Unexpected discovery of a diffuse astrocytoma of the conus medullaris in an elderly NF1 patient.

Neurofibromatosis type 1 (NF1) is one of the most common genetic neurocutaneous disorders, and it is well known to be associated with peripheral or central nervous system malignancies. The most common malignant tumors are malignant peripheral nerve sheath tumors (MPNSTs); MPNSTs are the most common cause of death in patients with NF1. Central nervous system malignancies rarely occur. So far, the occurrence of spinal cord malignancies is exceedingly rare. Herein, we report a rare case of a 69-year-old male with NF1 following tumor resection twice for cutaneous MPNSTs developing intramedullary diffuse astrocytoma in the conus medullaris, which initially presented with traumatic spinal cord injury associated with a compression fracture from fall. Contrast-enhanced magnetic resonance imaging and biopsy of the spinal cord were required to establish the final diagnosis.

Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with Mucosa-associated Lymphoid Tissue Lymphoma.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) may develop in association with several malignancies. However, as an immunohistochemical analysis is not performed in the majority cases, its true cause is often uncertain. We herein report a case of SIADH following chemotherapy due to tumor-derived ADH production in a patient with mucosa-associated lymphoid tissue (MALT) lymphoma. A retrospective immunohistochemical analysis demonstrated ADH expression by lymphoma cells. These findings highlight the importance of using an immunohistochemical analysis to determine ADH production by tumor cells in patients with SIADH. Such analyses play an important role in elucidating the pathogenesis of SIADH and determining the most appropriate treatment.

Levels of soluble LR11/SorLA are highly increased in the bile of patients with biliary tract and pancreatic cancers.

BACKGROUND: The utility of molecules derived from cancer cells as biomarkers of the pathological status in biliary tract and pancreatic cancers is still limited. Soluble LDL receptor relative with 11 ligand-binding repeats (sLR11), a molecule released from immature cells, has been shown to be a circulating biomarker for early stage hematological malignancies. METHODS: We have evaluated the pathological significance of bile sLR11 levels in 147 samples from 72 patients with biliary tract cancer (BTC), pancreatic cancer (PC), or benign diseases. RESULTS: The bile sLR11 levels in the cancer patients were significantly increased compared with those in patients without cancer, independent of cytological detection of cancer cells in bile. The average bile sLR11 levels in cancer patients were significantly higher than in those with benign diseases, while levels of bile carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) were not different. LR11 protein was found to be highly expressed in the BTC and PC cells. The LR11 transcript levels in cholangiocarcinoma and pancreatic cancer cell lines were sharply induced during proliferation and significantly increased under hypoxic conditions. CONCLUSIONS: Therefore, sLR11 levels in bile may be indicative of cancer cell conditions and may serve as potential novel biomarker in patients with BTC and PC.

Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation.

Tangier disease, characterized by low or absent high-density lipoprotein (HDL), is a rare hereditary lipid storage disorder associated with frequent, but not obligatory, severe premature atherosclerosis due to disturbed reverse cholesterol transport from tissues. The reasons for the heterogeneity in atherogenicity in certain dyslipidemias have not been fully elucidated. Here, using high-performance liquid chromatography with a gel filtration column (HPLC-GFC), we have studied the lipoprotein profile of a 17-year old male patient with Tangier disease who to date has not developed manifest coronary atherosclerosis. The patient was shown to be homozygous for a novel mutation (Leu1097Pro) in the central cytoplasmic region of ATP-binding cassette transporter A1 (ABCA1). Serum total and HDL-cholesterol levels were 59mg/dl and 2mg/dl, respectively. Lipoprotein electrophoretic analyses on agarose and polyacrylamide gels showed the presence of massively abnormal lipoproteins. Further analysis by HPLC-GFC identified significant amounts of lipoproteins in low-density lipoprotein (LDL) subfractions. The lipoprotein particles found in the peak subfraction were smaller than normal LDL, were rich in triglycerides, but poor in cholesterol and phospholipids. These findings in an adolescent Tangier patient suggest that patients in whom these triglyceride-rich, cholesterol- and phospholipid-poor LDL-type particles accumulate over time, would experience an increased propensity for developing atherosclerosis.

