In the lung, thickened alveolar walls with numerous pulmonary capillaries were evident, findings very similar to PCH. PCH-like lesions and LVNC may have coexisted coincidentally, and both, or either of them, may have contributed to the development of his pulmonary hypertension.

Expressions of ATF6, XBP1, and GRP78 in normal tissue, atypical adenomatous hyperplasia, and adenocarcinoma of the lung.

Little is known about the association between the atypical adenomatous hyperplasia (AAH)-adenocarcinoma in situ sequence of the lung and endoplasmic reticulum-stress responders such as ATF6, XBP1, and GRP78. Using stored tissues, we examined (i) the percentage of a splicing form (active form) of XBP1 messenger RNA in normal lung tissue (NLT) and adenocarcinoma (ACA; using reverse-transcription polymerase chain reaction); (ii) ATF6 and GRP78 protein expressions in NLT and ACA (using Western blotting analysis); (iii) ATF6, XBP1, and GRP78 protein expressions in NLT, AAH, and ACA, including some adenocarcinoma in situ (using immunohistochemistry); and (iv) the incidence of nuclear translocation of the 3 proteins in these lesions. The percentage of the splicing form of XBP1 messenger RNA showed a borderline difference between NLT and ACA (P = .068). In the Western blotting analysis, the nuclear fractions of ATF6 (including the active form) and GRP78 proteins were higher in ACA than in NLT. In the immunohistochemistry, the values obtained for the incidence of the nuclear translocation of ATF6, XBP1, and GRP78 proteins were as follows, respectively: 13.3%, 2.2%, and 0.5% in low-grade AAH; 37.9%, 2.3%, and 2.2% in high-grade AAH; and 47.2%, 10.6%, and 4.4% in ACA. A significant difference was detected between low-grade AAH and ACA for ATF6. In terms of nuclear translocation, high-grade AAH seemed intermediate between low-grade AAH and ACA. These results support endoplasmic reticulum-stress responses, such as nuclear translocation of these 3 proteins (including their active forms), being in parallel with the progression of the adenoma-carcinoma sequence in the lung.