Journal of Pathology and Translational Medicine

Reviews

The Continuing Value of Ultrastructural Observation in Central Nervous System Neoplasms in Children: Na Rae Kim, Sung-Hye Park; J Pathol Transl Med. 2015;49(6):427-437. Published online October 13, 2015; DOI: https://doi.org/10.4132/jptm.2015.09.19

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Abstract PDF: Central nervous system (CNS) neoplasms are the second most common childhood malignancy after leukemia and the most common solid organ neoplasm in children. Diagnostic dilemmas with small specimens from CNS neoplasms are often the result of multifactorial etiologies such as frozen or fixation artifact, biopsy size, or lack of knowledge about rare or unfamiliar entities. Since the late 1950s, ultrastructural examination has been used in the diagnosis of CNS neoplasms, though it has largely been replaced by immunohistochemical and molecular cytogenetic studies. Nowadays, pathologic diagnosis of CNS neoplasms is achieved through intraoperative cytology, light microscopy, immunohistochemistry, and molecular cytogenetic results. However, the utility of electron microscopy (EM) in the final diagnosis of CNS neoplasms and investigation of its pathogenetic origin remains critical. Here, we reviewed the distinguishing ultrastructural features of pediatric CNS neoplasms and emphasize the continuing value of EM in the diagnosis of CNS neoplasms.

Advances in the Endoscopic Assessment of Inflammatory Bowel Diseases: Cooperation between Endoscopic and Pathologic Evaluations: Jae Hee Cheon; J Pathol Transl Med. 2015;49(3):209-217. Published online May 15, 2015; DOI: https://doi.org/10.4132/jptm.2015.04.09

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Endoscopic assessment has a crucial role in the management of inflammatory bowel disease (IBD). It is particularly useful for the assessment of IBD disease extension, severity, and neoplasia surveillance. Recent advances in endoscopic imaging techniques have been revolutionized over the past decades, progressing from conventional white light endoscopy to novel endoscopic techniques using molecular probes or electronic filter technologies. These new technologies allow for visualization of the mucosa in detail and monitor for inflammation/dysplasia at the cellular or sub-cellular level. These techniques may enable us to alter the IBD surveillance paradigm from four quadrant random biopsy to targeted biopsy and diagnosis. High definition endoscopy and dye-based chromoendoscopy can improve the detection rate of dysplasia and evaluate inflammatory changes with better visualization. Dye-less chromoendoscopy, including narrow band imaging, iScan, and autofluorescence imaging can also enhance surveillance in comparison to white light endoscopy with optical or electronic filter technologies. Moreover, confocal laser endomicroscopy or endocytoscopy have can achieve real-time histology evaluation in vivo and have greater accuracy in comparison with histology. These new technologies could be combined with standard endoscopy or further histologic confirmation in patients with IBD. This review offers an evidence-based overview of new endoscopic techniques in patients with IBD.

Citations

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Moxifloxacin promotes two-photon microscopic imaging for discriminating different stages of DSS-induced colitis on mice
Yingtong Chen, Xiaoyi Xu, Min Wang, Xiang Wang, Yan Wang, Yong Zhang, Jin Huang, Yuwen Tao, Wentao Fan, Lili Zhao, Li Liu, Zhining Fan
Photodiagnosis and Photodynamic Therapy.2024; 48: 104220. CrossRef
Colorectal cancer in inflammatory bowel disease: review of the evidence
D. S. Keller, A. Windsor, R. Cohen, M. Chand
Techniques in Coloproctology.2019; 23(1): 3. CrossRef
Probe-based confocal laser endomicroscopy in the differential diagnosis of inflammatory bowel diseases: a case series
Jung Won Park, Tae Il Kim, Jae Hee Cheon
Intestinal Research.2018; 16(4): 641. CrossRef
How to Assess and Document Endoscopies in IBD Patients by Including Standard Scoring Systems
Anna M. Buchner, Gary R. Lichtenstein
Inflammatory Bowel Diseases.2016; 22(4): 1010. CrossRef
Nodular lymphoid hyperplasia: A marker of low-grade inflammation in irritable bowel syndrome?
Anna Chiara Piscaglia, Lucrezia Laterza, Valentina Cesario, Viviana Gerardi, Rosario Landi, Loris Riccardo Lopetuso, Giovanni Calò, Giovanna Fabbretti, Massimo Brisigotti, Maria Loredana Stefanelli, Antonio Gasbarrini
World Journal of Gastroenterology.2016; 22(46): 10198. CrossRef

