Graphic and movie illustrations of human prenatal development and their application to embryological education based on the human embryo specimens in the Kyoto collection.

Morphogenesis in the developing embryo takes place in three dimensions, and in addition, the dimension of time is another important factor in development. Therefore, the presentation of sequential morphological changes occurring in the embryo (4D visualization) is essential for understanding the complex morphogenetic events and the underlying mechanisms. Until recently, 3D visualization of embryonic structures was possible only by reconstruction from serial histological sections, which was tedious and time-consuming. During the past two decades, 3D imaging techniques have made significant advances thanks to the progress in imaging and computer technologies, computer graphics, and other related techniques. Such novel tools have enabled precise visualization of the 3D topology of embryonic structures and to demonstrate spatiotemporal 4D sequences of organogenesis. Here, we describe a project in which staged human embryos are imaged by the magnetic resonance (MR) microscope, and 3D images of embryos and their organs at each developmental stage were reconstructed based on the MR data, with the aid of computer graphics techniques. On the basis of the 3D models of staged human embryos, we constructed a data set of 3D images of human embryos and made movies to illustrate the sequential process of human morphogenesis. Furthermore, a computer-based self-learning program of human embryology is being developed for educational purposes, using the photographs, histological sections, MR images, and 3D models of staged human embryos.     

A case of sarcomatoid carcinoma of the thymus

A 57-year-old woman presented with a 10×10 cm anterior mediations mass. The tumor had Invaded the pericardium, both lungs and the left brachiocephallc vein, and was treated by partial resection and postoperative radiation therapy. Pathological examination of the tumor revealed squamous cell carcinoma with a spindle cell sarcomatous component. Immunohistochemically, keratin and epithelial membrane antlgen were posltive In both the spindle cell sarcomatous areas and the squamous cell carcinomatous area and thus, a diagnosis of thymic carcinoma of sarcomatoid type was made. The patient died of recurrent disease 1 year after surgery. This case is the seventh reported In the English literature Because of the poor outcome, adjuvant therapy is recommended.     

Immunohistochemical studies of endocrine cells in heterotopic pancreas

Summary Twenty-one specimens of heterotopic pancreas were investigated using the indirect immunoperoxidase method for insulin, somatostatin, glucagon, pancreatic polypeptide (PP) and gastrin. Ten specimens showed ducts, acini and islets, seven showed ducts and acini, and four showed a ductal component alone. Pyloric gland-like mucous glands were occasionally identified in association with the ductal component. In eight of ten lesions containing islets, the islets were round and had a clearly defined outline with many glucagon cells and either none or a modest number of PP cells (dorsal type). In the remaining two lesions, the islets showed varying sizes and irregular outline with many PP cells and a few or no glucagon cells (ventral type). In either type of islets, insulin and somatostatin were detected, but gastrin cells were absent. Some isolated endocrine cells were also present among the acinar and ductal components. Their occurrence in ducts was more frequent in lesions or areas mainly composed of the ductal compoment than in those with less prominent ductal tissue. In eight lesions a few gastrin cells were found in the ductal component which showed goblet cell metaplasia and pyloric gland metaplasia. An intimate relationship between goblet cell metaplasia and appearance of G cells is noteworthy.     

Intracellular Ca antagonist TMB-8 blocks catecholamine secretion evoked by caffeine and acetylcholine from perfused cat adrenal glands in the absence of extracellular Ca

Unlike acetylcholine, caffeine was much more effective in releasing catecholamine in the absence of extracellular Ca²⁺ than in its presence in perfused cat adrenal glands. The intracellular Ca²⁺ antagonist, TMB-8 (10⁻⁴ M), inhibited reversibly the catecholamine secretion evoked by caffeine (40 mM) and that induced by acetylcholine (10⁻⁴ M) in the presence of hexamethonium (10⁻³ M) during perfusion with Ca²⁺-free Locke solution containing EGTA (10⁻⁵ M). These results support our view that muscarinic receptor activation causes catecholamine secretion by mobilizing Ca²⁺ from an intracellular pool just as caffeine does.     

Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.     

DNA analysis of two patients with a non-fluorescent y chromosome

Summary Results of DNA study on two patients of gonadal dysgenesis with a 45,X/46,X,Ynf (non-fluorescent Y chromosome) karyotype are described. In one patient who developed gonadoblastoma, all 12 loci on the non-fluorescent part of Yq were detected. Another patient did not have gonadoblastoma at 20 years, and only the proximal 6 loci out of 12 were detected.     

