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We report a case of an extremely rare type of duodenal gastrointestinal stromal tumor (GIST) that included neuronal components. Although gastrointestinal autonomic nerve tumors (GANTs), a subtype of GISTs, exhibit ultrastructural features of the nerve plexus, neuronal cells have not been observed within GANTs or GISTs. GISTs originate from interstitial cells of Cajal (ICCs), which are markedly different from the progenitor cells of neural elements and neural-crest-derived stem cells. This may explain why GISTs typically lack neuronal elements. It remains unclear that the neuronal components of this tumor are neoplastic or hyperplastic, but proliferation and survival of ICCs have recently been reported to be closely related to neurons. Although we could not find the KIT, PDGFR, and BRAF mutation as far as we examined, it may have had a rare mutation in NF1, a fusion of EVT6-NTRK3, or an as-yet-unknown KIT mutation that affected neurogenesis. Further investigation of related genetic mutations and accumulation of data from other similar cases is needed.

Collision tumor of the stomach is rare. We report a rare case of a gastric collision tumor consisting of gastrointestinal stromal tumors (GISTs) and leiomyosarcoma (LMS). Computed tomography scan revealed a 15 cm sized mass in the posterior wall of the body of the stomach. Gross examination of the wedge resection specimen showed the tumor located in the muscularis propria with extramural protrusion into the peritoneal cavity and the gastric cavity with geographic necrosis, hemorrhage, and mucosal ulceration. Histologically, the majority of the tumor consisted of the GIST component and the minor area in the submucosal region consisted of the LMS component. The tumor showed an abrupt transition between GIST and LMS by histologically and immunohistochemically, suggesting a collision tumor. Furthermore, the GIST components exhibited a c-kit exon 11 mutation. On the other hand, LMS component exhibited neither c-kit nor platelet-derived growth factor receptor-alpha (PDGFRA) mutation. Here we describe a case of the collision tumor consisting of GIST and LMS and its literature review.

We experienced a case of intraductal tubulopapillary neoplasms (ITPN) of the pancreas with severe calcification, which complicated image diagnosis. A pancreas head tumor was detected in a Japanese female in her 50s. Early enhancement by contrast-enhanced CT and coarse calcification suggested a neuroendocrine tumor, although the obstruction and dilation of the main pancreatic duct appeared to be an intraductal tumor. An endoscopic ultrasound-guided fine needle aspiration biopsy specimen revealed adenocarcinoma tissue. Pancreaticoduodenectomy was performed, and the patient has been well without evidence of recurrence for over 10 months. Pathological examination on the resected specimen revealed that the tumor showed papillary and tubulo-cribriform growth patterns. Together with typical immunohistochemical results, the final diagnosis of ITPN was made. Characteristically, this case showed extensive calcification of both psammoma body-type and non psammoma body-type with foamy macrophage aggregation. This is the first report of ITPN with two types of calcification and macrophage. Since calcification might be one of the characteristic histological findings in ITPN as shown in our case, the possibility of ITPN should be also considered when calcification is detected in pancreatic lesions by various imaging modalities.

Collision tumor of the stomach is rare. We report a rare case of a gastric collision tumor consisting of gastrointestinal stromal tumors (GISTs) and leiomyosarcoma (LMS). Computed tomography scan revealed a 15 cm sized mass in the posterior wall of the body of the stomach. Gross examination of the wedge resection specimen showed the tumor located in the muscularis propria with extramural protrusion into the peritoneal cavity and the gastric cavity with geographic necrosis, hemorrhage, and mucosal ulceration. Histologically, the majority of the tumor consisted of the GIST component and the minor area in the submucosal region consisted of the LMS component. The tumor showed an abrupt transition between GIST and LMS by histologically and immunohistochemically, suggesting a collision tumor. Furthermore, the GIST components exhibited a c-kit exon 11 mutation. On the other hand, LMS component exhibited neither c-kit nor platelet-derived growth factor receptor-alpha (PDGFRA) mutation. Here we describe a case of the collision tumor consisting of GIST and LMS and its literature review.