Atypical Distribution of Late Gadolinium Enhancement of the Left Ventricle on Cardiac Magnetic Resonance in Classical Anderson-Fabry Disease.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A. Approximately 50% of patients with AFD may have cardiac involvement. Gadolinium-enhanced cardiac magnetic resonance (CMR) is useful for the diagnosis of cardiac involvement of AFD by recognizing typical late gadolinium enhancement (LGE) patterns. We report a 48-year-old man with cardiac involvement in classical AFD, showing atypical distribution of the LGE at the mid-lateral wall of left ventricle, predominantly apical segments without basal involvement on gadolinium-enhanced CMR.

Primary retroperitoneal mucinous cystic tumors with borderline malignancy: a case report and literature review.

Primary retroperitoneal mucinous cystic tumors with borderline malignancy are rarely encountered. To date, only 12 cases have been reported in the literature. In this report, we present an additional case. A 65-year-old nulliparous woman complained of abdominal fullness. Her medical history included a hysterectomy and a single salpingo-oophorectomy performed 25 years prior to the present event. Physical examination revealed a large cystic mass in the abdomen and pelvis. During laparotomy, a cystic tumor measuring 21×14 cm in size was observed in the left retroperitoneal space. The tumor was resected, and the final diagnosis was primary retroperitoneal mucinous cystic cancer with borderline malignancy.

Association of D2-40 and MMP-1 expression with cyst formation in lung metastatic lesions of cutaneous angiosarcoma on the scalp: immunohistochemical analysis of 23 autopsy cases.

Cutaneous angiosarcoma of the scalp can rapidly develop into pulmonary metastasis. The pulmonary metastatic lesions display a unique appearance, so-called thin-walled cysts, which cause a fatal relapsed pneumothorax by rupturing. We analyzed 23 autopsy cases of angiosarcoma with pulmonary metastasis to elucidate the mechanism of the thin-walled cyst development. Of the 23 cases of cutaneous angiosarcoma of the scalp with pulmonary metastasis, radiological examination revealed pulmonary metastatic lesions as thin-walled cysts (39%), nodules (39%), mixed cysts and nodules (13%), and ground-glass opacity (9%). All the cases but one with cystic metastases were complicated by pneumothorax. The cystic lesions were accompanied by podoplanin (D2-40)-positive tumor cells in the luminal surface of the cysts. In both primary cutaneous lesions and pulmonary metastatic lesions, the D2-40 expression was positive for angiosarcoma cells in 100% and 92% of the cases, respectively. While the estrogen-regulated gene (ERG) expression was also positive for most of the primary and metastatic pulmonary angiosarcomas, D2-40 was a more useful marker to differentiate tumor cells from the background than was the ERG expression of the vascular endothelium. Matrix metalloproteinase-1 (MMP-1) expression was also predominant in primary lesions (95%) and pulmonary metastatic lesions (82.6%). Proteinases, like MMP-1, might be associated with a developing thin-walled cyst, although there were no differences in the MMP-1 expression in either the cystic or nodular metastasis. Two extremely aggressive cases showed cystic metastasis with central necrosis that was not observed in other cases. These results suggest a pathogenesis of thin-walled cysts in some progressive cases.

Round cell liposarcoma arising in the left foot: MRI and PET findings.

Liposarcomas are one of the most common soft-tissue sarcomas and commonly arise in the deep soft tissues of the extremities and retroperitoneum; however, the occurrence of liposarcomas in the foot or ankle is exceedingly rare. In this article, we present a 52-year-old man with round cell liposarcoma arising in the left foot. This tumor presented unusual manifestations of secondary osseous involvement in the metatarsal and tarsal bones of the left foot and solitary lymph node metastasis at the para-aortic region. Magnetic resonance imaging (MRI) and [(18)F]-fluoro-deoxy-glucose positron emission tomography computed tomography (FDG PET-CT) evaluation was considered to be useful for tumor grading and staging in this case.