Utility of Transmission Electron Microscopy in Small Round Cell Tumors: Na Rae Kim, Seung Yeon Ha, Hyun Yee Cho; J Pathol Transl Med. 2015;49(2):93-101. Published online March 12, 2015; DOI: https://doi.org/10.4132/jptm.2015.01.30

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Abstract PDF

Small round cell tumors (SRCTs) are a heterogeneous group of neoplasms composed of small, primitive, and undifferentiated cells sharing similar histology under light microscopy. SRCTs include Ewing sarcoma/peripheral neuroectodermal tumor family tumors, neuroblastoma, desmoplastic SRCT, rhabdomyosarcoma, poorly differentiated round cell synovial sarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, small cell malignant peripheral nerve sheath tumor, and small cell schwannoma. Non-Hodgkin’s malignant lymphoma, myeloid sarcoma, malignant melanoma, and gastrointestinal stromal tumor may also present as SRCT. The current shift towards immunohistochemistry and cytogenetic molecular techniques for SRCT may be inappropriate because of antigenic overlapping or inconclusive molecular results due to the lack of differentiation of primitive cells and unavailable genetic service or limited moleculocytogenetic experience. Although usage has declined, electron microscopy (EM) remains very useful and shows salient features for the diagnosis of SRCTs. Although EM is not always required, it provides reliability and validity in the diagnosis of SRCT. Here, the ultrastructural characteristics of SRCTs are reviewed and we suggest that EM would be utilized as one of the reliable modalities for the diagnosis of undifferentiated and poorly differentiated SRCTs.

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Electron Microscopy in the Context of a Children's Research Hospital
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Microscopy and Microanalysis.2020; 26(S2): 1610. CrossRef
Primary bilateral corneal nerve sheath neoplasm in a dog
Marina L. Leis, M. Elyse Salpeter, Bianca S. Bauer, Dale L. Godson, Bruce H. Grahn
Veterinary Ophthalmology.2017; 20(4): 365. CrossRef
Hirnbasissyndrom infolge eines Tumors bei einer 17 Monate alten Deutsch-Holstein-Färse
Wolf Wippermann, Sandra Schöniger, Kerstin Gerlach, Gerald Fritz Schusser, Gabor Köller, Alexander Starke
Tierärztliche Praxis Ausgabe G: Großtiere / Nutztiere.2016; 44(03): 180. CrossRef
The Continuing Value of Ultrastructural Observation in Central Nervous System Neoplasms in Children
Na Rae Kim, Sung-Hye Park
Journal of Pathology and Translational Medicine.2015; 49(6): 427. CrossRef

Case Reports

Multiple Jejunal Myeloid Sarcomas Presenting with Intestinal Obstruction in a Non-leukemic Patient: A Case Report with Ultrastructural Observations: Na Rae Kim, Woon Kee Lee, Jong In Lee, Hyun Yee Cho; Korean J Pathol. 2012;46(6):590-594. Published online December 26, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.6.590

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Abstract PDF

Myeloid sarcoma is a rare extramedullary myeloid tumor, which is frequently misdiagnosed when no evidence of leukemia is initially observed. Here, we report on a peculiar case of a 49-year-old man afflicted with multiple masses in the jejunum, the superior mesentery, and the serosa of the transverse colon, without leukemic manifestation. The tumor was composed of undifferentiated small round cells containing eosinophilic cytoplasm, which were negative for myeloperoxidase, nonspecific esterase, lysozyme, terminal deoxynucleotidyl transferase, leukocyte common antigen, CD3, CD4, CD15, CD20, CD30, CD43, CD56, CD68/PG-M1, CD79a, human melanoma black-45, c-kit, and CD34 with positivity only for CD68/KP1, CD99, and vimentin. Under electron microscopy, those cells had abundant membrane-bound cytoplasmic granules that measured 200 to 300 nm in diameter, which were consistent with granulocytic azurophilic granules. The tumor was finally diagnosed as a myeloid sarcoma. The presence of non-leukemic myeloid sarcomas showing immunonegativity for conventional myeloid-leukemic markers necessitated a diagnosis by ultrastructural observation.