Morphogenesis of nonpolypoid colorectal adenomas and early carcinomas assessed by cell proliferation and apoptosis

Nonpolypoid neoplasms, as well as ordinary polypoid tumours, are occasionally found in the colorectum. To clarify whether cell kinetic status affects the macroscopic morphology of colorectal neoplasms, we investigated proliferative indices (PI), apoptotic indices (AI), and the expression of apoptosis-related gene products. We examined 110 colorectal neoplasms comprised of 36 polypoid, 38 flat elevated and 36 depressed tumours. According to WHO’s criteria these tumours consisted of 61 adenomas with low grade dysplasia (LGD), 30 adenomas with high grade dysplasia (HGD) and 19 carcinomas with submucosal invasion. Apoptotic cells were detected by TUNEL staining. Proliferating cells and apoptosis-related gene products were assessed by immunohistochemistry for Ki-67, p53, Bcl-2, and Bax antigens. AI were closely associated with macroscopic morphology in adenomas but not in carcinomas. PI were relatively constant among the three macroscopic types in adenomas and carcinomas. Median AI values of polypoid, flat elevated and depressed tumours were 1.8%, 2.1% and 4.6% for adenomas with LGD, 0.8%, 2.4% and 6.2% for adenomas with HGD and 2.9%, 4.0% and 3.6% for carcinomas, respectively. Overall PI were significantly higher in carcinomas than in adenomas with LGD, whereas AI were not different. Although the incidence of expression was significantly higher in carcinomas for p53 and in adenomas for Bcl-2 than the others, the expression of apoptosis-related gene products (p53, Bcl-2 and Bax) was similar among polypoid, flat elevated and depressed tumours. Macroscopic morphology of colorectal adenomas is determined by the apoptosis not by proliferation, and high apoptosis found in depressed adenomas implies their low net growth. Received: 1 July 1999 / Accepted: 17 January 2000     

Primary renal angiosarcoma: A case report and review of the literature

Primary renal angiosarcoma is very rare. To our knowledge, only 15 cases have been reported to date. A 77-year-old Japanese man with a unilateral kidney presented with massive hematuria followed by renal failure. A renal tumor was suspected and a left nephrectomy was performed. The histopathological diagnosis was angiosarcoma of the kidney. A hemorrhagic tumor measuring 10 × 5 cm and clotted blood was found in the modularly area. The atypical tumor cells had a sinusoidal and solid appearance, and showed Immunohistochemically positive reactions for some of the endothelial markers. The patient died about 21 months after the nephrectomy and the autopsy revealed massive metastases to the liver and retroperitoneum. One of the differential diagnoses of the case was anglomyolipoma, because the tumor cells were relatively bland in their histological appearance with entrapped fat cells in the pelvic area. Fifteen case reports with titles that included the term 'hemangiosarcoma/anglosarcoma', 'hemangioendothelloma/endothelloma' or 'vascular sarcoma' of the kidney were reviewed and compared to the present case.     

Association of EGFR Gene Amplification and CDKN2 (p16/MTS1) Gene Deletion in Glioblastoma Multiforme

Glioblastoma multiforme (GBM) can be divided into genetic subsets: approximately one-third of GBM, primarily in older adults, have EGFR amplification; another one-third, primarily in younger adults, have TP53 mutation. The majority of GBM also have homozygous deletions of the CDKN2 (p16/MTS1) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between CDKN2 deletions and the GBM subsets as defined by EGFR amplification or TP53 mutation in 70 GBM. Twenty-eight cases (40%) had EGFR amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. CDKN2 deletions were present in 36 (51%) GBM. Of the 28 GBM with EGFR amplification, 20 (71%) had CDKN2 deletion (p = 0.0078). The remaining 16 cases with CDKN2 loss were divided between GBM with TP53 mutations (6 cases) and GBM with neither EGFR amplification nor TP53 mutation (10 cases). Thus, CDKN2 deletions occur twice as commonly in GBM with EGFR amplification (71%) than in GBM with TP53 mutation (29%). CDKN2 deletions occurred in GBM from patients somewhat older than those patients with GBM lacking CDKN2 deletion (mean age 53 vs. 48 years). Specifically among GBM with EGFR amplification, those with CDKN2 deletions also occurred in patients slightly older than those few GBM without CDKN2 deletions (mean age 55 vs. 51 years). The presence of CDKN2 deletions in most GBM with EGFR amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors.