Hiroshi Minato

Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner's tumor)

Chronic sclerosing sialadenitis (CSS) is a cryptogenic tumor-like condition of the salivary gland(s). While immune-mediated processes are suspected in its pathogenesis, and CSS is occasionally reported to be associated with sclerosing pancreatitis, an IgG4-related disease, the exact immunopathologic processes of CSS remain speculative. In this study, we examined the clinicopathologic findings of CSS (12 cases) in comparison with sialolithiasis (8 cases) and Sjögrens syndrome (13 cases), and tried to clarify whether CSS is an IgG4-related disease or not. Submandibular gland(s) were affected in all cases of CSS. CSS cases could be divided into two types: 5 cases were associated with sclerosing lesions in extrasalivary glandular tissue (systemic type), while only salivary gland(s) were affected in the remaining 7 cases (localized type). In the former type, which showed male predominance, bilateral salivary glands were frequently affected, and eosinophilia and elevations of γ-globulin and IgG in serum were frequently found. Histologically, all cases of CSS showed marked lymphoplasmacytic infiltration admixed with fibrosis and the destruction of glandular lobules. Obliterative phlebitis was found in the affected salivary glands in all cases of CSS. Immunohistochemically, the proportion of IgG4/IgG-positive plasma cells was more than 45% in CSS, while it was less than 5% in controls. The resemblance of the clinicopathologic features of CSS with those of sclerosing pancreatitis suggests the participation of a similar immunopathologic process with IgG4 disturbance in CSS. The abundance of IgG4-positive plasma cells in the lesions would be useful for distinguishing CSS from other forms of sialadenitis.

Invasive micropapillary salivary duct carcinoma : a distinct histologic variant with biologic significance

An invasive micropapillary component has been described in tumors of several organs and is nearly always associated with aggressive biologic behavior. We present 14 cases of salivary duct carcinoma (SDC) with an invasive micropapillary component (invasive micropapillary SDC) and compare the clinicopathologic findings of these cases with those of cases of conventional SDC. The mean age of the 14 patients (10 men, 4 women) was 65.8 years (range, 26–80 years). The mean size of the tumors was 2.4 cm (range, 1.3–5 cm). The parotid gland was involved in 12 patients and the submandibular gland in 2. Histologically, all tumors had an invasive micropapillary architecture admixed with features typical for SDC. Invasive micropapillary carcinoma was characterized by morula-like small cell clusters without fibrovascular cores, surrounded by a clear space. Tumor cells exhibited moderate- to high-grade nuclear features, conspicuous nucleoli, and eosinophilic cytoplasm. This component was distributed diffusely in 9 tumors and focally in 5. Angiolymphatic and perineural invasion was seen in all tumors. A residual pleomorphic adenoma was detected in four tumors. Of the 12 tumors examined, all were diffusely positive for cytokeratin 7 and epithelial membrane antigen (with a distinctive “inside-out” pattern) but negative for cytokeratin 20. Tumors were frequently immunoreactive for BRST-2 (gross cystic disease fluid protein-15) and androgen receptor protein. Aberrant expression of HER-2/neu or p53 was detected in seven tumors each. The mean Ki-67 labeling index was 33.1% (range, 6.3%–61.6%). All 14 patients with invasive micropapillary SDC had cervical or periglandular lymph node metastasis, and this value was significantly higher than for conventional SDCs. Local recurrence developed in 4 patients and distant metastatic disease in 9. Clinical follow-up (mean, 25.5 months) was available for 13 patients: 9 died of disease within 24 months after the diagnosis (mean, 17.6 months), 1 was alive with metastatic disease at 19 months, and 3 were free of disease. Overall survival of these patients with invasive micropapillary SDC was significantly shorter than that of patients with conventional SDC (n = 49) in our series (P = 0.031). Our results suggest that invasive micropapillary SDC is a distinct, aggressive variant of SDC, with a propensity for extensive lymph node metastasis and rapid disease progression.

Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1–3; stage 3, score 4–6; and stage 4, score 7–9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0–3, and HA0–3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease.

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed.

