IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4 þ cells in affected tissues and elevation of serum IgG4 levels. In 2009, we were the first to report skin lesions in patients with IgG4-related disease, but no large case series has been reported and clinicopathological findings remain unclear. To clarify these features, we herein report 10 patients (9 men and 1 woman; median age, 64 years; age range, 46-81 years) with IgG4-related skin disease. All patients had erythematous and itchy plaques or subcutaneous nodules on the skin of the head and neck, particularly in the periauricular, cheek, and mandible regions, except for one patient, whose forearm and waist skin were affected. In addition, eight patients had extracutaneous lesions: these were found on the lymph nodes in six patients, the lacrimal glands in three patients, the parotid glands in three patients, and the kidney in one patient. Histologically examined extracutaneous lesions were consistent with IgG4-related disease; five of six lymph node lesions showed progressively transformed germinal centers-type IgG4-related lymphadenopathy. Cases of IgG4-related skin disease were classified into two histological patterns: those exhibiting a nodular dermatitis pattern and those with a subcutaneous nodule pattern. The infiltrate was rich in plasma cells, small lymphocytes, and eosinophils; the majority of the plasma cells were IgG4 þ . The IgG4 þ cell count was 49-396 per high-power field (mean±s.d., 172±129), with an IgG4 þ /IgG þ cell ratio ranging from 62 to 92%. Serum IgG4 levels were elevated in all examined patients. In conclusion, patients with IgG4-related skin disease had uniform clinicopathology. Lesions were frequently present on the skin of the periauricular, cheek, and mandible regions, and were frequently accompanied by IgG4-related lymphadenopathy.

Background: The human homologue of the Drosophila discs large tumour suppressor protein (hDLG) and closely related proteins such as postsynaptic density protein 95 kDa (PSD-95) are associated with N-methyl-D-aspartate receptors (NMDA-R) and Shaker-type K þ channels, and are thought to be involved in their clustering.

Aims: Angiofibroma of soft tissue (AFST) is a rare soft tissue neoplasm characterized by a fibroblastic cytomorphology and a prominent vascular structure. AFSTs possess a novel fusion gene, i.e. NCOA2-AHRR/ AHRR-NCOA2 or GTF2I-NCOA2, providing a useful approach to diagnosing AFST. Morphologically, AFSTs span a wide spectrum, making diagnosis a challenge. The aim of this study was to review AFST cases and to report previously unknown histological features, which we confirmed by genetic analysis. Methods and results: We reviewed 276 cases diagnosed as solitary fibrous tumours/haemangiopericytomas (232 cases), unclassified tumours of fibroblastic differentiation (36 cases), and recently diagnosed AFSTs (eight cases), and retrieved 13 cases compatible with AFST. Immunohistochemical staining was performed for these cases, all 13 of which were analysed by reverse transcription polymerase chain reaction and fluorescence in-situ hybridization. The histological findings were as follows: amianthoid fibres, extravasation of red blood cells, haemosiderin deposition, aggregates of foamy histiocytes, cystic change, necrosis, and haemorrhage. Immunohistochemically, the tumour cells were positive for epithelial membrane antigen (four of 13 cases), desmin (six of 13 cases), CD163 (13 of 13 cases), CD68 (seven of 13 cases), oestrogen receptor (13 of 13 cases), progesterone receptor (three of 13 cases), and STAT6 (one of 13 cases, weak nuclear staining), but they were negative for CD34, a-smooth muscle actin, , S100, pan-cytokeratin, MDM2, and CDK4. The AHRR-NCOA2 fusion gene was detected in eight cases, and NCOA2 gene rearrangement in nine cases. Conclusion: We revealed the previously unreported histological variation and immunohistochemical findings of AFST, and confirmed them by using genetic methods. The results suggested that AFST should be considered in the diagnosis of fibrous or fibrohistiocytic tumours with the above histological features.

Results suggest that duodenal follicular lymphomas have intermediate characteristics of MALT lymphomas and nodal follicular lymphomas.

Dear Sir,Lung cancer is one of the most common malignant diseases in developed countries and is classified into nonsmall cell lung cancer (NSCLC) and small cell lung cancer.1 Adenocarcinoma and squamous cell carcinoma are the 2 major subtypes of NSCLC. However, significant differences in etiology and genetic and epigenetic alterations exist between these 2 subtypes.2-4 For example, squamous cell carcinoma generally arises in smokers and rarely occurs in never-smokers; mutations in the K-ras and EGFR genes are also infrequent. In contrast, adenocarcinoma is the dominant histological subtype in female never-smokers, and K-ras or EGFR mutations are frequently present in this subtype. 5,6 Adenosquamous carcinoma of the lung is a rather rare subtype of NSCLC, comprising 0.4-4% of pulmonary carcinomas.3 According to the World Health Organization's classification, adenosquamous carcinoma is defined as a carcinoma showing components of both adenocarcinoma and squamous cell carcinoma, with each component comprising at least 10% of the tumor. 3 The etiology of adenosquamous carcinoma, including age, smoking status and race, is similar to that of other types of lung cancers.7 A clinicopathological analysis has demonstrated that adenosquamous carcinoma is more aggressive and results in a poorer prognosis than does adenocarcinoma or squamous cell carcinoma, 7 indicating that its biological features are different from these major types of NSCLCs. Regarding the histogenesis of adenosquamous carcinoma, monoclonal or polyclonal pathways have been proposed. Monoclonality is considered to be a fundamental feature of neoplasms and consists of the transformation of 1 component to the other, whereas the polyclonal pathway may result from a collision of 2 types of independent tumors. 8,9 However, little is known about the progenitor cells and the process of tumorigenesis in adenosquamous carcinoma of the lung.3 Information on genetic alterations is also limited; only TP53, K-ras mutation and loss of heterozygosity at several loci have been reported in a limited number of adenosquamous carcinomas. [10][11][12] In our study, we investigated the molecular features of adenosquamous carcinoma, a typical heterogeneous tumor of the lung.In our previous analysis for EGFR mutation in 397 cases of NSCLCs, we found somatic mutations in 2 cases for EGFR and 1 for K-ras out of 6 adenosquamous carcinomas by direct sequence of exon 18-21 for EGFR and codon 12 and 13 for K-ras genes.13,14 The rates of EGFR mutation in each histology of lung cancer are shown in Table I. In our study, we added 5 new cases of adenosquamous carcinomas of the lung for EGFR and K-ras analysis, and EGFR mutation was present in 1 case and K-ras mutation was absent in 5 cases. Thus, 4 of 11 cases showed either EGFR or K-ras mutations (27% for EGFR and 9% for K-ras). The characteristics of 11 cases are exhibited in Table II. These results provoked considerable interest, because mutations in these genes were assumed to be usually present in adenocarcinoma and rarely present in ...