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Primary ileal myeloid sarcoma presenting with bowel obstruction: a case report
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Rie Mizumoto, Masanori Tsujie, Tomoko Wakasa, Kotaro Kitani, Hironobu Manabe, Shuichi Fukuda, Kaoru Okada, Shumpei Satoi, Hajime Ishikawa, Toshihiko Kawasaki, Hitoshi Hanamoto, Masao Yukawa, Masatoshi Inoue
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Andrej Nikolovski, Dragoslav Mladenovikj, Aleksandra Veljanovska, Gordana Petrusevka
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Utility of Transmission Electron Microscopy in Small Round Cell Tumors
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Primary Hepatic Neuroblastoma: A Case Report.: Geunyoung Jung, Jihun Kim; Korean J Pathol. 2011;45(4):423-427.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.4.423

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Abstract PDF

Neuroblastoma is a malignant tumor of primordial neural crest origin. It usually develops along the sympathetic nervous system, such as the adrenal glands or paramedian sympathetic chain and metastasizes to the liver most frequently. However, a primary hepatic neuroblastoma has not been reported yet. Here, we report a case of 29-year-old woman who presented with a solitary hepatic mass. Grossly, the mass was large, creamy, rubbery firm, and showed focal hemorrhage and central cavitation. Microscopically, the tumor cells were arranged in small nests of spindle to ovoid cells with abundant neuropil. The neuroblastic nature of the tumor was confirmed by immunohistochemistry and electron microscopy. No extrahepatic mass was found, despite a thorough systemic survey such as chest and abdominopelvic computed tomography (CT) scans and a whole body positron emission tomography-CT study. To the best of our knowledge, this is the first report of a bona fide primary hepatic neuroblastoma.

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Primary hepatic neuroblastoma in a 19-month-old child: A case report
Jovana Dimić, Dejan Skorić, Aleksandar Sretenović, Slaviša Đuričić
Medicinska istrazivanja.2022; 55(2): 41. CrossRef
Morphologic Alteration of Metastatic Neuroblastic Tumor in Bone Marrow after Chemotherapy
Go Eun Bae, Yeon-Lim Suh, Ki Woong Sung, Jung-Sun Kim
Korean Journal of Pathology.2013; 47(5): 433. CrossRef

Epithelioid Hemangioendothelioma of Liver: A case report.: Yoo Jin Kim, Jae Hwa Lee, Bang Hur, Man Ha Hur; Korean J Pathol. 1995;29(3):378-384.

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Abstract PDF: Epithelioid hemangioendothelioma of liver is a very rare tumor of vascular origin, the most peculiar feature of which is that it is composed of endothelial cells closely resembling epithelial cells. We present a primary epithelioid hemangioendothelioma of liver in a 40-year-old male. This tumor was composed of an ill-defined yellowish white, 7 x 4cm sized, firm, solid mass and small satellite nodules in the right lobe of liver. Microscopically, two types of tumor cells-dendritic and epithelioid-were identified. The neoplastic cells infiltrated into sinusoids and intrahepatic veins. The background of tumor showed marked sclerotic change and focal proliferation of bile ductules. Confirmation of the endothelial origin of these cells was provided by positive immunoperoxidase staining for factor VIII-related antigen, and by electron mi-croscopic demonstration of Weibel-Palade body. This is the first case of epithelioid heman- gioendothelioma of liver documented in Korea. We report this case in view of its scarcity and distinctive morphologic features that allow differentiation from sclerosing carcinoma and angiosarcoma.

Original Articles

Large Cell Neuroendocrine Carcinoma of the Lung: Report of three cases.: Jai Hyang Go, Sun Ree Jung, Dong Hwan Shin, Woo Hee Jung; Korean J Pathol. 1995;29(4):511-516.

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Abstract PDF: We report three cases of neuroendocrine tumors of the lung characterized by large pleomorphic cell with frequent mitosis, which show neuroendocrine differentiation by both light microscopy or electron microscopy and iminunohistochemistry. These tumors have been categorized as large cell neuroendocrine carcinoma by Travis et al.(1991) in contrast with non-small cell lung cancer with neuroendocrine differentiation. In the latter, neuroendocrine differentiation is not evident by light microscopy and must be demonstrated by imunohistochemstry or by electron microscopy. The prognosis of large cell neuroendocrine carcinoma, together with non-small cell lung cancer with neuroendocrine differentiation, appears to be worse than cancer without neuroendocrine differentiation and intermediate between atypical carcinoid and small cell lung cancer. Larger numbers of patients will be needed to demonstrate significant differences in survival.

