Yoshio Kushida

The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients

BACKGROUND Angiogenesis and lymphangiogenesis have been reported to affect malignant phenotype. METHOD We investigated 147 patients with non-small cell lung cancer (NSCLC). Immunohistochemistry using D2-40 was performed to evaluate lymphatic vessel density (LVD), including Micro-LVD (without lumen), Tubal-LVD (with lumen) and lymphatic vessel invasion (LVI). The intratumoural microvessel density (MVD) was evaluated by CD-34 immunostaining. The expressions of vascular endothelial growth factor-A (VEGF-A) and VEGF-C were also studied. RESULTS Lymphangiogenesis was significantly associated with Micro-LVD (p=0.0003). The VEGF-C expression was significantly associated with the Micro-LVD (p=0.0057). In contrast, the VEGF-A expression was significantly associated with the MVD (p=0.0092). The survival was significantly lower in patients with Micro-LVD-high tumours than in patients with Micro-LVD-low tumours (p=0.0397). Survival was also significantly lower in patients with MVD-high tumours than in patients with MVD-low tumours (p=0.0334). A multivariate analysis demonstrated that the Micro-LVD (p=0.0363) and the MVD (p=0.0232) were independent prognostic factors for NSCLC patients. CONCLUSIONS Lymphangiogenesis, specifically Micro-LVD and angiogenesis are independently associated with a poor prognosis in NSCLC patients.

Epidermoid Cyst in an Intrapancreatic Accessory Spleen: Three Case Reports and Review of the Literatures

The development of an epidermoid cyst in an intrapancreatic accessory spleen is an extremely rare lesion, with only 17 cases being reported in the English literature. All such cases were located in the pancreatic tail, some of which showed carbohydrate antigen 19-9 (CA19-9) immunoreactivity in the lining of the epithelium. A few of them indicated an elevation of the serum CA19-9 level. Here we report three cases of an epidermoid cyst in an intrapancreatic accessory spleen. Cases 1 and 2 were 57-year-old and 70-year-old women, while case 3 was a 37-year-old man. All three cases were asymptomatic. Serum CA19-9 levels showed within normal limits (case 1), slightly elevated (case 2), and clearly elevated (case 3). They underwent a distal pancreatectomy with splenectomy (cases 1 and 2) and without splenectomy (case 3). Grossly, the surgical specimen was a well-demarcated, multiple (case 1) or solitary (cases 2 and 3) cystic mass in the pancreatic tail. A high level of fluid CA 19-9 was detected in case 1. Microscopically, the cystic walls were lined with squamous and cuboidal epithelium, which were surrounded by normal splenic tissue and hyalinized fibrous tissue. The lining squamous epithelium was revealed as nonkeratinizing (Cases 1and 2) or keratinizing (Case 3). Immunohistochemically, CA19-9 was positive in the monolayer and surface layer of the cuboidal epithelium, but negative for the keratinizing squamous epithelium. As for the histogenesis, it is suggested that the cystic lining of the epithelium may derive from the pancreatic duct which protrudes into the accessory spleen.

Loss of heterozygosity in actinic keratosis, squamous cell carcinoma and sun-exposed normal-appearing skin in Japanese: difference between Japanese and Caucasians

Actinic keratosis (AK) has been considered to be a precursor of squamous cell carcinoma (SCC). However, based on epidemiological and molecular studies, it has become questionable to regard AK as a precancerous lesion. We analyzed 37 AKs and 14 sporadic SCCs using six microsatellite markers in order to elucidate if any genetic instability or loss of heterozygosity (LOH) was implicated in tumorigenesis and progression of non-melanocytic skin tumor. Microsatellite instability (MSI) was not found in any of the AKs or SCCs indicating that genetic instability has little implication in the tumorigenesis of sporadic non-melanocytic skin tumor. LOH was found in seven of 37 lesions of AK, but in only one of 14 lesions of SCC. The significantly lower frequency of LOH than that previously reported in Caucasians suggested that the molecular pathogenesis of AKs and SCCs might be different between Japanese and Caucasians. The higher frequency of LOH in AKs than in SCCs in the present study supported the previous epidemiological and molecular studies that AK was not likely to proceed to SCC. LOH was also demonstrated in histologically normal-appearing skin in three cases suggesting that genetic alteration occurs before histological change appears in the sun-exposed skin.

Utility of pancreatic duct brushing for diagnosis of pancreatic carcinoma

BackgroundThe aim of this study was to evaluate the usefulness of pancreatic duct brushing for diagnosis of pancreatic carcinoma.MethodsBrush cytology was attempted in 58 patients suspected of having pancreatic malignancy because of stricture of the main pancreatic duct, confirmed by endoscopic retrograde cholangiopancreatography. Thirty-eight patients were finally diagnosed by an operation or the clinical course as having pancreatic carcinoma, and the remaining 20 patients as having chronic pancreatitis. The usefulness of brush cytology for diagnosis of pancreatic carcinoma was estimated. We interpreted failures of pancreatic duct brushing to be false negatives when the lesion was malignant.ResultsIn 48 of 58 patients (82.8%), brushing was successfully performed and satisfactory specimens were obtained. Brush cytology was positive in 25 of 38 patients with pancreatic carcinoma (sensitivity 65.8%) and negative in all patients without malignancy (specificity 100%). Overall accuracy was 76.4%. During 2001–2005, the number of back-and-forth motions of the brush was increased to more than 30 times. The sensitivity significantly improved from 43.8% in 1997–2000 to 81.8% in 2001–2005 (P < 0.05). The increased success rate of brushing by improvement of skill in manipulating the guidewire and increased number of cells smeared on glass slides by increased back-and-forth motion of the brush may account for this improvement over time. Moreover, the sensitivity in 2001–2005 was 85.7% if failures of brushing with pancreatic carcinoma are excluded. No major complications occurred, except for two patients with a moderate grade of acute pancreatitis.ConclusionsAlthough further studies with a large number of patients are needed, our results suggest that with recent improvements of the brushing technique, pancreatic duct brushing is a useful and safe method for the differential diagnosis of malignancy from benign diseases of the pancreas.

