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IgG4-related disease is diagnosed when both the elevation of the serum IgG4 level and invasion of IgG4-positive interstitial cells and sclerosis to a tumor are noted. Some cases have demonstrated malignant disease. In the head and neck lesion in particular, IgG4-producing mucosa-associated lymphoid tissue (MALT) lymphoma has arisen during the treatment of IgG4-related disease. We herein report the first case of IgG4-producing MALT lymphoma during the treatment of IgG4-related disease in the renal hilum. A 79-year-old man was being followed for autoimmune pancreatitis and IgG4-related sclerosing cholangitis. During follow-up, magnetic resonance cholangiopancreatography detected a mass in the renal hilum, so he was referred to our department for a further examination. Positron emission tomography-computed tomography detected a standard uptake of 9.7, and the tumor size was gradually increasing. Due to these findings, laparoscopic nephro-ureterectomy was performed. A pathological examination revealed IgG4-producing marginal zone B cell lymphoma. We herein report a rare case of IgG4-producing B cell lymphoma in the renal hilum.

Malignant phyllodes tumors of the breast occur infrequently and are difficult to treat with chemotherapy. Here, we present an effective chemotherapy strategy for recurrent malignant breast phyllodes tumors. A 48-year-old woman was diagnosed with a malignant phyllodes tumor in her right breast and underwent total right mastectomy. One year later, the tumor recurred in the right (a 2.2 cm mass) and left (a 10 cm mass) lungs; pleural effusion was also observed in the left lung. Eight courses of doxorubicin-ifosfamide (AI) therapy were administered. After treatment, the right lung mass and pleural effusion regressed completely and the left lung mass regressed to 2 cm. In conclusion, AI therapy is useful for treating recurrent malignant breast phyllodes tumors.

A 50-year-old Japanese man with a two-year history of a painless right scrotal mass visited our hospital. Considering laboratory findings and computed tomography, the patient was diagnosed with an uncharacteristic testicular tumor. No metastases were present on radiographic study at the first visit. Emergent high radical orchiectomy was performed, and the tumor was identified as a squamous cell carcinoma (SCC) of a testicular epidermal cyst. He is alive without recurrence or metastasis six months after surgery. Testicular SCC is an extremely rare tumor. This is the third case of testicular SCC associated with an epidermal cyst in English literature.

Neural epidermal growth factor-like like (NELL) 1 and 2 constitute a family of multimeric and multimodular extracellular glycoproteins. Although the osteogenic effects of NELL1 and functions of NELL2 in neural development have been reported, their expression and functions in cancer are largely unknown. In this study, we examined expression of NELL1 and NELL2 in renal cell carcinoma (RCC) using clinical specimens and cell lines. We show that, whereas NELL1 and NELL2 proteins are strongly expressed in renal tubules in non-cancerous areas of RCC specimens, their expression is significantly downregulated in cancerous areas. Silencing of NELL1 and NELL2 mRNA expression was also detected in RCC cell lines. Analysis of NELL1/2 promoter methylation status indicated that the CpG islands in the NELL1 and NELL2 genes are hypermethylated in RCC cell lines. NELL1 and NELL2 bind to RCC cells, suggesting that these cells express a receptor for NELL1 and NELL2 that can transduce signals. Furthermore, we found that both NELL1 and NELL2 inhibit RCC cell migration, and NELL1 further inhibits RCC cell adhesion. These results suggest that silencing of NELL gene expression by promoter hypermethylation plays roles in RCC progression by affecting cancer cell behavior. We found that the down-regulation of NELL1 and NELL2 in renal cell carcinoma (RCC) is in part due to the hypermethylation of CpG islands in their putative promoter regions. Furthermore, we found that NELL1 suppresses and NELL2 partially suppresses RCC cell migration, and NELL1 further inhibits RCC cell adhesion. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