A Scanning Electron Microscopic Study on Microvascular Changes in the Monocrotaline-induced Rat Lung by Corrosion Casting Method.: Na Hye Myong, Eui Keun Ham; Korean J Pathol. 1995;29(5):644-659.

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Abstract: To investigate the microvascular changes in primary pulmonary hypertension, the lungs of 24 Sprague-Dawley rats were treated by an intraperitoneal injection of 2% monocrotaline(MCT) solution and then examined with scanning electron microscopy(SEM) after microvascular corrosion casting. Histologic examination revealed significant medial thickening in the small to medium-sized pulmonary arteries. Scanning electron microscopic findings of the normal lungs showed two kinds of microvascular structures. One showed a well-fortned three-dimensional basket structure of uniform flat-tubular alveolar capillaries, which were connected to each other in a T or Y shape or at right angles. The other revealed a two-dimensional reticular sheet of round tubular branches mainly in the bronchial artery-supplying regions. The MCT-treated groups(remodelling) showed apparent changes in both kinds of microvasculatures in comparison to the normal group but the more prominent change was found in Lbe bronchial artery microvasculature showing the dense thick encasement around large pulmonary arteries. Alveolar microvasculature of the pulmonary artery revealed individually enlarged angular appearance, with generally deformed alveolar architecture. Quantitatively, the significant enlargement of diameter and intercapillary distance appeared in both microvasculatures of MCT-induced rat lungs, but the density was increased only in the bronchial artery microvasculature. In conclusion, our three-dimensional microvascular study of the MCT-treated rat lungs demonstrates a new morphologic finding of vascular remodeling in primary puhnonary hypertension, which is thought to play an important vascular role in the pathogenesis in addition to interstitial fibrosis.

Ultrastructural Changes in Rat Kidney after Lead Acetate Administration.: Hyun Chul Kim, Seung Pil Kim, Kwan Kyu Park; Korean J Pathol. 1996;30(2):73-88.

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Abstract PDF: This study was carried out to investigate the ultrastructural findings of rats after administration of 0.5% lead acetate with drinking water. The Sprague-Dawley rats were divided into control and experimental groups. The control group was composed of 12 rats and was orally administered with 0.5% sodium acetate. The experimental group was composed of 36 rats and orally administered with 0.5% lead acetate. Two rats in the control group and four rats in the experimental group were sacrificed on day 2, and week 1, 2, 4, 6 and 8 after administration. The kidney was extirpated and examined by electron microscopy. The results obtained were as follows: The blood lead concentration in the experimental group began to increase from the second day after administration and it increased gradually until the 6th week and it decreased at the 8 week. The urinary excretion of delta-ALA also increased from the secondary and gradually increased up to the 8th week. On electron microscopic examination, the proximal tubular cells showed fat droplets, dilatation of the endoplasmic reticulum, mitochondrial swelling, increased numbers of secondary lysosomes and myelin figure-like residual bodies and intranuclear inclusion bodies. All these findings peaked at the eighth week after administration. Ultrastructural findings after Timm sulphide silver reaction revealed the lead granules in the proximal tubular lumen and between the microvilli of the proximal tubular cells without membrane-bounded. It can be concluded that most of the changes of micro-organelles are compatible with degenerative changes of lead exposure and passive diffusion of lead granules are involved in the proximal tubular cells.

Ultrastructural Changes of the Bile Canaliculi after Common Bile Duct Ligation.: Kook Seon Yoo, Suk Hee Lee, Hee Kyung Park, Chang Ho Cho, Jong Min Chae; Korean J Pathol. 1996;30(3):175-183.

