Shigemichi Hirose

Expression of vascular endothelial growth factor isoforms and their receptors Flt-1, KDR, and neuropilin-1 in synovial tissues of rheumatoid arthritis

Angiogenesis is an indispensable process in the chronic proliferative synovitis and pannus formation of rheumatoid arthritis (RA). This study examined the expression of vascular endothelial growth factor (VEGF) isoforms and VEGF receptors, Flt‐1, KDR and neuropilin‐1, in RA and osteoarthritis (OA) synovia, and studied the relationship between their expression and the synovial angiogenesis. By RT‐PCR analysis, the isoform VEGF121 was constitutively expressed in all the RA (17/17 patients) and OA (8/8 patients) synovia. In contrast, the expression of the isoform VEGF165 was observed in 41% of the RA synovia (7/17 patients), but was undetectable in the OA samples (0/8 patients). The receptor Flt‐1 was almost constitutively expressed in RA (15/17 patients) and OA (8/8 patients) synovia, while the expression of KDR was detected in the synovia of six RA patients (6/17 patients; 35%) but none of the OA patients (0/8 patients). The expression of neuropilin‐1, an isoform‐specific receptor for VEGF165 which enhances the binding of VEGF165 to KDR, was also up‐regulated in the same RA synovia that expressed KDR. Furthermore, there was a close correlation between the expression of isoform VEGF165 and that of its receptors KDR and neuropilin‐1. Morphometric analysis demonstrated that the vascular density is significantly higher in the RA synovial tissues with expression of VEGF165, KDR, and neuropilin‐1 than in those without their expression (p<0.01). In situ hybridization and immunohistochemical studies indicated that the cells expressing VEGF are macrophage‐like synovial lining cells and spindle‐shaped cells in the sublining cell layer. These results suggest that the selective up‐regulation of the isoform VEGF165 and its signalling via KDR and neuropilin‐1 play an important role in the synovial angiogenesis which occurs in RA. Copyright

Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension.

The pulmonary vasculature exhibits various morphological changes in patients with pulmonary hypertension (PH). Among them, the plexiform lesion is one of the most characteristic vascular lesions, although nothing is known about the molecular mechanisms of its formation. In the present study, the expression of vascular endothelial growth factor (VEGF), an endothelial cell‐specific angiogenic mitogen, and its receptors, fms‐like tyrosine kinase (Flt‐1) and kinase insert domain‐containing receptor (KDR), in the lungs of five cases with PH, were examined. By in situ hybridization, VEGF expression was found in modified smooth muscle cells inside the plexiform lesions as well as in medial smooth muscle cells of the arteries adjacent to the lesions. The expression of Flt‐1 mRNA was observed in endothelial cells of the arteries adjacent to the plexiform lesions, while KDR mRNA was expressed in the endothelial cells inside the plexiform lesions. VEGF was immunolocalized to the endothelial cells expressing its receptors as well as the modified smooth muscle cells producing VEGF. These results demonstrate that VEGF and its receptors are upregulated with a close correlation to the plexiform lesions, and suggest that VEGF expressed by smooth muscle cells may activate the endothelial cells to form the plexiform lesions.

Histopathological studies on spontaneous occlusion of the circle of Willis (cerebrovascular Moyamoya disease)

Spontaneous occlusion of the circle of Willis (cerebrovascular Moyamoya disease; SOCW) was first described by Japanese surgeons and is thought to have a high incidence in the Japanese population. SOCW is characterized by the angiographical findings of the obstructive vascular lesions around the terminal portions of the internal carotid arteries and the formation of abnormal vascular networks visualized in the arterial phase without any definite underlying conditions. Here, we present a detailed histopathological observation of 31 autopsy cases with SOCW to discuss its etiology which is still a matter of dispute. The obstructive vascular lesion around the terminal portions of the internal carotid arteries which is thought to be the primary site affected in SOCW is due to multilayered eccentric intimal fibrous thickening suggestive of organized mural thrombi. In fact, we found thrombotic lesions frequently in the major cerebral arteries, including those of the circle of Willis, of autopsy cases with SOCW. This fact supports the idea that thrombi play an important role in establishment of the vascular lesions. Extracranial vessels are also shown to be involved and it is conceivable that the systemic etiologic factor, such as the systemic background to form thrombi, exists in patients with SOCW.

Prognostic significance of HLA class I expression in Ewing's sarcoma family of tumors.

Ewings sarcoma family of tumors (ESFT) is one of the most malignant groups of tumors in young people. Human leukocyte antigen (HLA) class I displays endogenously processed peptides to CD8+ T lymphocytes and has a key role for host immune surveillance. In ESFT, the investigation concerning both HLA class I expression and T‐cell infiltration has yet to be reported.