Molecular detection of FUS-CREB3L2 fusion transcripts in low-grade fibromyxoid sarcoma using formalin-fixed, paraffin-embedded tissue specimens

A diagnosis of low-grade fibromyxoid sarcoma (LGFMS) remains problematic because of its bland-looking histologic features that can be potentially confused with other benign or low-grade fibromyxoid lesions. Recent cytogenetic and molecular analyses have shown that most LGFMSs have a characteristic chromosomal abnormality, t(7;16)(q33;p11), resulting in the FUS-CREB3L2 fusion gene. However, such assays have only rarely been used to analyze formalin-fixed, paraffin-embedded tumor samples. In the present study, we conducted a reverse transcription-polymerase chain reaction assay to detect the FUS-CREB3L2 fusion transcripts using formalin-fixed, paraffin-embedded tumor tissue specimens from 16 LGFMSs including 3 cases with giant collagen rosettes. The primers were newly designed to specifically amplify most of the junctional regions of the FUS-CREB3L2 fusion gene transcripts previously reported. The FUS-CREB3L2 fusion gene transcripts were detected in 14/16 (88%) cases of LGFMS. A nucleotide sequence analysis of the PCR products revealed that different portions of the FUS exon 6 or 7 were fused with various sites of the CREB3L2 exon 5, resulting in 12 different nucleotide sequences. We also tested a primer set to detect the FUS-CREB3L1 fusion transcript, which is a rare variant of the gene fusion in LGFMS, although no PCR products were identified in any case. The FUS-CREB3L2 fusion transcripts were not detected in any of the 123 other soft-tissue tumors, including desmoid-type fibromatoses, myxofibrosarcomas, soft-tissue perineuriomas, and congenital or adult fibrosarcomas. These data suggest that our reverse transcription-polymerase chain reaction assay is a reliable method to detect FUS-CREB3L2, which can thus help in accurately diagnosing LGFMS.

Hepatic Hilar Inflammatory Pseudotumor Mimicking Cholangiocarcinoma with Cholangitis and Phlebitis AVariant of Primary Sclerosing Cholangitis

Inflammatory pseudotumor (IPT) of the liver is rare. We present a case of hepatic IPT mimicking cholangiocarcinoma in which the tumor was located at the left porta hepatis. The patient was a 64-year-old man in whom abnormal liver function test results had been noted incidentally during an annual health checkup in 1993: the patient declined to go to the hospital for further examination. At the annual health checkup the following year, abnormal liver function test results were noticed again, and this time he did go to a hospital, where a hepatic mass was found. Laboratory test results were unremarkable. Based on the location of the lesion and the findings of a variety of imaging modalities, such as ultrasound and computed tomography examination, the lesion was preoperatively diagnosed as hilar cholangiocarcinoma and was surgically resected. Pathologic examination of the resected lesion, however, revealed that it was not a true tumor but an inflammatory pseudotumor with marked destructive and sclerosing cholangitis mimicking primary sclerosing cholangitis (PSC) and obliterative phlebitis. Since the location and features of the tumor in the present case are very pertinent to the relationship between IPT and PSC, we describe its clinical and histologic features and discuss the findings in relation to PSC in the context of our literature review.

IgG4-related sclerosing mesenteritis : A rare mesenteric disease of unknown etiology

Sclerosing mesenteritis is a rare inflammatory and fibrosing disorder of unknown etiology, while IgG4‐related disease (IgG4‐RD) consists of mass‐forming, fibroinflammatory lesions characterized by high serum IgG4 levels and tissue infiltration of many IgG4‐positive plasma cells; obliterative phlebitis is common. This report describes a case of sclerosing mesenteritis that was considered a manifestation of IgG4‐RD. A 53‐year‐old man underwent right hemicolectomy because of an ileocecal mass that did not improve with conservative therapy. The ill‐defined fibroinflammatory lesion extended in the mesentery with storiform fibrosis, obliterative phlebitis, and infiltration of many IgG4‐positive plasma cells. The ratio of IgG4‐positive/IgG‐positive cells was 64%, and the ratio of forkhead box protein 3 (FOXP3)‐positive/CD4‐positive cells was elevated (13%). It is likely that at least some cases of sclerosing mesenteritis are a manifestation of IgG4‐RD. It is important to investigate this relationship because steroid therapy may benefit such cases.