A needle biopsy of a mass in the right breast of a 36-year-old woman revealed invasive ductal carcinoma (IDC), and approximately 20% of cancer cells showed unequivocal membranous staining with the HercepTest. After systemic therapy with trastuzumab and paclitaxel followed by FEC (fluorouracil + epirubicin + cyclophosphamide), a right mastectomy was performed. By histological and immunohistochemical examinations, the resected tumor consisted mainly of E-cadherin-negative invasive lobular carcinoma (ILC), and the rest was ERBB2-positive IDC; thus, the diagnosis was mixed ductal and lobular carcinoma. Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization (FISH) analyses revealed that ILC and IDC shared high-level amplification of CCND1 in homogeneously staining regions (HSR) and that IDC had an additional HSR-type amplicon of ERBB2. These findings strongly indicate that IDC and ILC had a common precursor cell with CCND1 amplification. Review of the biopsy specimen with FISH showed IDC with gene amplifications of CCND1 and ERBB2 as a minor component, IDC without amplification of CCND1 or ERBB2 as a major component, and a minute portion of ILC with CCND1 amplification. We speculate that chemotherapy and trastuzumab caused a marked reduction in IDC; however, ILC with CCND1 amplification was resistant to chemotherapy and grew.

Background: The maximum standardized uptake value (SUVmax) of 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is an essential tool for making a diagnosis and determining treatment response. This study aimed whether the SUVmax of 18 F-FDG PET/CT could replace pathological diagnosis in luminal type breast cancer. Methods: We retrospectively enrolled 85 patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer (luminal-type) between August 2013 and January 2018 who underwent 18 F-FDG PET/CT scans before surgery and had not received any treatment before surgery at Fujisawa City Hospital. We evaluated the relationship between the SUVmax of 18 F-FDG PET/CT and the Ki-67 labeling index (LI) or other clinicopathological features in luminal-type breast cancer; furthermore, we evaluated whether the SUVmax of PET/CT can help determine whether adjuvant chemotherapy is indicated. Results: The SUVmax differed significantly between the positive and negative groups that showed lymphatic invasion (P=0.018), nuclear grade (P=0.019), and lymph node metastasis (P=0.035). In addition, a significant correlation was observed between the SUVmax and Ki-67 LI (r=0.516, P Conclusions: The SUVmax of 18 F-FDG PET/CT could replace pathological diagnosis in luminal breast cancer.

A 31-year-old nulligravid woman with a 3 year history of infertility visited our hospital. After consultation and a transvaginal ultrasound and MR imaging, her uterine anomaly was identified as complete septate uterus: class V (a) by the American Fertility Society (AFS). She had a doubled uterine cervix and a vaginal septum. Hysteroscopic metroplasty was performed with the aid of a laparoscopy. Both tubal patencies were confirmed with indigocarmine in a laparoscopic image. Laparoscopic electronic cautery was also done on the left ovarian endometrioma (stage 1 endometriosis; the revised American Society for Reproductive Medicine (rASRM) classification 4 point minimal). We distrained an intrauterine device in the uterine cavity and removed it after two cycles of menstruation. The patient subsequently became pregnant during her third menstrual cycle and the current progress of her pregnancy is favorable.

EGFR and ERBB2 belong to the EGFR gene family. In esophageal squamous cell carcinomas (SCCs), amplification of EGFR or ERBB2 is usually mutually exclusive. EGFR amplification occurs in approximately 15% of SCCs, ERBB2 occurs in less than 5%. Here, we report the co-amplification of EGFR and ERBB2 in an ulcerative and infiltrating-type SCC that measured approximately 4.2 × 2.7 × 1.2cm with a superficial lesion occurring in the thoracic esophagus of a 72-year-old man. Multiplex ligation-dependent probe amplification using representative tumor sections showed gain of CCND1 and coincident amplification of ERBB2 or EGFR or neither. Immunohistochemistry and fluorescence in situ hybridization revealed that the tumor comprised three cancer-cell populations: well-differentiated SCC with high-level ERBB2 amplification and ERBB2 overexpression, more infiltrative poorly-differentiated SCC with high-level EGFR amplification and EGFR overexpression, and poorly-differentiated SCC lacking any ERBB2 or EGFR abnormality. These three populations each had low-level CCND1 amplification and nuclear cyclin D1 overexpression. This histological topology and gene amplification combinations suggested that genetic instability first produced CCND1 amplification, and then ERBB2 or EGFR gene amplification occurred. It is further speculated that during cancer progression and clonal selection indecisive predominance of either clone caused the rare co-amplification of ERBB2 and EGFR in a single chimeric tumor. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd., 発行後1年より全文公開

