Cholesterol Crystals in the Retrieved Thrombus by Mechanical Thrombectomy for Cerebral Embolism: A Case Report and Literature Review.

There are only a few case reports in which cholesterol crystals were found in the thrombus retrieved by mechanical thrombectomy for cryptogenic stroke, leading to a definitive diagnosis. We herein report a case of aortogenic embolic stroke diagnosed by the presence of rich cholesterol crystals in the retrieved thrombus and review the previously reported cases. A woman in her 80s was transferred as an emergency due to consciousness disturbance, right conjugate deviation, and severe left hemiparesis. Magnetic resonance imaging showed occlusion of the right middle cerebral artery (MCA) and acute infarction in the territory. The MCA was recanalized by thrombectomy using an aspiration catheter and stent retriever, and the symptoms improved. Although the physiological examination did not detect the embolic source during hospitalization, pathological examination of the thrombus revealed atheroma with numerous cholesterol crystal clefts and intermixing of fibrin. Contrast-enhanced computed tomography performed based on the pathological results showed atheromatous lesions in the aortic arch as the embolic source. As a subsequent treatment, medications of a strong statin and an antiplatelet agent were continued, and the patient had no recurrence. The finding that the retrieved thrombus is a simple atheroma containing cholesterol crystals with poor hemocytes suggests embolism due to plaque rupture. Pathological examination of the thrombus obtained by thrombectomy is one of the useful diagnostic approaches for stroke etiology and the determination of its treatment.

Intralobular distribution of ovarian-like stroma in pancreatic mucinous cystic neoplasms: a discussion on its tumorigenesis.

Pancreatic mucinous cystic neoplasm (MCN) has two histological components: tumor epithelia and ovarian-like stroma (OLS). To examine the progression and changes in pancreatic MCNs, we analyzed the distribution, amount, immunohistochemical phenotype, presence of theca cells of OLS, and tumor epithelium in 45 surgically resected MCN cases, comparing them with tumor sizes. The OLS data of female MCN cases were also compared between those who were ≤ 51 years old and those > 51 years old to see the effect of menopause on MCN histology. Non-mucinous type epithelium was present in all low-grade MCNs, but its ratio decreased with tumor size (p < 0.001), suggesting that epithelial mucinous changes are a progression phenomenon. The intralobular distribution of OLS was observed in 28.8% of MCN cases and was related to smaller tumor size (p < 0.0001), suggesting intralobular involvement of early MCNs. The nuclear expression of ß-catenin and the cytoplasmic expression of α-smooth muscle actin (SMA) was observed in almost all OLS. OLS tended to be lesser among female cases aged > 51 years than those ≤ 51 years old, however it did not reach statistical significance. This is the first study to show the intralobular distribution of OLS.

Immunotherapy against esophageal primary amelanotic malignant melanoma relapse.

Melanoma is a malignant tumor derived from melanocytes. Esophageal melanomas occur infrequently, especially primary amelanotic malignant melanoma of the esophagus (PAMME), which is extremely rare. Here, we report the case of a 74-year-old man with an esophageal amelanotic melanoma on the esophagogastric junction (EGJ) found on esophagogastroduodenoscopy. Radical surgery for the tumor at the EGJ was performed with total gastrectomy and D2 lymph node dissection. Diagnosis of PAMME was confirmed postoperatively by immunohistochemical staining. Four months after the surgery, abdominal computed tomography revealed multiple liver metastases. The patient received seven cycles of nivolumab monotherapy and two subsequent cycles of nivolumab and ipilimumab, and these metastases diminished. Recently, new therapeutic agents including immunotherapy have been developed for malignant melanoma and these agents have the potential of improving the prognosis of PAMME. Here, we present new insights into the diagnosis and therapeutic methods that can be used against primary esophageal melanoma.

Clinicopathological features of intraductal papillary neoplasms of the bile duct: a comparison with intraductal papillary mucinous neoplasm of the pancreas with reference to subtypes.