RHEUMATOID ARTHRITIS COMPLICATED BY PACHY- AND LEPTOMENINGEAL RHEUMATOID NODULE-LIKE GRANULOMAS AND SYSTEMIC VASCULITIS

Rheumatoid nodule is a frequent and characteristic extra‐articular manifestation of rheumatoid arthritis (RA). Its involvement of central nervous system is a rare occurrence with only a few reported cases. A 78‐year‐old man with severe arthritis showing the formation of rheumatoid nodule‐like granulomas in the dura and subarachnoid space along with the spleen is presented. The characteristic morphological finding of the granulomas was the presence of neutrophlls and the absence of definite fibrinoid necrosis, which differed from the typical features of rheumatoid nodules previously described. The diagnosis should be based on the exclusion of diseases that may cause similar granulomatous reactions including infectious diseases. Additionally, there was systemic necrotizing vasculitis in the dura and multiple cerebral Infarcts, although the association between vasculitis and cerebral infarcts was not clear.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after treatment for Hodgkin’s lymphoma

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system (CNS) disorder with distinct radiological features. However, CLIPEERS may mimic CNS lymphoma, and several cases in which CLIPPERS occurred premonitory to CNS lymphoma have been reported. We report a 31-year-old man presenting with progressive gait ataxia and the characteristic MRI features of CLIPPERS. He was diagnosed with stage II Hodgkin’s lymphoma at the age of 15, and we considered the possibility of newly emerged CNS lymphoma occurring in the immunosuppressive condition after the treatment of Hodgkin’s lymphoma. Histological findings showed no evidence of CNS lymphoma and the neurological symptoms were resolved by steroids. Although CLIPPERS developed in the reverse order in this case, CLIPPERS should be considered in different diagnosis for CNS lymphoma.

Differential pathological response to preoperative chemotherapy across breast cancer intrinsic subtypes

Background: Breast cancer is a heterogeneous disease with a diversity of clinical behaviors. The purpose of this study was to evaluate the utility of breast cancer intrinsic subtypes in the prediction of pathological complete response (pCR) in a cohort of breast cancer patients receiving preoperative chemotherapy. Methods: Patients with stage II/III breast cancer received 4 cycles of XT (capecitabine and docetaxel) followed by 4 cycles of FEC (fluorouracil, epirubicin, and cyclophosphamide) as preoperative chemotherapy. Tumors were classified as luminal A, luminal B, luminal/HER2, HER2, basal-like, or non-basal-like triple negative by immunohistochemical analysis in core needle biopsy samples at baseline. Results: The overall pCR rate was 11.9% (12/101). Multivariate analysis showed that intrinsic subtype was an independent factor to predict pCR. With luminal A patients as the reference group, luminal B (OR = 16.39; 95% CI 1.44–185.88; p = 0.024), HER2 (OR = 14.73; 95% CI 1.19–180.84; p = 0.035), and basal-like (OR = 13.27; 95% CI 1.27–138.79; p = 0.031) patients had a significantly higher likelihood of pCR. Conclusion: The present data indicate that intrinsic subtypes may be useful predictive biomarkers of pCR in breast cancer patients treated with preoperative chemotherapy.

Optic nerve sheath solitary fibrous tumor

Dear Editor Solitary fibrous tumors (SFTs) were first reported as pleural spindle-cell tumors in 1931, but are now considered to originate from mesenchymal fibroblast-like cells. Orbital SFTs are rare, with only 80 reported cases, and the periorbita is the suspected source. This is the first reported case of an SFT originating in the optic nerve sheath (ONS). A 64-year-old woman with right-eye impairment visited our hospital in 2005. Orbital magnetic resonance imaging (MRI) was normal. However, the visual disturbance gradually worsened, and she lost vision in that eye in 2007. She visited the same hospital in 2010 following several months of right exophthalmos. Orbital MRI revealed a 33-mm-sized, well-demarcated right intraconal tumor (Fig. 1a). The tumor was removed by right frontal craniotomy and superolateral orbitotomy. It was pinkish, elastic, hard and tightly adherent to the orbital fat, but was separated from the orbital wall. The tumor was continuous with the optic nerve. The optic nerve was incised proximally and distally to the tumor, and en bloc tumor resection was performed (Fig. 1b). The postoperative course was uneventful except for right ptosis, and the exophthalmos improved significantly. Histopathology showed a flow pattern of spindle-cell proliferation, but no evidence of malignancy (Fig. 1c). Some sections showed no structures between optic nerve fibers and the tumor (Fig. 1d). The tumor was positive for CD34, vimentin, Bcl-2 and CD99, and was diagnosed as SFT. In contrast, it was negative for S-100 protein, glial fibrillary acidic protein, cytokeratin and c-kit. The MIB-1 index was 1.0–2.1%. Genetic analysis by comparative genomic hybridization revealed loss of 9q31-33 and Xp21-22.1 (Fig. 1e). MRI 14 months postoperatively revealed no tumor recurrence. We reviewed 80 orbital SFT cases (range, 9–94 years; average, 43.6 years). Our study is the first to report SFT originating in the ONS. In cases reported to date, the tumor was located in the extraconal portion or was in contact with a part of the orbital wall. In our case, no part of the tumor was in contact with the orbital wall and was clearly intraconal. Intraoperative findings strongly suggested that SFT emerged from the ONS, with the optic nerve appearing partially swollen. Tissue representing the normal optic nerve was present at the tumor ends, strongly suggesting that the tumor had originated in the optic nerve. The optic nerve comprises nerve axon fibers, pia mater and ONS, which contains arachnoid and dura mater. However, ONS is the only possible origin of an SFT. Moreover, all central nervous system SFTs have been reported as meningeal lesions except for a few intraventricular lesions [1, 4]. Our pathological findings strongly suggested an ONS origin. If the tumor arose from outside the optic nerve, some structures such as the tumor capsule or normal ONS tissue would have separated the tumor from the axons. Visual impairment was the sole initial clinical manifestation. However, proptosis/exophthalmos is the most common initial manifestation in orbital SFT, occurring in 53 of 73 cases, with relatively rare visual impairment. The clinical Y. Kitamura (*) : T. Akiyama :K. Yoshida Department of Neurosurgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: ykita@sc4.so-net.ne.jp