A humanized monoclonal antibody against ERBB2 is used in neoadjuvant therapy for patients with gastric cancer. A critical factor in determining patient eligibility and predicting outcomes of this therapy is the intratumoral heterogeneity of ERBB2 amplification in gastric adenocarcinomas. The aims of this study are to assess the underlying mechanisms of intratumoral heterogeneity of ERBB2 amplification; to characterize the diversity of coamplified oncogenes such as EGFR, FGFR2, MET, MYC, CCND1, and MDM2; and to examine the usefulness of multiple ligation-dependent probe amplification (MLPA) in the semicomprehensive detection of these gene amplifications. A combined analysis of immunohistochemistry and fluorescence in situ hybridization revealed ERBB2-amplified cancer cells in 51 of 475 formalin-fixed, paraffin-embedded gastric adenocarcinomas. The fraction of amplification-positive cells in each tumor ranged from less than 10% to almost 100%. Intratumoral heterogeneity of ERBB2 amplification, defined as less than 50% of cancer cells positive for ERBB2 amplification, was found in 41% (21/51) of ERBB2-amplified tumors. The combined analysis of MLPA and fluorescence in situ hybridization revealed that ERBB2 was coamplified with EGFR in 7 tumors, FGFR2 in 1 tumor, and FGFR2 and MET in 1 tumor; however, the respective genes were amplified in mutually exclusive cells. Coamplified ERBB2 and MYC coexisted within single nuclei in 4 tumors, and one of these cases had suspected coamplification in the same amplicon of ERBB2 with MYC. In conclusion, the amplification status of ERBB2 and other genes can be obtained semicomprehensively by MLPA and could be useful to plan individualized molecularly targeted therapy against gastric cancers. © 2014 Elsevier Inc.

Salivary gland carcinomas encompass a wide spectrum of histological entities. To identify candidate therapeutic targets and innovative treatment options for these carcinomas, we examined epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), HER2, and phosphorylated forms of Akt (p-Akt) and mammalian target of rapamycin (p-mTOR) in 47 salivary gland tumors using immunohistochemistry. EGFR overexpression was found in 51 % of the tumors (24/47); in particular, EGFR overexpression occurred in mucoepidermoid (seven out of seven) and salivary duct carcinomas (9/12). Although EGFR amplification was not detected by fluorescence in situ hybridization analysis, increased copy number due to polysomy of chromosome 7, which houses EGFR, was observed in 4 of the 24 tumors with EGFR overexpression; this polysomy occurred most frequently in salivary duct carcinomas (three out of nine). HER2 overexpression was observed in 21 % (10/47) of all tumors; in these 10 tumors, HER2 gene amplification was found in seven cases. p-Akt was found in 51 % (24/47) of all tumors, most frequently in mucoepidermoid carcinomas (six out of seven). p-mTOR was found in 57 % of the latter (four out of seven). Consequently, different signaling cascades were found activated: (1) an EGFR/HER2(-Akt)-mTOR-dependent axis, with gene gains of HER2 and/or EGFR, activated in salivary duct carcinoma and carcinoma ex pleomorphic adenoma; (2) an EGFR(-Akt)-mTOR-dependent pathway activated in mucoepidermoid carcinoma or acinic cell carcinoma, without HER2 or EGFR gene alterations; and (3) an Akt-dependent pathway without EGFR/HER2 activation in other types. These findings indicate that phosphoprotein mapping of components in the EGFR/HER2-Akt-mTOR pathways may be a useful guide to select appropriate targeting regimens.