Yoshiko Keira

Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: Results from the SMART database

Abstract Objective. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a new disease entity that has only been identified this century. Clinical information is thus lacking. We established the Sapporo Medical University and Related Institutes Database for Investigation and Best Treatments of IgG4-related Disease (SMART) to clarify the clinical features of IgG4-RD and provide useful information for clinicians. Methods. Participants comprised 122 patients with IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), representing lacrimal and/or salivary lesions of IgG4-RD, followed-up in December 2013. We analyzed the sex ratio, mean age at onset, organ dysfunction, history or complications of malignancy, treatments, rate of clinical remission, and relapse. Results. The sex ratio was roughly equal. Mean age at diagnosis was 59.0 years. Positron emission tomography revealed that the ratio of other organ involvements was 61.4%. Complications of malignancy were observed in 7.4% of cases. Glucocorticoid was used to treat 92.1% of cases, and the mean maintenance dose of prednisolone was 4.8 mg/day. Rituximab was added in three cases, and showed good steroid-sparing effect. The clinical remission rate was 73.8%, and the annual relapse rate was 11.5%. Half of the cases experienced relapses within 7 years of initial treatment. Conclusion. We analyzed the clinical features and treatments of IgG4-DS using SMART, providing useful information for everyday clinical practice.

Detection of specific genetic abnormalities by fluorescence in situ hybridization in soft tissue tumors

For the detection of chromosome translocations/chimeric genes and specific genetic abnormalities in soft tissue tumors, we conducted fluorescence in situ hybridization (FISH) analysis on 280 cases of soft tissue and other tumors using formalin‐fixed paraffin‐embedded tissue sections. The detection rate of the FISH split‐signal was 84% (129/154 cases) for the translocation‐associated soft tissue tumors, such as Ewings sarcoma/primitive neuroectodermal tumor, synovial sarcoma, alveolar rhabdomyosarcoma, myxoid liposarcoma, clear cell sarcoma and so forth. Positive split‐signals from EWSR1, SS18 and FOXO1A probes were detected in 3% (2/64) of various histological types of carcinoma, lymphoma, melanoma, meningioma and soft tissue tumors. In FISH using the INI1/CEP22 probe, the INI1 deletion signal was detected in 100% (9/9) of epithelioid sarcoma. In well‐differentiated and dedifferentiated liposarcomas, detection of MDM2 amplification signals in FISH using the MDM2/CEP12 probe were both as high as 85% (11/13) and 100% (13/13), respectively. In other adipocytic and non‐adipocytic tumors requiring differentiation from these types, detection was only 13% (5/39), and CEP12 polysomy was frequently detected. As these results demonstrate the high sensitivity and specificity of FISH, we concluded FISH to be a useful pathological diagnostic adjunct for definite and differential diagnosis of soft tissue tumors.

Evaluation of submandibular versus labial salivary gland fibrosis in IgG4-related disease

Abstract The newly comprehensive diagnostic criteria in 2011 emphasize the importance of IgG4-positive plasmacyte infiltration along with storiform or swirling fibrosis and obliterative phlebitis in diagnosing IgG4-related disease(RD). Although labial salivary gland (LSG) biopsy is a minimally invasive and convenient procedure for obtaining tissues, LSG fibrosis is thought to be inconspicuous or absent in IgG4-RD cases. In this study we evaluated 15 patients with IgG4-RD, in whom both submandibular gland (SMG) and LSG biopsies were performed at the same time. Histological evaluation revealed fibrosis in all the SMG specimens but in only one LSG specimen (6.7%). The diagnosis of IgG4-RD is primarily based on its morphological appearance on biopsy. The results of this study demonstrated that although more invasive than LSG biopsy, SMG biopsy is recommended for accurate diagnosis of IgG4-related MD and to exclude malignant diseases.

Diagnostic utility of NCOA2 fluorescence in situ hybridization and Stat6 immunohistochemistry staining for soft tissue angiofibroma and morphologically similar fibrovascular tumors

Soft tissue angiofibroma (STA), a recently suggested new histologic entity, is a benign fibrovascular soft tissue tumor composed of bland spindle-shaped tumor cells with abundant collagenous to myxoid stroma and branching small vessels. The lesion has a characteristic AHRR-NCOA2 fusion gene derived from chromosomal translocation of t(5;8)(p15;q13). However, morphologically similar tumors containing abundant fibrovascular and myxoid stroma can complicate diagnosis. We designed an original DNA probe for detecting NCOA2 split signals on fluorescence in situ hybridization (FISH) and estimated its utility with 20 fibrovascular tumors: 4 each of STAs, solitary fibrous tumors (SFTs), and cellular angiofibromas and 3 each of low-grade myxofibrosarcomas, myxoid liposarcomas, and low-grade fibromyxoid sarcomas. We also performed FISH for 13q14 deletion and immunohistochemistry (IHC) staining for estrogen receptor, progesterone receptor, retinoblastoma protein, and MUC-4 expression. Furthermore, IHC for Stat6 was conducted in the 20 cases analyzed by FISH and in an additional 26 SFTs. We found moderate to strong nuclear Stat6 expression in all SFTs but no expression in the other tumors. Both estrogen receptor and progesterone receptor expressions were observed in STAs, SFTs, and cellular angiofibromas. Expression of retinoblastoma protein was found in less than 10% of cells in all tumor types except myxoid liposarcoma. The low-grade fibromyxoid sarcomas were strongly positive for MUC-4. All STAs showed NCOA2 split signals on FISH. All tumors, regardless of histologic type, had 13q14 deletion. The NCOA2 FISH technique is a practical method for confirming STA diagnosis. The combination of NCOA2 FISH and Stat6 IHC proved effective for the differential diagnosis of STA, even when using small biopsy specimens.