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Abstract PDF: The purpose of this study was to investigate the morphologic changes of the bile canaliculi and its associated structures of the liver induced by common bile duct ligation(CBDL) in the rat. The canalicular surface and lateral surface of the dry-fractured hepatocytes was studied with scanning electron microscopy at 1~6 weeks post ligation. The first week after CBDL, the bile canaliculi were dilated. The microvilli were increased in number and the lumens contained granular materials After 2 weeks or more, the bile canaliculi were dilated to a variable degree, and with irregularity, measuring from 1.5 to 5 micrometer in diameter, and in the advanced stage, the canaliculi showed blunting and the disappearance of microvilli. Some canaliculi had sprouting side branches. At 4~6 weeks post-ligation, the lateral surface of the hepatocytes also showed some irregularity and a tortuous appearance, and numerous small sized microvillous projections were formed. The tubular structures of the proliferated SER distributed adjacent to the lateral surface of the hepatocytes, and the direct connection of a tubular structure and the cytoplasmic membrane was observed. These results suggest that the deformity and loss of microvilli of bile canaliculi reflect the disturbance of bile secretion from the hepatocytes. And prolonged obstruction of bile flow may result in bile excretion via the lateral surface of hepatocytes.

The Morphologic Changes of the Sinusoidal Endothelial Cells in N-diethylnitrosamine Induced Cirrhotic Rat Liver.: Ok Ji Paik, Hee Kyung Park, Jong Min Chae, Jyung Sik Kwak, Tae Joong Sohn; Korean J Pathol. 1996;30(7):604-615.

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Abstract PDF: The purpose of this study is to investigate the morphologic changes of the sinusoidal endothelial cells and the associated structures of the cirrhotic rat liver induced by repeat intraperitoneal injections of N-diethylnitrosamine (DEN) (100 mg/kg/week). One day to 6 weeks later, rat livers were observed under the light, transmission and scanning electron microscopy, and immunostained with laminin antibody. Two weeks after DEN treatment, the fibrillar material in Disse's space was noted, and then a basement membrane-like structure was found at 4 weeks after treatment. Laminin was detected in perisinusoidal areas after 4 weeks. Laminin was strongly positive on the fibrous septum and in the sinusoidal wall of cirrhotic nodules after 6 weeks of treatment. The diameters and numbers of sinusoidal endothelial fenestrations did not change significantly until 2 weeks. They decreased within 4 weeks, and then the sinusoidal endothelium was poorly fenestrated at 6 weeks after DEN treatment. These results suggest that as fibrosis develops in cirrhosis, the deposit of extracellular matrix such as laminin within Disse's space is a major contributing factor in the structural alteration of sinusoidal endothelial cells, and the capillarization of the sinusoidal endothelial cells may be a contributor to impairment of the hepatic function in cirrhosis.

Case Reports

Creutzfeldt-Jakob Disease: Histopathologic, Electron Microscopic and Immunohistochemical Studies of 2 Cases.: Duck Hwan Kim, Yeon Lim Suh, Duck Ryul Na, Won Kyu Joo, Yong Sun Kim; Korean J Pathol. 1996;30(9):830-838.

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Abstract PDF: Creutzfeldt-Jakob disease(CJD) is characterized clinically by rapidly progressive dementia with pyramidal, extrapyramidal, and cerebellar symptoms and signs, and histologically by spongiform change, neuronal loss and reactive gliosis. We have experienced 2 cases of CJD. Case 1 was a 36-year-old male who had suffered from myoclonus and cerebellar symptoms including sluggish speech, gait and balance disturbance. Case 2 was a 70-year-old female who had showed cognitive dysfunction, ataxic gait and disturbance of extraocular movement. Both patients, underwent brain biopsy.
Case
1 revealed marked cortical atrophy, 2mm in thickness, with neuronal loss and astrocytic proliferation extending into white matter. The spongiform change, made up of many small, usually rounded or oval, vacuoles was noted mainly in the neuropil. Case 2 revealed remarkable spongiform change throughout the cortex and cytoplasmic vacuoles compressing the nuclei of neuronal cells were numerous. Neuronal loss and gliosis were also found without considerable change in the white matter. On double immunostaining against GFAP and PrP(Prion Protein), there was a weak positive reaction for PrP in the perinuclear cytoplasm in case 1, and a strongly positive reaction in case 2. The electron microscopic examination showed numerous membrane-bound vacuoles in neuropil and perikarya of neurons. The majority of the vacuoles were multiseptated by thin membranous structures. They demonstrated curled, or disrupted membrane, that had foldings and protrusions into the vacuolar clear spaces. There were neither identifiable virus-like particles nor amyloid deposition.