Cystic adventitial disease (CAD) is a rare peripheral artery disorder which shows the development of gelatinous cysts in the adventitia. Although several theories for the pathogenesis of CAD have been postulated, the etiology of CAD remains unclear. Histological examination of three CAD cases revealed that these cyst walls were composed of fibrous tissue and lacked both epithelial and endothelial lining. The surfaces of these cysts were partially covered with spindle-shaped cells, similar to the interstitial cells within the cyst wall. A pool of mucinous material in the adventitia was evident. Distribution of vimentin-positive spindle-shaped cells and scattered CD68-positive oval-shaped cells in the cyst wall was revealed by immunohistochemistry. A part of vimentin-positive spindle-shaped cells demonstrated to be positive for α-smooth muscle actin, indicating the presence of myofibroblasts in the cyst wall. A focal tenascin-C-positive area was observed in the cyst wall of our CAD cases. Presence of two different cell types, proliferation of myofibroblasts and expression of tenascin-C were consistent with those of cyst walls of 20 surgically resected ganglions. These results suggest that CAD may arise as capsular synovial structures, similar to ganglion cysts.

Retinoic acid (RA) is a vitamin A derivative that exerts pleiotropic biological effects. Intracellular transport and metabolism of RA are regulated by cellular retinol-binding proteins (CRBP). CRBP-1 is transiently expressed in granulation tissue fibroblasts during wound healing; however, its role in cardiac remodeling remains unknown. A rat myocardial infarction (MI) model was established by ligation of the left coronary artery, and hearts were obtained at 3, 6, 15, 30 and 45 days after operation. Heart sections were examined immunohistochemically using anti-vimentin, anti-α-smooth muscle actin (α-SMA), anti-matrix metalloproteinase (MMP)-2, anti-MMP-9 and anti-CRBP-1 antibodies. Infarction involved 48.8 ± 3.6% of the left ventricle and was followed by an important cardiac remodeling. Vimentin-positive fibroblastic cells including α-SMA-positive myofibroblasts expressed CRBP-1 at 3-, 6-, and 15-days after MI. Expression of CRBP-1 reached a maximum at 6-days after infarction. Thereafter, CRBP-1 expression was dramatically decreased, showing a similar tendency to MMP expression. Human heart specimens of individuals with a recent myocardial infarction demonstrated presence of CRBP-1-positive fibroblasts by immunohistochemistry. We have demonstrated that CRBP-1 is transiently expressed by fibroblasts during cardiac remodeling. Our results suggest that CRBP-1 plays a role in ventricular remodeling after MI allegedly through its RA binding activity.

Plexiform lesions in pulmonary arteries are a characteristic histological feature for idiopathic pulmonary arterial hypertension (IPAH). The pathogenesis of the plexiform lesion is not fully understood, although it may be related to endothelial cell dysfunction and local inflammation. CD44 is a cell adhesion molecule and it is also involved in angiogenesis, endothelial cell proliferation and migration. The expression of CD44 was examined in lung plexiform lesions obtained from patients with IPAH (IPAH group, n= 7) and pulmonary arterial hypertension associated with atrial septal defect (ASD-PAH group, n= 4). Expression of CD44 was detected in 49 out of 52 plexiform lesions (93%) from all patients in the IPAH group, whereas 31 plexiform lesions obtained from the ASD-PAH group lacked CD44 positivity by immunohistochemistry. In the IPAH group, CD44 was localized in the endothelial cells of microvessels within plexiform lesions and activated T cells in and around the lesions. Furthermore, T cell infiltration and endothelial cell proliferation activity were prominent in the plexiform lesions of the IPAH group, compared to those of the ASD-PAH group. These findings suggest that CD44 and activated T cell infiltration play an important role in the development of plexiform lesions particularly in IPAH.

Endocervicosis of the urinary bladder is a very rare tumor-like benign lesion. In the present report, a case in a 34-year-old woman, who has a prior Caesarean section at the age of 30 and 2-years history of dysuria, is described. Transvaginal ultrasound, cystoscopy and magnetic resonance imaging demonstrated a solid mass in the posterior wall of the bladder. The mass was removed and histology revealed a haphazard proliferation of endocervical-type mucinous glands scattered through the muscularis propria of bladder wall. Immunohistochemical phenotype of these glands was compared with three normal uterine endocervices and two cases of well-differentiated mucinous adenocarcinoma of the uterine cervix. Endocervicosis glands displayed positive reaction for antibodies against estrogen receptor, progesterone receptor, CAM 5.2, cytokeratin 7, CA125, HBME-1 and carcinoembryonic antigen, which showed positivity in normal endocervices. On the other hand, only glands of well-differentiated mucinous adenocarcinoma expressed human gastric mucin and showed high proliferative index of Ki-67. These results supported the hypothesis of its Mullerian origin. Furthermore, diffuse distribution of estrogen and progesterone receptors, lack of human gastric mucin and low proliferative activity were distinct features for endocervicosis compared to well-differentiated mucinous adenocarcinoma.

We experienced a case of intraductal tubulopapillary neoplasms (ITPN) of the pancreas with severe calcification, which complicated image diagnosis. A pancreas head tumor was detected in a Japanese female in her 50s. Early enhancement by contrast-enhanced CT and coarse calcification suggested a neuroendocrine tumor, although the obstruction and dilation of the main pancreatic duct appeared to be an intraductal tumor. An endoscopic ultrasound-guided fine needle aspiration biopsy specimen revealed adenocarcinoma tissue. Pancreaticoduodenectomy was performed, and the patient has been well without evidence of recurrence for over 10 months. Pathological examination on the resected specimen revealed that the tumor showed papillary and tubulo-cribriform growth patterns. Together with typical immunohistochemical results, the final diagnosis of ITPN was made. Characteristically, this case showed extensive calcification of both psammoma body-type and non psammoma body-type with foamy macrophage aggregation. This is the first report of ITPN with two types of calcification and macrophage. Since calcification might be one of the characteristic histological findings in ITPN as shown in our case, the possibility of ITPN should be also considered when calcification is detected in pancreatic lesions by various imaging modalities.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c-kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c-kit gene. These facts strongly suggest that the c-kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c-kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c-kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c-kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c-kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents.

A case of gastric carcinoma with psammomatous calcification arising in the remnant stomach after Billroth II reconstruction is reported. Borrmann type 1 gastric carcinoma was detected in the remnant stomach of an 82-year-old woman, who had a past history of distal partial gastrectomy for a perforated gastric ulcer, with Billroth II reconstruction at 40 years of age. Histologically, the tumor was a tubular adenocarcinoma that invaded the muscularis propria. Numerous psammoma bodies were found in the lumens of the tumor glands. Dystrophic calcification of gastric cancer is rare and psammomatous calcification of gastric cancer has only been reported in five cases previously. To our knowledge, this is the first case of gastric carcinoma with psammomatous calcification arising in the remnant stomach. We also review previously published reports regarding gastric carcinoma with psammomatous calcification.

Interstitial cells of Cajal (ICC) are believed to initiate the basic contractile activity of the gastrointestinal tract. Interstitial cells of Cajal express c-kit receptor tyrosine kinase and are deficient in Ws/Ws mutant rats with a small deletion of the c-kit gene. As Ws/Ws rats show remarkable bile reflux to the stomach, the contraction pressure of the pylorus was compared between Ws/Ws and control +/+ rats. The contraction pressure of the pylorus was measured using a microtransducer, which was inserted through a pin-hole in the anterior wall of the stomach under anesthesia. The magnitude of bile reflux was estimated by measuring the content of bile acids in the stomach. The c-kit messenger RNA-expressing cells were detected by in situ hybridization. Frequency and the maximum pressure of the contraction were comparable between Ws/Ws and +/+ rats, but the duration of the contraction was significantly shorter in Ws/Ws rats than in +/+ rats. The number of c-kit messenger RNA-expressing ICC in the pylorus of Ws/Ws rats was 1.7% that of +/+ rats. The bile reflux observed in Ws/Ws rats was attributed to the decrease in the duration of the pyloric contraction, which appeared to result from the deficiency of c-kit messenger RNA-expressing ICC.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and typically present as discrete well-circumscribed but non-encapsulated tumor masses. In this report, we describe a case of colonic perforation caused by an unusual form of GIST. A 72-year-old Japanese woman presented to the emergency department with acute abdominal pain. Under the provisional diagnosis of sigmoid colon perforation, a laparoscopic sigmoidectomy was performed. Although the tumor mass was undetectable during the preoperative examination, a spindle cell lesion with a diffuse longitudinal growth pattern replacing the muscularis propria was revealed by microscopic examination. The spindle cell lesion was exposed at the perforation, suggesting a causal relationship between the lesion and the perforation. The spindle cell lesion was KIT-positive and had a mutation in the C-KIT gene at exon 11. We diagnosed it as diffuse infiltrating GIST. We consider that the lesion would be a cause of the colonic perforation, and emphasize the importance of accurate diagnosis of the lesion by histological, immunohistochemical and genetic examinations.

Cystic adventitial disease (CAD) is a rare peripheral artery disorder which shows the development of gelatinous cysts in the adventitia. Although several theories for the pathogenesis of CAD have been postulated, the etiology of CAD remains unclear. Histological examination of three CAD cases revealed that these cyst walls were composed of fibrous tissue and lacked both epithelial and endothelial lining. The surfaces of these cysts were partially covered with spindle-shaped cells, similar to the interstitial cells within the cyst wall. A pool of mucinous material in the adventitia was evident. Distribution of vimentin-positive spindle-shaped cells and scattered CD68-positive oval-shaped cells in the cyst wall was revealed by immunohistochemistry. A part of vimentin-positive spindle-shaped cells demonstrated to be positive for α-smooth muscle actin, indicating the presence of myofibroblasts in the cyst wall. A focal tenascin-C-positive area was observed in the cyst wall of our CAD cases. Presence of two different cell types, proliferation of myofibroblasts and expression of tenascin-C were consistent with those of cyst walls of 20 surgically resected ganglions. These results suggest that CAD may arise as capsular synovial structures, similar to ganglion cysts.

Plexiform lesions in pulmonary arteries are a characteristic histological feature for idiopathic pulmonary arterial hypertension (IPAH). The pathogenesis of the plexiform lesion is not fully understood, although it may be related to endothelial cell dysfunction and local inflammation. CD44 is a cell adhesion molecule and it is also involved in angiogenesis, endothelial cell proliferation and migration. The expression of CD44 was examined in lung plexiform lesions obtained from patients with IPAH (IPAH group, n= 7) and pulmonary arterial hypertension associated with atrial septal defect (ASD-PAH group, n= 4). Expression of CD44 was detected in 49 out of 52 plexiform lesions (93%) from all patients in the IPAH group, whereas 31 plexiform lesions obtained from the ASD-PAH group lacked CD44 positivity by immunohistochemistry. In the IPAH group, CD44 was localized in the endothelial cells of microvessels within plexiform lesions and activated T cells in and around the lesions. Furthermore, T cell infiltration and endothelial cell proliferation activity were prominent in the plexiform lesions of the IPAH group, compared to those of the ASD-PAH group. These findings suggest that CD44 and activated T cell infiltration play an important role in the development of plexiform lesions particularly in IPAH.

Endocervicosis of the urinary bladder is a very rare tumor-like benign lesion. In the present report, a case in a 34-year-old woman, who has a prior Caesarean section at the age of 30 and 2-years history of dysuria, is described. Transvaginal ultrasound, cystoscopy and magnetic resonance imaging demonstrated a solid mass in the posterior wall of the bladder. The mass was removed and histology revealed a haphazard proliferation of endocervical-type mucinous glands scattered through the muscularis propria of bladder wall. Immunohistochemical phenotype of these glands was compared with three normal uterine endocervices and two cases of well-differentiated mucinous adenocarcinoma of the uterine cervix. Endocervicosis glands displayed positive reaction for antibodies against estrogen receptor, progesterone receptor, CAM 5.2, cytokeratin 7, CA125, HBME-1 and carcinoembryonic antigen, which showed positivity in normal endocervices. On the other hand, only glands of well-differentiated mucinous adenocarcinoma expressed human gastric mucin and showed high proliferative index of Ki-67. These results supported the hypothesis of its Müllerian origin. Furthermore, diffuse distribution of estrogen and progesterone receptors, lack of human gastric mucin and low proliferative activity were distinct features for endocervicosis compared to well-differentiated mucinous adenocarcinoma.

Reported herein is a gastric leiomyosarcoma, which, nowadays, is extremely rare. Attention was focused not only on pathological findings but also on the histological basis of magnetic resonance imaging (MRI) findings. The patient was a 29-year-old Japanese woman. Preoperative T2-weighted MRI showed a large high-intensity gastric tumor with isointense streaks. The tumor was a broad-based large polypoid lesion and histologically consisted of fascicles of spindled cells having eosinophilic cytoplasm and cigar-shaped nuclei. Immunoreactivity for several smooth muscle markers including desmin on tumor cells, low amplification of both c-kit and PDGFRA cDNA on polymerase chain reaction, and absence of c-kit gene mutation in exons 9 and 11 strongly suggested that the tumor was not a gastrointestinal stromal tumor but a true leiomyosarcoma. In vitro MRI of the fresh tumor was obtained to explain the radiological findings on a morphological basis. In vitro MRI clearly depicted the very high-intensity areas separated by radially extended isointense lines. This radiological finding corresponded best to the most characteristic histological feature, that is, linearly extended fascicles of the tumor cells often with myxedematous change separated by radially elongated thin fibrovascular stroma: in other words, spouting appearance.

We describe a case of cardiac myxoma in a 44-year-old Japanese man, who died after developing metastases in the skin, brain and muscle. A satellite tumor which was attached to the wall of the abdominal aorta induced marked hypertension due to obstruction of the renal arteries. Although the primary heart tumor had typical histological features of benign cardiac myxoma, the recurrent heart tumor, which was partly resected three months before the patient's death, showed apparently malignant characteristics resembling malignant fibrous histiocytoma (MFH). Since the histological features of the initial and recurrent tumors were different, the grade of malignancy was investigated using the cellularity of the tumor as an arbitrary criterion. A gradual but significant increase in the cellularity was observed over the course of five years. Immunohistochemically, tumor cells in the muscle metastasis contained vimentin and factor VIII-related antigen, and multinucleated giant cells in the recurrent heart tumor contained desmin, which is rarely detectable in MFH. Therefore, we considered that the present case represented malignant transformation of benign cardiac myxoma.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c-kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c-kit gene. These facts strongly suggest that the c-kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c-kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c-kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c-kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c-kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents.

Calcified psammoma bodies often appear in human ovarian serous papillary cystadenocarcinoma. Osteocalcin (OC), osteonectin (ON) and osteopontin (OPN) are three members of non-collagenous bone-related proteins known to be related with mineralization of bone. To clarify possible involvement of these bone matrix proteins in the calcification of the psammoma bodies, the expression of OC, ON and OPN was analyzed by immunohistochemical and in situ hybridization studies using 15 surgical specimens. OPN protein was detected in the calcified area of the psammoma bodies which was positively stained by von Kossa’s staining, while OC and ON proteins were not. OPN protein was not detected in any cells in tissues, but OPN messenger ribonucleic acid (mRNA) was detected in CD68-positive macrophages, indicating that OPN was produced and promptly secreted by macrophages. These results suggest that OPN produced and promptly secreted by macrophages and subsequently translocated to psammoma bodies may be causally related with the calcium phosphate deposition in the psammoma bodies of the ovarian serous papillary cystadenocarcinomas.

Edema occurs in some types of chronic inflammation such as nasal polyps, uterine cervical polyps and gastric hyper-plastic polyps. However, the factors or cellular components involved in the development of edema in chronic inflammation remain to be clarified. Recently, the gene encoding vascular permeability factor (VPF) or vascular endothelial growth factor (VEGF) and the genes encoding its receptors (kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 [fit-1]) have been cloned. VPF/VEGF induces vascular hyperpermeability and vascular endothe lial proliferation through KDR or fit-1 receptors. As there is a possibility that VPF/VEGF may play a role in the development of edema in chronic inflammation, we examined the messenger (m) RNA expression of VPF/VEGF and its recep tors in nasal polyp tissues, which is an example of chronic inflammation with remarkable edema. Using northern blotting, all nasal polyp tissues examined expressed mRNA of VPF/VEGF and KDR. In situ hybridization revealed that VPF/ VEGF mRNA-expressing cells were scattered in the edematous stroma of nasal polyps. In the adjacent sections, these cells showed the morphological features of plasma cells and expressed mRNA of immunoglobulin light chains. Human B cell leukemia and plasmacytoma cell lines expressed VPF/VEGF mRNA but human mast-cell leukemia and T cell leukemia cell lines did not. The alternatively spliced pattern of VPF/VEGF transcripts observed in nasal polyp tissues was consistent with that in plasmacytoma cell lines. Taken together, the VPF/VEGF mRNA-expressing cells in nasal polyps appeared to be plasma cells, suggesting that plasma cells may play an important role in the development of edema in chronic inflammation through the production of VPF/VEGF.