Yorihisa Orita

Clinicopathologic analysis of IgG4-related skin disease

IgG4-related disease is a recently recognized systemic syndrome characterized by mass-forming lesions with lymphoplasmacytic infiltration, increase in the number of IgG4+ 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+. The IgG4+ cell count was 49–396 per high-power field (mean±s.d., 172±129), with an IgG4+/IgG+ 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.

Prognostic factors and the therapeutic strategy for patients with bone metastasis from differentiated thyroid carcinoma.

BACKGROUND The treatment of bone metastasis in association with thyroid cancer represents a difficult challenge. Given the paucity of patients with bone metastasis and the difficulty of treating this disease, few studies have investigated the clinical features and prognostic factors of bone metastasis from differentiated thyroid cancer. METHODS During the 31-year-period from 1976 to 2006, a total of 1,398 patients underwent initial thyroidectomy at Cancer Institute Hospital for differentiated thyroid carcinomas, including standard papillary thyroid carcinoma, papillary microcarcinoma (primary tumor diameter < or =1.0 cm), and follicular thyroid carcinoma. Among these, 25 (2%) patients displayed bone metastasis at initial presentation (synchronous) and 27 patients showed bone metastasis during follow-up (metachronous). The records for these 52 patients were reviewed retrospectively to identify prognostic factors and analyze treatment strategies. RESULTS Univariate analysis for disease-specific survival indicated metachronous bone metastasis and the presence of distant metastasis at sites other than bone as indicators of significantly worse prognosis. The type of cancer (papillary thyroid carcinoma versus follicular thyroid carcinoma) was not a significant indicator of prognosis; however, patients with papillary microcarcinoma showed significantly worse survival than patients with standard papillary and follicular thyroid carcinoma. A significant survival advantage was observed among patients who underwent radioactive iodine therapy, and better prognosis seemed to be obtained with greater doses of radioactive iodine. Operative resection of metastatic bone lesions also seemed to be associated with better prognosis. A multivariate analysis for disease-specific survival identified the coexistence of distant metastasis at sites other than bone as the only independent variable indicative of poor prognosis. CONCLUSION In the absence of definitive, effective treatments for this disease, radioactive iodine therapy combined with resection of bone metastasis, wherever possible, seems to represent the most potent therapy available. Although bone metastasis is a strong sign of poor prognosis, early detection and administration of appropriate therapy using radioactive iodine seems likely to improve the survival rate and quality of life in patients with bone metastasis from differentiated thyroid carcinoma.

Zoledronic Acid in the Treatment of Bone Metastases from Differentiated Thyroid Carcinoma

BACKGROUND Currently bisphosphonates are often administered to patients with osteolytic bone metastases from several neoplasms. Based on favorable experience in other cancers with bone metastases and the lack of effective treatment, we started to use zoledronic acid (ZA), a recently developed synthetic bisphosphonate drug, in the treatment of this disease. In the present study, we retrospectively evaluated the efficacy of ZA for bone metastases from differentiated thyroid carcinoma. METHODS The study consisted of 50 patients with bone metastases from differentiated thyroid carcinoma treated at the Cancer Institute Hospital of Tokyo between 1976 and 2008. Among them, 28 patients who did not undergo bisphosphonate therapy were defined as group A and 22 patients who received ZA therapy were defined as group B. The primary efficacy endpoint for ZA treatment was the reduction in the percentage of patients who developed skeletal-related events (SREs), including bone fracture, spinal cord compression, and hypercalcemia. A secondary endpoint was the interval between a presentation of bone metastases and appearance of SREs. RESULTS SREs occurred in significantly lower frequency in group B (3 of 22 patients, 14%) than group A (14 of 28 patients, 50%) (p = 0.007). The use of ZA significantly retarded the onset of the first SRE (p = 0.04). Two group-B patients developed bisphosphonate-related osteonecrosis of the jaw. CONCLUSION Treatment with ZA was effective in reducing SREs or delaying their appearance in patients with bone metastases from differentiated thyroid carcinoma.

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFβ1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

Programmed cell death in the developing epithelium of the mouse inner ear

Programmed cell death is as essential to development as is proliferation. Thus, the objective of this study was to elucidate the spatiotemporal involvement of programmed cell death in the development of the inner ear epithelia. Programmed cell death is seen in situ as apoptosis. A time-sequence study was performed on the distribution of apoptosis during the development of the inner ear epithelia of the mouse using the TdT-mediated dUTP-biotin nick labeling (TUNEL) method to detect apoptosis histochemically. Apoptosis occurred during the early stages of development of the inner ear and took place earlier in the organs of equilibrium than in the cochlea. These periods corresponded to those of active proliferation of epithelial cells in the inner ear. Since cell-cell interactions change after the removal of neighboring cells by apoptosis, apoptosis may influence cytodifferentiation.

Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4+ progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4+ plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4+ progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

Analysis of Spiral Ganglion Cell Populations in Children with Normal and Pathological Ears

This study analyzed features of total and segmental spiral ganglion cell populations in children with normal ears and those with various pathological conditions. Sixty-three human temporal bone specimens, obtained from 43 children 4 days to 9 years of age, were studied histopathologically. These specimens were divided into 5 diagnostic groups: group 1, normal ears (13 ears); group 2, congenital infectious diseases (13 ears); group 3, chromosomal aberrations (11 ears); group 4, multiple craniofacial anomalies with hereditary or genetic causes (21 ears); and group 5, perinatal and postnatal asphyxia (5 ears). Eighteen of the 63 ears had documented profound deafness. In either normal ears (group 1) or those with various pathological conditions (groups 2 through 5), the total number of ganglion cells did not change as a function of age during the first 10 years. The total number of ganglion cells was significantly larger in group 1 (33,702) than in each of groups 2, 3, 4, and 5 (p < .01), and the number was significantly larger in group 2 than in each of groups 4 and 5 (p < .01 and p < .05, respectively). The ratio of basal to apical ganglion cell populations remained constant in both normal and pathological ears. Each ratio of the number of basal and apical ganglion cells in groups 2, 3, 4, and 5 to the mean number in group 1 (basal and apical survival ratios) was at least approximately 40%. There was no statistical difference between these Two ratios in groups 2, 3, 4, and 5. The mean (±SD) total number of ganglion cells in ears with documented profound deafness was 15,417 ± 5,944, which is approximately 40% of those present in normal ears. Our results suggest that normally, cochlear neurons are completely present at birth and minimally regress during the first decade of life. In addition, although intergroup differences among various pathological groups were present, the majority of pathological ears had more than 10,000 spiral ganglion cells present. Cochlear implantation has gradually been recognized as an effective and reliable tool for rehabilitation of children who have profound deafness, even congenitally or prelingually deafened children. On the basis of the results obtained in this study, we discuss the implications for cochlear implantation in children.

TUNEL staining of inner ear structures may reflect autolysis, not apoptosis

A recent study (Usami et al., 1997) using the TUNEL method has suggested that age-related cell death in the senescence-accelerated mouse inner ear is due to apoptosis. TUNEL staining detects not only apoptosis but also late necrosis or autolysis because it detects DNA breaks. Autolysis may occur in inner ear structures during fixation. To determine whether or not age-related cell death is due to apoptosis, TUNEL staining of the inner ear of normal mice should be understood. However, studies of TUNEL staining of the normal inner ear have not yet been reported. We investigated whether the fixation method or the interval between the death of normal mice and the initiation of fixation influences the results of TUNEL staining of the inner ear. Marginal cells of the stria vascularis and hair cells of the saccule were TUNEL-positive, irrespective of the fixation method or the interval between death and fixation. Interdental cells, Reissner membrane cells, fibrocytes in the suprastrial region, and inner and outer hair cells were also occasionally stained. Transmission electron microscopy showed no morphological characteristics of apoptosis in the hair cells of the saccule. Moreover, patterns of TUNEL staining in the normal and senescence-accelerated mouse inner ear were similar. These stained tissues may require a high level of oxygen, making them more susceptible to autolysis. We concluded that the results of TUNEL staining in the inner ear require confirmation by morphological studies.

Ménière's disease in childhood

We report 3 rare cases of Ménières disease in children. In Case 1 and 3, vertigo, hearing loss and tinnitus recovered soon after medical therapy. In Case 2, however, vertigo recurred and the hearing level on the right side markedly deteriorated. The equal-loudness contours on three-dimensional audiogram showed that right-sided aggravated hearing loss fluctuated for 4 years at middle-and low-frequencies despite medication. Finally intratympanic injection of gentamicin sulfate was performed. The patient has had no definitive spell of vertigo after gentamicin therapy. At our department, the incidence of Ménières disease in pediatric patients with vertigo was 2.9%.

IgG4-related disease involving the sclera

Abstract A 49-year-old female patient previously treated for scleritis and uveitis-induced cataract in the right eye presented with a subretinal white lesion in the same eye. With a preliminary diagnosis of choroidal tumor, enucleation of the eyeball was performed in accordance with the patient’s request. Histologic and immunohistologic examinations were consistent with immunoglobulin G4-related disease. The case demonstrates that it is important to consider IgG4-related disease in the differential diagnosis of an intraocular tumor.