Primary central nervous system large B-cell lymphoma with prolific, mixed T-cell and macrophage infiltrates, mimicking multiple sclerosis.

Although tissue confirmation is essential for a diagnosis of primary central nervous system large B-cell lymphoma (PCNSBL), accurate assessment may still be difficult, even when tissue is obtained. We report a 59-year-old man, first diagnosed as multiple sclerosis by open biopsy at another institution, who was then correctly diagnosed as PCNSBL after stereotactic biopsy at our hospital. The initial biopsy showed heavy lymphoid and macrophage influx with visible demyelination. On rebiopsy, a diffuse infiltrate of small to medium-sized lymphocytes was prominent and largely stained as T cells (CD3) by immunohistochemistry. There was also an admixture of macrophages, but this time, relatively low numbers of large malignant cells were also identified. The latter stained as B cells (CD20), enabling a diagnosis of B-cell lymphoma, and the condition responded fully to high-dose methotrexate. It is thus possible for PCNSBL to be histologically misinterpreted as a result of ancillary inflammation, characterized here as a profusion of T cells and macrophages.

Autocrine and paracrine roles of VEGF/VEGFR-2 and VEGF-C/VEGFR-3 signaling in angiosarcomas of the scalp and face.

Angiosarcoma of the skin is an extremely rare malignant tumor of vascular origin that usually arises in the scalp and face of elderly persons. To clarify its characteristic features and cell cycle kinetics, we quantitatively evaluated the expression of cell cycle-related molecules and vascular endothelial growth factors using immunohistochemical staining, for comparison with 2 benign vascular tumors of the skin, the capillary hemangioma and the cavernous hemangioma. Cell proliferation, determined with reference to the Ki-67 labeling index, was highest in angiosarcomas and lowest in cavernous hemangiomas (angiosarcomas versus capillary hemangioma, P = .014; capillary hemangioma versus cavernous hemangiomas, P = 1.4 x 10(-4)). Similar differences were also found in cyclin A, cyclin E, and p21(Waf1) expression. Expressions of cyclin D1 and p16(INK4A) were also significantly higher in angiosarcoma than in cavernous hemangioma. Expressions of these 5 proteins showed significant positive correlations with Ki-67 labeling indices (Spearman rho = 0.91-0.43). Expression levels of vascular endothelial growth factor and its receptor, VEGFR-2, were highest in angiosarcomas. VEGF-C expression in angiosarcomas was significantly higher than in cavernous hemangiomas, and its receptor VEGFR-3 expression was highest in angiosarcomas. Furthermore, significant positive correlations of these protein expression with Ki-67 labeling indices were noted (Spearman rho = 0.88-0.40). Among them, VEGFR-3 showed the highest correlation coefficient. These results suggest that not only VEGFR-2-mediated signal but also VEGFR-3-mediated signal may contribute to proliferation of vascular tumor cells as autocrine and paracrine signaling factors.

Familial motor neuron disease with prominent onion-bulb-like structures and axonal swelling restricted to the spinal ventral root: autopsy findings in two siblings.

We report autopsy cases of two siblings who developed muscular atrophy and dementia, clinically considered to be familial motor neuron disease (MND). They presented with motor neuron signs predominantly in the distal limbs without sensory impairment. At autopsy, severe neuronal loss in the anterior horn consistent with MND was found, but histopathological hallmarks like Bunina bodies and skein-like inclusions were absent. Surprisingly, numerous huge axonal swellings (about 30 microm in diameter) and onion-bulb-like structures were found in the spinal ventral roots. These changes were not observed in spinal dorsal roots or peripheral nerves. However, obvious segmental demyelination of the ventral root was not found. In addition, neurofibrillary tangles (NFTs) and neuritic plaques were present in the frontal cortex, temporal cortex and hippocampus, and to a lesser degree, in the amygdala, substantia nigra and thalamus. Our two cases are a hitherto unreported type of MND, which shows focal giant axonopathy and prominent formation of onion-bulb-like structures due to Schwann cell proliferation restricted to the spinal ventral roots.

