Hiroko Noguchi

Necessity of early intervention for IgG4-related disease—delayed treatment induces fibrosis progression

OBJECTIVE Despite ongoing research, the clinical and histopathological natural history of immunoglobulin (Ig) G4-related disease (IgG4-RD) remains unclear and the optimal time to initiate treatment is unknown. A focus on clinical symptoms rather than image finding is recommended for therapeutic initiation in autoimmune pancreatitis, but evidence for this approach is lacking. We aimed to retrospectively analyse disease duration, efficacy of treatment with glucocorticoids and results of histopathological examination of submandibular gland specimens to clarify the necessity for early intervention in IgG4-RD. METHODS Salivary secretions were assessed before and after treatment in 26 cases of IgG4-related Mikuliczs disease (IgG4-MD). Relationships between disease duration, amount of salivary secretion before treatment, improvement of salivary secretion and ratios of areas of residual acini, fibrosis and lymphoid follicles in the involved submandibular gland specimens were analysed. RESULTS Salivary secretions were significantly reduced in cases with illness of >2 years (P < 0.05). An inverse correlation was seen between improved amount of salivary secretion and amount of salivary secretion before treatment (r = -0.60). Improved amount of salivary secretion was also associated with each histological factor (acini, r = 0.29; fibrosis, r = -0.23; lymphoid follicles, r = -0.31), which showed interrelationships (acini and lymphoid follicles, r = -0.23; acini and fibrosis, r = 0.42; lymphoid follicles and fibrosis, r = 0.30). CONCLUSION Salivary secretion can be improved even in cases with lower levels of salivary secretion before treatment in IgG4-RD, but improvements in the amount of salivary secretion decrease with histological changes with delayed therapeutic intervention. These data suggest that early intervention is needed to improve outcomes in patients with IgG4-MD.

Excessive androgen exposure in female-to-male transsexual persons of reproductive age induces hyperplasia of the ovarian cortex and stroma but not polycystic ovary morphology.

STUDY QUESTION Does administration of androgen to female-to-male transsexual persons (FTMs) of reproductive age induce polycystic ovary (PCO) morphology? SUMMARY ANSWER Administration of high-dose androgen to women causes pathognomonic changes to the ovarian cortex and stroma that resemble Stein-Leventhal syndrome but it does not induce PCO morphology. WHAT IS KNOWN ALREADY Androgen is thought to play a key role in follicular development and to be involved in the pathophysiology of polycystic ovary syndrome (PCOS). In several experimental models, animals given high-dose androgen show ovarian changes similar to those in women with PCOS. In previous human studies, the ovaries of FTMs who received androgen for long periods also exhibited PCO morphology. STUDY DESIGN, SIZE, DURATION We conducted a retrospective case-control study of women, all without PCOS, undergoing salpingo-oophorectomy. The case group consisted of 11 FTMs taking testosterone (duration range: 17 months to 14 years), while the control group consisted of 10 patients with gynaecologic malignancies who did not receive testosterone. PARTICIPANTS/MATERIALS, SETTING, METHODS Resected ovaries from both groups were compared histologically with respect to changes in the cortex and stroma, and the number of follicles at each maturation stage. MAIN RESULTS AND THE ROLE OF CHANCE Compared with controls, the FTM group had a thicker ovarian cortex (P = 0.0001), and more hyperplastic collagen (P = 0.001), ovarian stromal hyperplasia (P = 0.003) and stromal luteinization, i.e. luteinized stromal cells with a small dark central nucleus surrounded by clear cytoplasm (P = 0.004). Isolated clusters of such stromal luteinized cells were found only in the testosterone-treated ovaries of FTMs. The number of primordial follicles was similar in the two groups (P = 0.22). The numbers of early stage (primary, pre-antral and early antral) follicles, which are dependent on androgen, were also similar (P = 0.81), as were the numbers of antral follicles (P = 0.97). In contrast, significantly greater numbers of atretic follicles were seen in the FTM than that in the control group (P = 0.01). LIMITATIONS, REASON FOR CAUTION In addition to the low numbers in the study groups, the histological changes in FTMs were investigated after testosterone administration, therefore it is possible that some of the observed changes were already present, before androgen administration. WIDER IMPLICATION OF THE FINDINGS Our results are at variance with those of earlier studies and suggest that excessive androgen exposure in women of reproductive age may not be a factor in the pathogenesis of PCOS.

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.

Fluorescence in situ hybridization analysis of extraskeletal myxoid chondrosarcomas using EWSR1 and NR4A3 probes