Pleomorphic carcinoma showing rapid growth, multiple metastases, and intestinal perforation.

Pleomorphic carcinoma is a rare and very aggressive subtype of lung cancer that tends to grow rapidly and invade adjacent structures. Here we report a case of pleomorphic carcinoma with rapid growth, multiple metastases, and intestinal perforation. A 46-year-old man was admitted to our hospital because of lung abscess. Several antibiotics were administered for 2 weeks, but his condition did not improve. F18-fluorodeoxyglucose positron emission tomography revealed high uptake in the right lung, stomach, and pancreas. CT-fluoroscopic lung biopsy was performed, and a diagnosis of pleomorphic carcinoma was made. His performance status worsened each day, and the lung tumor grew within 1 month. In addition, sudden severe abdominal pain and tenderness developed 10 days after lung biopsy. He was diagnosed with gastrointestinal perforation, and he underwent surgery. However, he died 2 weeks after the surgery. Autopsy revealed the presence of an enormous tumor in the right lung and multiple metastases in the stomach, duodenum, intestine, bilateral kidneys, pancreas, gallbladder, right adrenal gland and thyroid.

Extent of lymph node involvement in breast cancer patients with sentinel lymph node metastasis.

199 Background: Axillary lymph node dissection (ALND) is a standard procedure in patients with positive sentinel lymph node (SLN). However, the appropriate level of ALND remains to be elucidated. The aim of this study is to determine the extent of lymph node involvement and predictors to assess non-SLN status in patients with metastatic SLNs. METHODS A prospective database of 235 breast cancer patients with metastases in SLNs who underwent ALND at Keio University Hospital from January 2001 to December 2011 was reviewed. RESULTS The median age of the patients was 54 years (range 28-86 years) and the mean tumor size was 2.08±0.74 cm. The mean total number of sentinel, level I, and level II lymph nodes removed was 2.72, 18.2, and 2.47, respectively. Other tumor factors include 66.5 % lymphatic invasion positive, 23.7% being nuclear grade 3, 89.4% estrogen receptor positive, and 83.2% progesterone receptor positive. Among 235 patients with SLN involvement, non-SLN metastases were identified in 72 (30.7%) patients and 13 (5.5%) patients had metastases at level II nodes.A univariate analysis showed a significant correlation between non-SLN involvement and number of tumor-involved SLNs. The mean number of tumor-involved SLNs in patients with positive non-SLNs was 1.86 compared with 1.33 in patients with negative non-SLNs (p=0.001). Patients with 2 or more positive SLNs showed a significantly higher rate of non-SLN metastases compared with patients with 1 positive SLNs (47.4% (37/78) vs. 22.3% (35/157), p<0.001).The mean number of tumor-involved SLNs in patients with positive lymph nodes in level II was 2.08 compared with 1.46 in patients with negative lymph nodes in level II (p=0.016). Patients with 2 or more positive SLNs showed a significantly higher rate of metastases at level II nodes compared with patients with 1 positive SLNs (10.3% (8/78) vs. 3.2% (5/157), p=0.0026). CONCLUSIONS Among 235 patients with SLN involvement, the positive rate of non-SLN metastases was 30.7%, whereas that of level II lymph nodes was 5.5%. The number of tumor-involved SLNs was a significant predictor of non-SLN involvement and level II lymph node metastases.