Intraductal papillary epithelial neoplasms of the pancreatobiliary system (intraductal papillary neoplasm of the bile duct (IPNB) and intraductal papillary mucinous neoplasm (IPMN)) seem to share many clinicopathological features; however, IPNB has not been fully characterized. In order to understand the clinicopathological/immunohistochemical features of IPNB better, we compared 52 cases of IPNB with 42 cases of IPMNs with mural nodules. The IPNB cases were divided into two groups according to their histological similarity and according to five key histological findings. All IPNB and IPMN cases mainly affected middle-aged to elderly people, predominantly men. Mucin hypersecretion was less frequent in IPNB compared to IPMN. Group 2 IPNB more frequently had a higher histopathological grade and more extensive stromal invasion than IPMN. Group 1 IPNB and IPMN were further classified into four subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). Although each subtype of IPNB and IPMN showed similar histology, the immunohistochemical results were different. The gastric type of IPNB was less frequently positive for CDX2, and intestinal IPNB was more frequently positive for MUC1 and less frequently positive for MUC2, MUC5AC, and CDX2 compared to each subtype of IPMN, respectively. In conclusion, IPNB and IPMN have some clinicopathological features in common, but mucin hypersecretion was less frequent both in IPNBs than in IPMN. Group 2 IPNB differed from IPMN in several parameters of tumor aggressiveness. Additional clinicopathological and molecular studies should be performed with respect to the subtypes of IPNB and IPMN.

Characterization of intraductal papillary neoplasm of bile duct with respect to histopathologic similarities to pancreatic intraductal papillary mucinous neoplasm.

Intraductal papillary neoplasm of bile duct (IPNB) is a papillary tumor covered by well-differentiated neoplastic epithelium with fine fibrovascular cores in the dilated bile ducts. It reportedly shows similarities to intraductal papillary mucinous neoplasm of pancreas (IPMN), to various degrees. Herein, IPNB was pathologically analyzed by classifying 52 cases into 4 groups based on the histopathologic similarities to IPMN: group A (identical to IPMN, 19 cases), group B (similar to but slightly different from IPMN, 18 cases), group C (vaguely similar to IPMN, 5 cases), and group D (different from IPMN, 10 cases). In group A, intrahepatic and perihilar regions were mainly affected, most cases were of low/intermediate or high grade without invasion, and gastric type was the most common phenotype, followed by oncocytic and intestinal types. In groups C and D, perihilar and distal bile ducts were affected, almost all cases were of high grade with invasion, and most of them were of intestinal and pancreatobiliary phenotypes. Most group B cases were of intestinal phenotype, and all were of high grade with or without invasion. In conclusion, these 4 groups of IPNB showed unique pathologic features and behaviors. Group A cases were less aggressive and shared many features with IPMN, whereas group C and D cases were more aggressive and mainly found in perihilar and distal bile ducts. Group B resembling IPMN was intermediate between them. This classification may be useful in clinical practice and holds promise for a novel approach to analyze IPNB tumorigenesis.

Report of a case: Retroperitoneal mucinous cystadenocarcinoma with rapid progression.

INTRODUCTION: Retroperitoneal mucinous cystic neoplasms are uncommon, and little is known about the etiology of the disease. Malignant forms of these are extremely rare. Here, we report a case of primary retroperitoneal mucinous cystadenocarcinoma (PRMC), which demonstrated unexpectedly aggressive progression despite finding only a limited area of adenocarcinoma. PRESENTATION OF CASE: A 62-year-old woman with a complaint of abdominal discomfort was admitted to the hospital. Abdominal CT and MRI showed multiple large retroperitoneal cysts dislocating the right kidney nearly to the center of the abdomen. Transabdominal resection of the cysts was performed. Those cysts contained 1100ml of mucinous fluids in total. Cytological examination of those fluids revealed no malignant cells. The cyst wall was lined with mucinous epithelial cells, and contained some ovarian-type stroma. Also, there was a focal area of adenocarcinoma in the cyst wall, and the lesion was diagnosed as primary retroperitoneal mucinous cystadenocarcinoma. Eight months later, the patient developed lumbar bone metastasis. Chemotherapy with S-1, an oral fluoropyrimidine, and docetaxel had been begun immediately; however, the disease had rapidly spread in the retroperitoneum. Eventually, the patient died of the disease 15 months after surgery. DISCUSSION: Retroperitoneal mucinous cystic neoplasms are considered to be metaplasia of embryonal coelomic epithelium. Complete excision without rupture is essential. However, variance of biological aggressiveness might exist in PRMCs. CONCLUSION: Retroperitoneal mucinous cystadenocarcinoma is a rare tumor, and it is urgently necessary to elucidate the etiology of an effective therapy for the disease.

Laparoscopic resection of schwannoma of the ascending colon.