Extraskeletal myxoid chondrosarcomas (EMCs) are characterized histologically by a cord-like or lace-like arrangement of small round cells or short spindle cells with eosinophilic cytoplasm distributed in a rich myxoid matrix. Atypical cases of EMC have also been described, with areas of poor mucus production and high cellularity and a transition to typical EMC. Most cases of EMC harbor the chromosomal reciprocal translocation t(9;22) (q22;q12) and the resultant fused gene, Ewing sarcoma region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). Other translocations, such as those involving the NR4A3 gene, have also been noted, although these occur at a lower frequency. On this basis, we conducted a fluorescence in situ hybridization (FISH) analysis of 18 cases of EMC in which patients presented with typical or atypical (areas of high cellularity) histologic features of EMC. We used an EWSR1 probe and a newly prepared NR4A3 probe to evaluate the usefulness of FISH in the pathologic diagnosis of EMC. FISH analysis using the EWSR1 or NR4A3 probe showed split signals in 83% (15/18) of the cases, regardless of the presence of typical/atypical histologic features. Gene rearrangement of EWSR1 was noted in 72% (13/18) of the cases, and rearrangement of NR4A3 was noted in 61% (11/18) of the cases. The NR4A3 rearrangement was detected in 2 cases not carrying any EWSR1 rearrangement, as determined by reverse transcription-polymerase chain reaction. These results suggest that FISH analysis of formalin-fixed, paraffin-embedded specimens using EWSR1 and NR4A3 probes is useful and convenient and may provide an ancillary method for the diagnosis of EMC.

Glioblastoma simultaneously present with adjacent meningioma: case report and review of the literature

The simultaneous occurrence of multiple primary intracranial tumors has been reported previously. However, most of these tumors arise after cranial radiotherapy or in association with familial tumor syndromes. Double tumors of different histologies that are unrelated to radiotherapy or genetic disorders are very rare. We present a case of two primary intracranial tumors occurring simultaneously at adjacent sites. Preoperative gadolinium-enhanced magnetic resonance imaging of these tumors revealed a single continuous lesion. Postoperative histological examination revealed the presence of two distinct tumors, meningioma and glioblastoma multiforme. To elucidate the mechanism of synchronous tumor formation, we performed immunohistochemical analysis of the proteins involved in the receptor tyrosine kinase, Wnt, and Notch signaling pathways. These analyses showed that platelet-derived growth factor (PDGF) receptors-α and β were overexpressed in both tumors, thereby indicating the oncogenic effects of activated signaling of these receptors. The PDGF-mediated paracrine system may induce one tumor from another.

A case of angioimmunoblastic T-cell lymphoma with high serum VEGF preceded by RS3PE syndrome

We report the case of a 76-year-old man diagnosed with angioimmunoblastic T-cell lymphoma (AITL) with high serum vascular endothelial growth factor (VEGF) preceded by Remitting seronegative symmetrical synovitis with pitting edema syndrome. He suffered respiratory discomfort caused by large amounts of pleural effusion. Interestingly, changes in serum VEGF measured over time were similar to changes in pleural effusion. Whether VEGF is related to the pathological condition of AITL is a very important question.

Extramedullary relapse in RARA rearrangement-negative acute promyelocytic leukemia successfully treated in combination with chemotherapy, local radiotherapy, and cord blood transplantation.

RARA rearrangement-negative acute promyelocytic leukemia (APL) is uncommon, and its extramedullary relapse is extremely rare. We report a 5-year-old girl with RARA rearrangement-negative APL, which recurred solely at the external auditory canal and mastoid air cells. She was successfully treated with chemotherapy, local radiotherapy, and unrelated cord blood transplantation. She has maintained complete remission for 24 months after transplantation. The clinical features and our therapeutic strategy in this patient will provide valuable information for extramedullary relapse of RARA rearrangement-negative APL.

Successful treatment of childhood hypocellular acute myeloid leukemia.

Hypocellular acute myeloid leukemia (AML) is extremely rare in childhood. We report on a 7-year-old girl with hypocellular AML who was treated successfully with granulocyte-colony stimulating factor (G-CSF) and combined chemotherapy. High-dose G-CSF induced complete remission and she subsequently received reduced intensity conditioning and unrelated cord blood transplantation; however, this resulted in early rejection. After a complete hematological recovery, she received 3 courses of combination chemotherapy oriented toward AML. She has remained in complete remission for over 1 year after the completion of the therapy. G-CSF effectively induced remission, and combination chemotherapy has been proven to be feasible for patients with childhood hypocellular AML.

A case of progressively transformed germinal center-type IgG4-related lymphadenopathy

Progressively transformed germinal centers (PTGC), a lymph node process unfamiliar to most otolaryngologists, is a morphological variant of reactive lymphofollicular hyperplasia of lymph nodes. Immunoglobulin (Ig)G4-related disease (IgG4-RD) is a newly identified condition, characterized by hyper-IgG4-γ-globulinemia and mass-forming or hypertrophic lesions associated with infiltration of IgG4(+) plasma cells in the affected organs. Recently, a case study of PTGC was reported that fulfilled the diagnostic criteria of IgG4-RD (IgG4(+) PTGC) [1]. A 68-year-old male was referred to our hospital with swelling in the left submandibular region. Palpation revealed swollen lymph nodes, the largest of which measured 5cm in diameter. (18)F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography identified lymphadenopathy with high (18)F-FDG uptake in the left submandibular region. We strongly suspected malignant lymphoma, and excisional biopsy of the submandibular lymph node was performed under general anesthesia. Pathological findings were consistent with IgG4(+) PTGC, and serological examination demonstrated elevated levels of IgG4. These findings were consistent with IgG4-RD. The patient did not have systemic lesions; therefore, he has not undergone corticosteroid therapy. IgG4(+) PTGC should be considered as a differential diagnosis for cervical lymphadenopathy by otolaryngologists as well as pathologists.