Comparative Immunohistochemical Analysis of IMP3, GLUT1, EMA, CD146, and Desmin for Distinguishing Malignant Mesothelioma From Reactive Mesothelial Cells

OBJECTIVES To identify useful biomarkers for differentiating between malignant mesothelioma (MM) and reactive mesothelial cells (RMCs). METHODS Formalin-fixed, paraffin-embedded (FFPE) tissues from 34 MM and 40 RMC samples were analyzed using immunohistochemistry, and the findings were compared. RESULTS Positive markers for MM included insulin-like growth factor 2 messenger RNA binding protein 3 (IMP3), glucose transporter 1 (GLUT1), epithelial membrane antigen (EMA), and CD146, which showed sensitivities of 94%, 85%, 79%, and 71% and specificities of 78%, 100%, 88%, and 98%, respectively. In sarcomatoid MM, EMA had significantly lower expression than did IMP3, GLUT1, and CD146 (P < .001). The areas under receiver operating characteristic curves were the highest for IMP3 (0.95), followed by GLUT1 (0.93). When the optimal cutoff points for IMP3 (30%) and GLUT1 (10%) were used, the sensitivity of IMP3 and GLUT1 for MM was 100%, and the specificity of both for MM was 95%. CONCLUSIONS The combination of IMP3 and GLUT1 is most appropriate for distinguishing MM from RMC using FFPE sections.

Breakages at YWHAE, FAM22A, and FAM22B loci in uterine angiosarcoma: a case report with immunohistochemical and genetic analysis.

Described herein is the first reported case of a uterine angiosarcoma with breakages at three loci, YWHAE (17p13), FAM22A (10q23) and FAM22B (10q22). A 62-year-old postmenopausal woman was found to have endometrial thickening of her uterus. An endometrial biopsy indicated a malignant, spindle cell neoplasm. A total hysterectomy with bilateral salpingooophorectomy was performed. Histologic examination of the uterine specimen showed a malignant tumor consisting of irregular rudimentary vascular channels and solid small nests diffusely infiltrating to the middle of the myometrial wall. The tumor cells were epithelioid, and displayed eosinophilic cytoplasm and vesicular nuclei in some areas of the tumor. Immunohistochemically, the tumor cells showed vascular differentiation; they were diffusely positive for CD31 and D2-40 but were negative for factor VIII and CD34. In the course of the procedure of differential diagnoses, we included fluorescence in situ hybridization analysis for detection of a FAM22B-YWHAE fusion gene resulting from t(10;17)(q22;p13), recently reported in a series of endometrial stromal sarcoma, and unexpectedly identified breakages at three loci, i.e. YWHAE (17p13), FAM22A (10q23) and FAM22B (10q22). Collectively, these findings suggest that abnormality in the loci of YWHAE, FAM22A and FAM22B, which are known to be associated with oncogenesis of endometrial stromal sarcoma, may contribute to the development of uterine angiosarcoma.

Clinicopathological study of surgically treated cases of tracheobronchial adenoid cystic carcinoma.

Between 1980 and 2007, five patients were pathologically diagnosed as tracheobronchial adenoid cystic carcinoma (ACC). All five patients were women aged 37–67 years. Four tumors were located in the larger airways, and one tumor was located in the peripheral lung. The following operations were done: bronchoplastic procedures in three (carinal resection with doublebarreled carinoplasty in one, sleeve right pneumonectomy in one, sleeve middle lobectomy in one), left pneumonectomy in one, and left upper lobectomy in one. Three of the five patients have survived for 172, 144, and 10 months after surgery, respectively. The best local treatment for ACC of the major airway is considered to be sleeve resection of the trachea or bronchus in an area where airway reconstruction may not be disturbed and to add postoperative irradiation when there is residual carcinoma at the stump. However, it seems controversial to recommend adjuvant radiotherapy in all patients undergoing resection.