Transcription of the mat1-Pm gene of Schizosaccharomyces pombe controlling entry into meiosis is stimulated by the mating pheromone, M-factor. We have studied its expression by monitoring beta-galactosidase activity in cells carrying a plasmid-borne mat1-Pm/lacZ fusion construct. Stimulation required the M-factor receptor (Map3) and other proteins (Gpa1, Byr1, Byr2 and Spk1) thought to be involved in propagating the pheromone signal within the cell. Mutational activation of gpa1 encoding an alpha subunit of the receptor-coupled heterotrimeric G protein causes full expression of mat1-Pm even in the absence of pheromone, suggesting that Gpa1 is a key signal transmitter. Furthermore, an activated ras1val17 mutant exhibited a much stronger level of induction than wild-type cells, though full expression needs M-factor treatment. Deletion analysis of the mat1-Pm promoter region identified a stretch of 21 bp that is shown to play a critical role in controlling expression. This region lies just upstream of a TATA-like box and contains a TR-box (TTCTTTGTTY) motif which is the recognition site of a putative transcription factor Ste11. Point mutations in the TR-box motif abolished the expression of mat1-Pm/lacZ. Almost no expression of mat1-Pm was detected in a ste11 deletion mutant, whereas overproduction of Ste11 greatly increased the expression.

Delta-like 1 protein (Dlk-1), also known as preadipocyte factor 1 (Pref-1), is a transmembrane and secreted protein with epidermal growth factor (EGF)-like repeats. Dlk-1 is known to be expressed in foetal liver, but absent in neonatal and adult liver in mice and rats. Dlk-1 is also expressed in a subpopulation of hepatic oval cells, which are considered as stem/progenitor cells in rat adult liver. In this study, we generated monoclonal antibodies against human Dlk-1 (hDlk-1) and investigated hDlk-1 expression in human liver and hepatocellular carcinoma (HCC). Like rodent livers, hDlk-1 was detected in foetal liver, but not in adult liver. In HCC, hDlk-1 was positive for 20.5% of the cases examined and was localized in both cytoplasm and cell membrane, whereas hDlk-1 was undetected in viral hepatitis, nodular cirrhosis. Interestingly, hDlk-1 positive HCC was found more frequently in younger patients and its expression was correlated with alpha-fetoprotein expression. Furthermore, hDlk-1 was also detected frequently in colon adenocarcinomas (58%), pancreatic islet carcinoma (50%), and small cell lung carcinoma (50%). Thus, hDlk-1 is a cell surface protein expressed in many carcinomas including HCC and may be a potential target for monoclonal antibody therapy for carcinomas.

Undifferentiated sarcoma harboring the BCOR-CCNB3 fusion is characterized by its predilection to affect skeletons of adolescent males, cellular small round/spindle cell morphology, and CCNB3 immunoreactivity. We analyzed 11 cases of BCOR-CCNB3 sarcoma, 10 of which were identified in a reverse transcription-polymerase chain reaction-based screen of 85 patient samples recorded in our database as unclassified small round or spindle cell sarcomas. BCOR rearrangements were confirmed by fluorescence in situ hybridization in 8 tumors. All patients were males aged between 6 and 31 years. In addition to 5 tumors in soft tissue and 4 in the axial or appendicular skeletons, which are typical locations, a tumor was located in the paranasal sinus and another in the lung. Microscopically, the tumors comprised proliferating atypical spindle and/or small round cells with diverse morphologic features such as small concentric whorls, myxoid stroma, a hemangiopericytomatous appearance, and/or hyalinized collagen resembling a solitary fibrous tumor, and angiomatous or slit-like spaces containing extravasated erythrocytes. Tumor cells were immunoreactive to CCNB3 (9/11), BCOR (10/10), TLE1 (6/10), bcl-2 (9/11), CD99 (8/10), CD56 (8/10), c-kit (4/10), and cyclin D1 (10/10). In an immunohistochemical analysis of an additional 412 small round or spindle cell tumors, CCNB3 was detected in 6 (1.5%) and BCOR in 18 (4.4%). Our analysis highlights the varying clinicopathologic features of this tumor, which partially overlap with other small round or spindle cell tumors, including solitary fibrous tumor and vascular tumors. Because CCNB3 and BCOR immunohistochemistry lacks adequate sensitivity and specificity, a molecular genetic approach remains essential for diagnosis.