Tumor budding is predictive of lymphatic involvement and lymph node metastases in submucosal invasive colorectal adenocarcinomas and in non-polypoid compared with polypoid growths.

OBJECTIVE: Early colorectal carcinomas (submucosal invasive adenocarcinomas) can be classified into polypoid and non-polypoid growth types, the latter progressing more rapidly to advanced malignancy. The aim of this study was to investigate the differences between invasive features of the two types of carcinoma by focusing on tumor budding (isolated single cells or small cell clusters (up to four cells) scattered at invasive tumor margins). MATERIAL AND METHODS: The number of foci in the field with the most frequent tumor budding was regarded as "activity". Tumor budding was examined using anti-cytokeratin antibodies in 98 colorectal submucosal invasive adenocarcinomas and compared with the clinicopathological findings. In addition, the relationships between tumor budding and beta-catenin and laminin-5gamma2 expression were analyzed. RESULTS: Tumor budding activity was significantly higher in non-polypoid growth carcinomas compared with polypoid growth carcinomas (p = 0.0006) and values for left-sided lesions were higher than those for right-sided lesions of the colon (p = 0.0108). Positive links with tumor budding were evident for lymphatic involvement and lymph node metastasis in non-polypoid growth carcinomas, and with laminin-5gamma2 cytoplasmic expression in polypoid growth carcinomas. Multivariate logistic analysis revealed that the activity of tumor budding was an independent risk factor for lymphatic involvement. CONCLUSIONS: The results indicate that tumor budding makes a greater contribution to progression in non-polypoid than in polypoid growth carcinomas, with possible involvement of lymph node metastasis.

Midkine expression in colorectal tumors: correlation with Ki-67 labeling in sporadic, but not ulcerative colitis-associated ones.

Midkine (MK) is a heparin-binding growth factor encoded by a retinoic acid responsive gene. To investigate the possible contribution of MK to genesis of colorectal carcinomas, an immunohistochemical examination of protein expression was conducted in sporadic and ulcerative colitis (UC)-associated tumors. MK expression significantly differed among normal mucosa, adenomas with low-grade dysplasia (LGD), adenomas with high-grade dysplasia (HGD) and invasive adenocarcinomas: MK expression was increased along with tumor progression. UC-associated lesions (regenerative mucosa of UC, UC-associated dysplasia and UC-associated adenocarcinoma) had similar variations. MK expression in UC-associated lesions was significantly higher than in normal mucosa, although there was no significant difference among UC-associated lesions. However, in UC-associated dysplasia, MK expression did not differ between the upper and lower halves, in contrast to adenoma with LGD and HGD, in which MK expression was significantly higher in the upper than lower halves, corresponding to cell proliferative zone. Furthermore, correlations with Ki-67 and single-strand DNA labeling, respectively, reflecting cellular proliferative activity and apoptosis, were noted in sporadic but not UC-associated lesions. These results suggest that MK is involved in genesis/development of sporadic colorectal tumors as well as of UC-associated tumors, but might contribute differently to genesis/development in these two types of tumors.

Significant increase of colonic mutated crypts correlates with age in sporadic cancer and diverticulosis cases, with higher frequency in the left- than right-side colorectum.