Schwannomas of the colon are rare and difficult to diagnose preoperatively. We report a case of schwannoma of the ascending colon that was resected laparoscopically. A 64-year-old woman was referred to our hospital by her local clinic for further evaluation and management of a submucosal tumor of the ascending colon. A definitive preoperative diagnosis could not be reached despite examinations. Gastrointestinal stromal tumor, leiomyoma and lymphoma were the differential diagnoses. We performed a laparoscopic right hemicolectomy with D2 lymph node dissection. Histological findings with hematoxylin-eosin staining revealed spindle-like tumor cells, and immunohistochemical analysis showed that the tumor was positive for S-100 but negative for c-kit, CD34, smooth muscle actin and desmin, with a Ki-67 index of <5%. Thus, the diagnosis in this case was benign schwannoma of the ascending colon.

Gastric cancer with multiple intramural metastases and metastasis to the small intestine which eventually developed Trousseau's syndrome: report of a case.

Here we report a rare case of Trousseau's syndrome in a patient with gastric cancer with multiple intramural metastases and metastasis to the small intestine. A 70 year-old male complaining of appetite loss and weight loss of 7 kg within 3 months was admitted to hospital. Esophagogastroduodenal endoscopy revealed an advanced gastric cancer at the pylorus almost occluding the outlet of the stomach, and multiple ulcerative lesions throughout the stomach. A biopsy showed poorly differentiated adenocarcinoma. The patient underwent total gastrectomy. During surgery, part of the distal ileum was found to be abnormally firm and approximately 1 m of the ileum with the cecum colon was resected. Pathologic examination confirmed poorly differentiated adenocarcinoma at the pylorus and multiple intramural metastases in most other areas of the stomach. Lymph node metastases were confirmed in 12 out of 40 harvested regional lymph nodes including one positive paraaortic lymph node. The resected ileum contained multiple tumors with ulceration. Massive lymphatic invasion in the stomach and the small intestine was observed, which strongly suggested lymphatic spread of the gastric cancer. The patient was discharged on post-operative day 21; however, 2 months after surgery, he developed multiple cerebral thromboembolisms and died 2 weeks later.

Amount of CD4+CD25+ regulatory T cells in autoimmune pancreatitis and pilonidal sinus.

OBJECTIVES: Infiltration of many IgG4-positive plasma cells (G4-Ps) is seen in IgG4-related diseases and in several "non-IgG4-related diseases," such as pilonidal sinus (PS) as well. The involvement of CD4+CD25+ regulatory T cells (CD4CD25 Tregs) in IgG4-related diseases has been reported. To see whether CD4+CD25+ Tregs are involved in autoimmune pancreatitis (AIP)/non-IgG4-related diseases with many G4-Ps, we investigated the amount of G4-Ps and CD4+CD25+ Tregs histologically in AIP/PS. METHODS: Four AIP and 10 PS were immunostained with IgG4/Foxp3, a specific marker for CD4+CD25+ Tregs. Double immunohistochemistry and dual fluorescent immunohistochemistry were conducted to see the amount of CD4+CD25+ Tregs. RESULTS: All AIP and 30% of PS showed abundant G4-Ps. G4-Ps infiltrated diffusely for all AIPs and in a patchy pattern for PS at the abscess/granulation foci. Foxp3 immunostaining/double immunohistochemistry showed moderate to abundant CD4+CD25+ Tregs in AIP and abscess of PS, but few to moderate in granulation of PS. Dual fluorescent immunohistochemistry also showed many CD4+CD25+ Tregs in AIP. CONCLUSIONS: Many CD4+CD25+ Tregs were seen in AIP lesions, abscess of PS, but not in granulation of PS, suggesting that the amount of CD4+CD25+ Tregs sometimes do not synchronize with that of G4-Ps and might relate to the inflammatory activity of both AIP and PS.

Development and congenital anomalies of the pancreas.

Understanding how the pancreas develops is essential to understand the pathogenesis of congenital pancreatic anomalies. Recent studies have shown the advantages of investigating the development of frogs, mice, and chickens for understanding early embryonic development of the pancreas and congenital anomalies, such as choledochal cysts, anomalous pancreaticobiliary junction, annular pancreas, and pancreas divisum. These anomalies arise from failure of complete rotation and fusion during embryogenesis. There are many theories in the etiology of congenital anomalies of the pancreas. We review pancreas development in humans and other vertebrates. In addition, we attempt to clarify how developmental failure is related to congenital pancreatic anomalies.

Evidence of immunopathological traces in mucormycosis: an autopsy case.