Clear Cell Sarcoma of the Kidney: A case in 39 year old man.: Hyun Ju Yoo, Yun Kyung Kang, Mee Joo, Hye Kyung Lee, Dae Woo Kim, Suk San Park; Korean J Pathol. 1996;30(12):1138-1143.

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Abstract PDF: Clear cell sarcoma of kidney(CCSK) is a rare pediatric neoplasm characterized by a predominating component of clear cells, a predilection for metastases to bone, and a poor prognosis. The incidence of CCSK peaks during the 2nd year of life and adult cases are very rare. We report a case of CCSK encountered in the right kidney of a 39-year-old man. Grossly, it was a lobulated mass showing infiltrative margin, measured 7x5.5x5cm and had a homogeneous gray-tan color with a soft, fish-flesh consistency. Microscopically, about half of the tumor revealed the classic pattern of CCSK, having tumor cell cords or nests separated by the characteristic alveolar capillary networks. The tumor cells had clear pale cytoplasm, bland looking round nuclei and inconspicuous nucleoli. The other half showed the epithelioid-trabecular pattern forming pseudorosette or cord-like structures. Immunohistochemically, there was only a focal positive reaction to vimentin. Ultrastructurally, the tumor cells showed the primitive nephrogenic mesenchymal differentiation such as electron lucent cytoplasm, a small amount of organelles, scanty heterochromatin, inconspicuous nucleoli, and a lack of flocculant basal lamina material around the cytoplasmic membrane. We consider that this is a case of CCSK occuring in the oldest patient ever reported, confirmed by both immunohistochemistry and electron microscopy.

Original Articles

The Effect of Ginseng Saponin on the Dopaminergic Neurons in the Parkinson's Disease Model in Mice.: Chang Ok Kim, Ki Sok Kim, Young Buhm Huh, Byeong Woo Ahn, Beom Seok Han, Kwang Sik Choi, Ki Yul Nam, Sang Woo Juhng; Korean J Pathol. 1997;31(9):805-814.

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Abstract PDF: Saponin has been known to be a major antioxidant component in panax ginseng. Recent experimental study suggests that some antioxidant materials prevent Parkinson's disease caused by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in an animal model. The present study was performed to demonstrate the effect of ginseng saponins in the Parkinson's disease model induced by MPTP. To verify the effect of ginseng saponin on dopaminergic neurons in the mice brain, the tyrosine hydroxylase-immunoreactive (TH-ir) neurons were observed by immunohistochemical stain and immunoelectron microscopy (preembedding method). Also, in order to estimate the immunoreactivity of dopaminergic neuropils, they were quantified by image analysis. The number of TH-ir neurons of substantia nigra was significantly increased in the high-dose (0.46 mg/kg) ginseng saponin group compared with the MPTP injected group. The immunoreactivity of TH-ir neuropils in striatum was significantly increased in both high and low-dose (0.1 mg/kg) ginseng saponin groups compared with the MPTP injected group. In immunoelectron microscopic observation, TH-ir neurons of the control and both ginseng saponin injected group showed normal nuclei and well preserved cytoplasmic organelles. In the MPTP injected group, dying dopaminergic neurons showed destroyed nuclei and cytoplasmic organelles. These results suggest that ginseng saponin has a protective effect on the Parkinson's disease model induced by MPTP.

Sarcomatoid Renal Cell Carcinoma; Special Reference to its Distinction from Carcinosarcoma.: Kee Taek Jang, Yeon Mee Kim, Je Geun Chi; Korean J Pathol. 1998;32(5):378-381.

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Abstract: Sarcomatoid renal cell carcinoma is an uncommon tumor that has to be distinguished from renal carcinosarcoma. We have described three cases of sarcomatoid renal cell carcinoma showing different clinical and light microscopic features. An ultrastructural study of the tumor cells from the sarcomatoid area revealed frequent desmosomal junction, confirming the epithelial nature of the neoplasm. All three cases showed an aggressive clinical course and tended to invade adjacent organs or tissues. We believe that an histological and immunohistochemical examination in conjunction with an electron microscopic examination are necessary to diagnose sarcomatoid renal cell carcinoma.

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