Mild periodic acid-Schiff (mPAS) staining can discriminate non-O-acetylated (mPAS-positive) from O-acetylated (mPAS-negative) epithelial sialoglycoproteins in human colonic mucosa, allowing the three haplotypes expressed from a single polymorphic autosomal gene (oat) to be distinguished. In heterozygotes, we previously demonstrated wholly mPAS-positive (stem cell mutated) crypts and clusters of two or more mPAS-positive crypts to be significantly increased with duration of ulcerative colitis. To establish whether such an increase in the number of mutated crypts with age also occurs in normal individuals or in cases with diverticulosis, the O-acetylation phenotype in the non-cancerous colonic mucosa of 47 sporadic colorectal cancer patients who were heterozygotes for oat was tested with mild-PAS staining. PAS-positive crypts were assessed histologically in relation to age and compared between the left (sigmoid colon and rectum) and right (cecum and ascending colon) sides of the colorectum. Wholly mPAS-positive (stem cell mutated) crypts and foci in heterozygotes were found to be increased significantly (P < 0.0001) in the left side with aging (r = 0.598 and 0.643, respectively). Such a positive correlation with aging was also confirmed in 19 diverticulosis cases without cancer (r = 0.797 and 0.793, respectively). The frequency of mutated crypts and foci on the right side was significantly lower than on the left side in both spontaneous colorectal cancer and diverticulosis cases. The results provide support for an intimate relationship between accumulation of mutated crypts with aging, possibly with significance for colorectal cancer development. Furthermore, the environment in the right side of the colon may be different from that in the left side in this regard.

Bottom-up cell proliferation with cyclin A and p27Kip1 expression in ulcerative colitis-associated dysplasia.

To analyze the cell kinetics of ulcerative colitis (UC)-associated dysplasia, cyclin A, cyclin D1, cyclin E, cdk2, cdk4, p21(Waf1), and p27(Kip1) were immunohistochemically examined, in comparison with sporadic tubular adenomas. Immunohistochemical labeling indices for each marker in formalin-fixed paraffin-embedded tissue sections were assessed in a total of 23 low-grade dysplasias, 27 high-grade dysplasias, and 14 invasive adenocarcinomas associated with UC. For comparison, 21 sporadic tubular adenomas with low-grade dysplasia, 33 with high-grade dysplasia, and 21 invasive adenocarcinomas were also examined. In UC-associated dysplasias, cyclin A and p27(Kip1) were located in the lower parts of the crypts and p21(Waf1) in the upper regions. In tubular adenomas, cyclin A, cdk4, p27(Kip1), and p21(Waf1) were all expressed in the upper parts of the crypts. The expression levels of cyclin D1, cyclin E, and cdk2 were low. The cell proliferation zone in UC-associated dysplasia is located towards the bases of the crypts with the strong expression of cyclin A and p27(Kip1), in contrast to tubular adenomas, which have their cell proliferation zone in the upper parts of neoplastic crypts. It is considered that tumorigenesis with UC-associated dysplasia is of the bottom-up type, related to altered expression of cyclin A and p27(Kip1).

Selective zif268 mRNA induction in the perirhinal cortex of macaque monkeys during formation of visual pair-association memory.

To elucidate the molecular basis of cognitive memory formation in the primate, transcriptional activation during learning of a visual pair-association (PA) task was evaluated systematically along the occipito-temporo-hippocampal pathway in the macaque monkey brain. Split-brain monkeys were used for intra-animal comparison, which enables elimination of animal-to-animal variation in gene expression. We found that the expression of the mRNA of an immediate-early gene (IEG), zif268, was up-regulated selectively in the perirhinal cortex (area 36) during the formation of PA memory compared to that during learning of a visual control task. The mRNA expression levels of another IEG, c-jun, were not up-regulated during the PA learning in any cortical areas examined. We also showed that cells strongly expressing zif268 mRNA accumulated in patches in area 36 during learning of the PA task. As the zif268 gene encodes a transcription factor, these results suggest that the activation of zif268 mRNA in area 36 may function as a trigger of the cascade of gene activation that leads to cellular events underlying neuronal reorganization for visual long-term memory formation.