A 77-year-old diabetic man newly contracted pulmonary mucormycosis. A rapidly progressing clinical course including severe worsening of pneumonia and renal failure culminated in death. This patient presented with hypocomplementemia and dermal vasculitis. Autopsied organs were examined by histological technique. Lung tissues showed pulmonary artery thrombosis and extensive alveolar invasion by Mucor hyphae with depositions of immunoglobulins, mannose-binding lectin (MBL) and C1q. The right internal jugular vein was occluded by thrombi containing numerous hyphae. The glomerular change was a hallmark of extra-capillary proliferative glomerulonephritis, which was overlying diabetic nephropathy. Depositions of IgM, C3 and C4 on glomeruli were also detected. Electron microscopy showed electron-dense deposits in the mesangial area and the wall of the afferent arteriole. This report shows evidence of complement opsonization of Mucor hyphae and refers to mucormycosis that developed small-sized vasculitis with complement activation.

Unusual fusion between ventral and dorsal primordia causes anomalous pancreaticobiliary junction.

Anomalous pancreaticobiliary junction (APBJ) is a congenital anomaly in which the pancreatic duct joins the common bile duct proximal to the sphincter of Oddi. Anatomical and immunohistochemical examination of the pancreas with APBJ has rarely been performed. A 72-year-old woman with gallbladder cancer and APBJ died of respiratory failure. Macroscopic features of the pancreas were examined in detail. Immunohistochemistry using anti-pancreatic polypeptide (anti-PP) antibody was done to discriminate ventral and dorsal pancreas. Macroscopically the inferior part of the head of the pancreas was smaller than normal. The posterior surface of the head was obliquely grooved. Part of the pancreatic head protruded into the posterior side of the pancreatic head. A PP-rich region was located in the superioposterior position of the pancreas head. Considering the relationship between the ventral and dorsal pancreas, it was inferred that the ventral primordium could obliquely fuse with the dorsal primordium during embryological development. As a result, APBJ occurs through an abnormal fusion between ventral and dorsal primordia.

Two distinct pathways of p16 gene inactivation in gallbladder cancer.

AIM: To examine the mechanism of inactivation of the p16 gene in gallbladder cancer, and to investigate p16 alterations and their correlation with clinicopathological features. METHODS: Specimens were collected surgically from 51 patients with gallbladder cancer. We evaluated the status of protein expression, loss of heterozygosity (LOH), homozygous deletion and promoter hypermethylation using immunohistochemistry, microsatellite analysis, quantitative real-time polymerase chain reaction (PCR) and methylation-specific PCR, respectively. In addition, mutations were examined by direct DNA sequencing. RESULTS: Homozygous deletions of the p16 gene exon2, LOH at 9p21-22, p16 promoter hypermethylation, and loss of p16 protein expression were detected in 26.0% (13/50), 56.9% (29/51), 72.5% (37/51) and 62.7% (32/51), respectively. No mutations were found. LOH at 9p21 correlated with the loss of p16 protein expression (P < 0.05). Homozygous deletion of the p16 gene, a combination LOH and promoter hypermethylation, and multiple LOH at 9p21 were significantly correlated with the loss of p16 protein expression (P < 0.05). LOH at 9p21 and promoter hypermethylation of the p16 gene were detected in 15.4% (2/13) and 92.3% (12/13) of the tumors with homozygous deletion of the p16 gene, respectively. P16 alterations were not associated with clinicopathological features. CONCLUSION: Our results suggest that LOH and homozygous deletion may be two distinct pathways in the inactivation of the p16 gene. Homozygous deletion, a combination of LOH and promoter hypermethylation, and multiple LOH are major mechanisms of p16 inactivation in gallbladder cancer.

Expression of transforming growth factor beta by small duct epithelium in chronic, cancer-associated, obstructive pancreatitis: an in situ hybridization study and review of the literature.

OBJECTIVES: Transforming growth factor beta (TGF-beta) is a dominant mediator of pancreatic fibrosis. The objective of this study was to identify cellular sources of TGF-beta mRNA and compare the results with previous immunohistochemical/in situ hybridization studies. METHODS: In situ hybridization of TGF-beta was conducted for 9 human tissues of chronic obstructive pancreatitis (COP) and 2 control specimens. By classifying these 9 COP tissues into 3 fibrosis phases by the amount of fibrotic space, histopathologic changes were examined for each fibrosis phase. Whether or not TGF-beta-positive cells were closely distributed to fibrosis was also investigated in control and COP cases. RESULTS: Three cases were categorized in early, intermediate, and advanced stages of fibrosis. Transforming growth factor beta mRNA was identified for a part of small duct epithelia, that is, intercalated ductule cells, centroacinar cells, and/or metaplastic ductal structures adjacent to acinar cells. The number of TGF-beta-positive cells was greater in COP cases than in controls. In controls and in the early stage of fibrosis, no fibrosis was seen near TGF-beta-positive cells. CONCLUSIONS: Small duct epithelia are the main cellular sources of TGF-beta in COP, and many of them may be working for COP fibrosis either directly or indirectly.