Malignant Adenomyoepithelioma of the Breast with Lung Metastases: Report of a Case

Abstract Adenomyoepithelioma of the breast is a rare lesion, and has a bicellular pattern of epithelial and myoepithelial cells which are regularly distributed in the tubular structures based on the histologic and ultrastructural features. It is thought to be a benign or a low-grade malignant disease. We herein describe a case of malignant adenomyoepithelioma of the breast with lung metastases in an 86-year-old woman. A primary massive tumor in the left breast grew rapidly within a short period of time. A simple mastectomy with sampling of the axillary lymph nodes was performed. The obtained lymph nodes did not include any metastatic lesions. Malignancy was evidenced by the presence of a high mitotic rate and severe nuclear atypia. Three months after the operation, radiology showed multiple lung metastases, and the patient died 2 weeks thereafter. Reviewing the literature, nine similar cases were reported, and the prognosis of malignant adenomyoepithelioma of the breast with distant metastases was very poor with the time of recurrence varying after initial treatments. Malignant adenomyoepithelioma should be followed up with careful screening for distant metastases.

Factors predicting survival and pathological subtype in patients with ampullary adenocarcinoma

Carcinoma of the ampulla of Vater is uncommon. This study aimed to clarify predictors of survival for ampullary adenocarcinoma and to identify characteristics of its two major pathological subtypes.

Evaluation of 3'-deoxy-3'-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas.

PurposeThe thymidine analog 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT) has been developed as a positron emission tomography (PET) tracer to assess the proliferation activity of tumors in vivo. The present study investigated the relationship between the kinetic parameters of 18F-FLT in vivo and thymidine kinase-1 (TK-1) expression and cell proliferation rate in vitro, and blood–brain barrier (BBB) breakdown in human brain gliomas.MethodsA total of 21 patients with newly diagnosed gliomas were examined by 18F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of 18F-FLT in the tumor and 18F-FLT kinetic parameters in the corresponding contralateral region were determined. The expression levels of TK-1 protein and mRNA were determined by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR), respectively, using surgical specimens. The cell proliferation rate of the tumor was determined in terms of the Ki-67 labeling index. BBB breakdown was evaluated on MR images with contrast enhancement.Results18F-FLT SUVmax and T/N ratio were significantly correlated with the influx rate constant (K1; P = 0.001 and P < 0.001, respectively), but not with the phosphorylation rate constant (k3). IHC and real-time PCR studies demonstrated a significant correlation between K1 and TK-1 mRNA expression (P = 0.001), but not between k3 and TK-1 protein and mRNA expression. Linear regression analysis revealed a significant correlation between K1 and the Ki-67 index (P = 0.003), but not between k3 and the Ki-67 index. TK-1 mRNA expression was significantly correlated with the Ki-67 index (P = 0.009). 18F-FLT SUVmax and T/N ratio were significantly correlated with BBB breakdown evaluated by contrast enhancement in MR images (P = 0.003 and P = 0.011, respectively).ConclusionThese results indicate that 18F-FLT uptake in the tumor is significantly related to transport through the disrupted BBB, but not through phosphorylation activity. Although the tissue TK-1 expression reflects tumor proliferation activity, the phosphorylation rate constant k3 determined by 18F-FLT PET kinetic analysis does not accurately reflect TK-1 expression in the tissue and should not be used as a surrogate biomarker of cell proliferation activity in human brain gliomas.

Pre-Existing Arteriosclerotic Intimal Thickening in Living-Donor Kidneys Reflects Allograft Function

Background: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient’s kidney function (allograft function) later in life. Methods: We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. Results: Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. Conclusions: The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.

Intrathyroidal branchial cleft‐like cyst in chronic thyroiditis

An extremely rare case of intrathyroidal branchial cleft‐like cyst is reported. A 71‐year‐old man complained of a growing mass in the right lateral neck. A cystic mass in the upper lobe of the right thyroid was demonstrated by ultrasonography and computed tomography. The surgical specimen revealed a cystic mass with dense fibrous capsule, 22 × 20 × 10 mm in size. Microscopically, the cyst walls and the surrounding thyroid tissue contained severe lymphoid cell infiltration with lymphoid follicle. Squamous epithelium lined the cyst wall. Immunohistochemically, squamous epithelium was positive for keratin, cytokeratin 19, carcinoembryonic antigen, and epithelial membrane antigen, but negative for calcitonin and chromogranin A. The patient is currently well with no evidence or recurrence for 43 months.

Sarcomatoid hepatocellular carcinoma with chondroid variant: Case report with immunohistochemical findings

A case of sarcomatoid hepatocellular carcinoma (HCC) with a chondroid variant in a 72‐year‐old woman is reported. Histologically, the tumor consisted of typical HCC of adult type, with an adenocarcinoma‐like structure and a sarcomatoid component containing multinodular chondroid foci. Transition from carcinoma to sarcomatoid component was observed. The cells containing mucus were extremely few in adenocarcinoma‐like structures. Immunohistochemically, other than typical HCC, some of the chondroid cells, adenocarcinoma‐like cells and sarcomatoid cells were positive for alpha‐fetoprotein.