Intramedullary spinal cord ganglioglioma presenting as hyperhidrosis: unique symptoms and magnetic resonance imaging findings: case report.

Hyperhidrosis is caused by a sympathetic dysfunction of the central or peripheral nervous system. Intramedullary spinal cord lesions can be a cause of hyperhidrosis. The authors report a rare case of intramedullary thoracic spinal cord ganglioglioma presenting as hyperhidrosis. This 16-year-old boy presented with abnormal sweating on the right side of the neck, chest, and the right arm that had been occurring for 6 years. Neurological examination revealed mild motor weakness of the right lower extremity and slightly decreased sensation in the left lower extremity. Hyperhidrosis was observed in the right C3-T8 dermatomes. Magnetic resonance imaging showed an intramedullary tumor at the right side of the spinal cord at the T2-3 level. The tumor showed partial enhancement after Gd administration. The patient underwent removal of the tumor via hemilaminectomy of T2-3. Only subtotal resection was achieved because the margins of the tumor were unclear. Histopathological examination revealed ganglioglioma. Hyperhidrosis gradually improved after surgery. Hyperhidrosis is a rare clinical manifestation of intramedullary spinal cord tumors, and only a few cases have been reported in the literature. The location of the tumor origin, around the right gray matter of the lateral spinal cord, may account for the hyperhidrosis as the initial symptom in this patient. Physicians should examine the spinal cord using MRI studies when a patient has hyperhidrosis with some motor or sensory symptoms of the extremities.

Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment

Secondary resistance of gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors occurs after several years’ administration. However, the mechanism of resistance has not been fully clarified. In this study, we analyzed the genotypes and the histologic and immunohistochemical phenotypes of metastatic GISTs with and without imatinib treatment, and clarified the pleomorphic nature of metastatic GISTs. We examined 31 autopsy cases in which the patients died of multiple metastases of GISTs, and two surgically resected specimens with and without imatinib treatment. A total of 152 primary and metastatic lesions in 33 cases of GISTs were examined for histologic and immunohistochemical expression of KIT and CD34. We analyzed the expression of other receptor tyrosine kinases (RTKs) in KIT‐negative lesions, including human EGFR‐related 2 (HER2), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), platelet‐derived growth factor receptor‐α (PDGFRA), and platelet‐derived growth factor receptor‐β (PDGFRB). Fifteen lesions in seven cases (9.9%) lacked KIT expression, and 74 (49%) in 22 cases lacked CD34 expression. Eight KIT‐negative lesions in five cases expressed PDGFRB, one of which also expressed EGFR, and three lesions in one case expressed MET. Results for the other RTKs were negative. Missense point mutations at PDGFRB gene exon 12 were detected in one PDGFRB‐positive case. Our results indicate that histomorphology, immunohistochemical phenotypes, and genotypes of metastatic GISTs vary among lesions, even in cases without imatinib treatment. A KIT‐independent mechanism, such as activation of other RTKs, might participate in the proliferation of late‐stage GISTs and might be a cause of secondary imatinib resistance.

Histopathological Aspects of Pancreatic Metastases in Renal Cell Carcinoma: Does the Mode of Invasion Permit Limited Resections?

Purpose: To investigate histopathological characteristics, we retrospectively analyzed data from patients who underwent resection of renal cell carcinoma pancreatic metastases (RCC-PMs). Methods: This study included 34 RCC-PM lesions in 13 patients who underwent 15 pancreatic operations. The clinicopathlogical characteristics were analyzed with special emphasis on tumor capsular formation, manner of peritumoral invasion, and presence of lymphovascular invasion. Results: Median duration to onset of RCC-PMs was 101 months from initial nephrectomy. Surgical procedures included distal pancreatectomy in 6 cases, pancreaticoduodenectomy in 4, total pancreatectomy in 1, and limited resections in 6 with two overlapping procedures. No perioperative deaths were encountered. One, three, and five year survival rates after pancreatic resection were 86.2%, 86.2%, and 76.6%, respectively. Of thirty- four lesions 32 lesions with tumor diameter ≤ 35 mm were encapsulated. Of these 32 lesions with capsule formation, extra capsular invasion was identified in 5 lesions. No lymphatic invasion was identified in any case. Venous invasion was presented just adjacent to the tumors in 2 lesions. Five year survival rates for the 11 cases with standard operations and 4 cases with limited resection were 70.7% and 100%, respectively without any significant difference. Conclusions: Small RCC-PMs were frequently encapsulated, seldom invaded into pancreatic parenchyma, and were rarely accompanied by microscopic lymph vascular invasion. Limited resection of the pancreas with adequate surgical margins may be oncologically acceptable.