Pathology of autoimmune pancreatitis and tumor-forming pancreatitis.

The most frequently recognized presentation of autoimmune pancreatitis (AIP) is that mimicking pancreatic cancer. It is also known that at some stage during the disease process chronic pancreatitis clinically presents as a tumorous swelling, often suspected of being a carcinoma. In Japan, this stage has also been proposed clinically to be tumor-forming pancreatitis. Hence, tumor-forming pancreatitis shows at least two distinct types: a reparative process for centriductal acute inflammation with a background of chronic pancreatitis, which is considered to have given rise to the tumor at some stage of chronic pancreatitis, and a lymphoplasmacytic infiltration with lymphoid and fibrous proliferation in normal pancreatic tissue, which corresponds to autoimmune pancreatitis. These tumorous lesions may be changeable along the disease process.

Activated perilobular, not periacinar, pancreatic stellate cells contribute to fibrogenesis in chronic alcoholic pancreatitis.

The authors investigated the role of activated perilobular, not periacinar, pancreatic stellate cells, in fibrogenesis in chronic pancreatitis, based on the distribution of myofibroblasts. Twenty-four patients with clinically diagnosed chronic alcoholic pancreatitis were studied histopathologically, immunohistochemically and quantitatively. In all cases, fibrosis was patchily distributed in the perilobular, or interlobular, areas, accompanied by a cirrhosis-like appearance; it had extended into the intralobular area in advanced cases. Seven patients had a massive or confluent loss of exocrine tissue, resulting in extensive interlobular fibrosis; the more extensive the interlobular fibrosis, the smaller the lobules. Immunoreactivity to alpha-smooth muscle actin, a myofibroblast marker, was found mostly in the same areas of the fibrosis, mainly the interlobular, and less often the periacinar, areas; the average percentage area of perilobular myofibroblasts was significantly higher than that of periacinar myofibroblasts in 20 randomly selected lobules (P > 0.001), in which the average value for the former was 38.03% (range: 13.54-61.32%; SD, 13.8%) and that for the latter was 4.85% (range 0.90-9.57%; SD, 2.22%). Fibrosis also immunostained positive for collagen types I and III. In conclusion, activated perilobular, not periacinar, pancreatic stellate cell contribute to fibrogenesis in chronic pancreatitis.

Autoimmune pancreatitis can be classified into early and advanced stages.

OBJECTIVES: Although a number of pathological studies using various names/synonyms for autoimmune pancreatitis (AIP) have been reported, they do not mention the pathological staging related to origin/pathogenesis. Here, we propose a pathological staging for AIP lesions. METHODS: We histopathologically examined pancreatic tissue specimens of 31 AIP patients (14 pancreatectomized and 17 needle-biopsied materials) provided by 15 hospitals in Japan and studied the relevance of clinical manifestations to the pathological stage of AIP. RESULTS: Based on the presence or absence of acinar cells in AIP lesions, pancreatic tissue specimens were successfully divided into 20 cases in the early stage and 11 cases in the advanced stage, respectively. In the early stage, fibrosis was distributed in the interlobular and intralobular areas, admixed with acinar atrophy. Lymphoplasmacytic infiltration caused the narrowing of the ductal lumen and obliterative phlebitis. The common bile duct wall was also involved. In the advanced stage, the lesion was replaced by massive/extensive interlobular fibrosis with lymphoplasmacytic infiltrates to various degrees. Phlebitis was mild. Comparative analysis of clinical parameters between the early and advanced stages showed a significantly higher prevalence of jaundice and positive antinuclear antibodies in the early stage, and decreased serum lipase levels in the advanced stage. CONCLUSIONS: Autoimmune pancreatitis can be divided into early and advanced stages according to the presence or absence of acinar cells. Our pathological staging will facilitate understanding and evaluation of the clinical course in AIP.

Pancreatic segmentation on an embryological and anatomical basis.

Limited resection of the pancreas is recommended for low-grade malignancies such as mucin-producing tumors. We propose a system of segmentation of the pancreas for the purposes of limited resection. The proposed system has an anatomical and embryological basis, and divides the pancreas into four segments, namely the anterior head, posterior head, body and tail. These segments are based on the conventional anatomical division of the pancreas, identification of the originating primordium, and distribution of the ventral and dorsal pancreas.