Toshiaki Kunimura

Intraductal Tubular Neoplasms of the Pancreas : Histogenesis and Differentiation

Objectives: Intraductal neoplasms of the pancreas are generally referred to as intraductal papillary mucin-producing neoplasms (IPMNs), according to the WHO classification system. Herein, we report that morphologic and immunohistochemical features of intraductal tubular carcinoma (ITC) are quite different from those of intraductal papillary mucinous carcinoma (IPMC). Methods: We analyzed histogenesis and differentiation of ITC by light microscopy and immunohistochemistry. Results: Histologically, ITC was characterized as an intraductal nodular appearances with a monotonous tubular growth pattern without papillary projection. ITC showed de novo-like appearance without sequential progression usually observed in IPMC, suggesting that ITC is a homogeneous neoplasm. Cuboidal tumor cells in ITC resembled normal pancreatic duct epithelia, and the characteristic growth pattern of ITC replaced that of normal pancreatic duct epithelium. Immunohistochemically, ITC cells were positive for MUC-1 on the apical side of the cell membrane. In contrast to ITC cells, IPMC cells were negative for MUC-1, and ductal adenocarcinoma cells were strongly positive for MUC-1, as was the stroma around the cancer. The immunohistochemical staining pattern of DUPAN-2 resembled that of MUC-1. Interestingly, localization of MUC-1 and DUPAN-2 staining in ITC cells was similar to that in normal pancreatic ductules. ITC cells were negative for MUC-2 and MUC-5AC. In contrast, most IPMC cells were positive for MUC-2 and MUC-5AC. Conclusion: Based on our histologic and immunohistochemical findings, the intraductal pancreatic neoplasm (IPN) can be classified into 2 groups: IPN with gastrointestinal differentiation and IPN with pancreatic duct differentiation. Our present data indicated that ITC cells may arise directly from duct epithelia without progression and possessed pancreatic duct differentiation. On the basis of our data, we suggest that classification of pancreatic neoplasms in the WHO and The Armed Forces Institute of Pathology (AFIP) systems should be reconsidered.

Epidermoid Cyst Derived from an Accessory Spleen in the Pancreas

A rare case of splenic epidermoid cyst (SEC) of the pancreas discovered in a 32‐year‐old Japanese female is reported. The lesion, 5x6cm in size including caseous material and serous fluid in the lumen, was discovered by ultrasonography and computed tomography at the tail of the pancreas and was easily removed. Histopathologically, the cystic wall consisted of three components: the inside was lined by mature squamous epithelium with keratinization, the middle layer consisted of splenic pulp with a sinus structure, and the peripheral layer was dense fibrous connective tissue in which some involutional pancreatic ducts and islets were recognized. The literature about SEC of the pancreas is discussed in comparison with other types of epidermoid cyst including lymphoepithelial cyst and dermoid cyst in the pancreas. Acta Pathol Jpn 41: 916 921, 1991.

Histologic and Immunohistochemical Comparison of Intraductal Tubular Carcinoma, Intraductal Papillary-Mucinous Carcinoma, and Ductal Adenocarcinoma of the Pancreas

Objective: To analyze the differences between intraductal tubular carcinoma (ITC) and intraductal papillary-mucinous carcinoma (IPMC), we performed light microscopic and immunohistochemical analysis of 4 cases of ITC, 6 cases of IPMC, and 9 cases of ductal adenocarcinoma of the pancreas. Methods and Results: Light microscopic examination showed no hyperplasia or adenoma around the carcinoma in ITC, and immunohistochemical analysis showed that the apical side of the cell membrane was positive for MUC-1 in almost all ITC cells. In contrast to ITC cells, all IPMC cells were negative for MUC-1 and ductal adenocarcinoma cells were strongly positive for MUC-1 in the cytoplasm and cell membrane. Immunohistochemical staining patterns of DUPAN-2 in ITC resembled those of MUC-1 in these cancers. ITC and IPMC cells were negative for carcinoembryonic antigen, but ductal adenocarcinoma cells were positive. There were no apparent differences in proliferative activity between ITC and IPMC, but ductal adenocarcinoma showed significantly greater activity than either ITC or IPMC. Conclusion: The PCNA-L.I of IPMC and ITC was lower and the cell atypia of them was more mild compared with those of ductal carcinoma, indicating that IPMC possess low-grade malignant potentials. However, we observed differences of growth patterns and mucous secretion between ITC and IPMC of the pancreas.

Multiparametric molecular characterization of pulmonary sarcomatoid carcinoma reveals a nonrandom amplification of anaplastic lymphoma kinase (ALK) gene

BACKGROUND Genetic alterations for targeting therapy are largely unexplored issues in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset. METHODS EGFR, HER2, KRAS, p53, CTNNB1, BRAF and PIK3CA mutations were assessed by direct sequencing, ALK, EGFR and HER2 gene status by fluorescence in situ hybridization (FISH), and ALK protein expression by immunohistochemistry (IHC) in 20 pleomorphic carcinomas (PLC), two pulmonary blastomas (PB) and one carcinosarcoma (CS). Surgical specimens and, in case of positivity, the corresponding preoperative biopsies were analyzed. Furthermore, 51 consecutive metastatic lung adenocarcinomas (MELAD) were used as controls for FISH and IHC assays of ALK gene. RESULTS While no rearrangements of ALK were detected in PSC, relevant amplification was identified 5/23 (22%) surgical specimens and paired biopsies (four PLC and one PB, two females and three males, four current and one never smoker, aged 30-83 years). Considering tumor heterogeneity, the percentage of ALK amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG ± SD) of 6.9 ± 0.8 and no signal differences between the epithelial (6.5 ± 0.9) and the sarcoma-like components (6.8 ± 0.9) of tumors. In the remaining 18 non-amplified PSC, the relevant value was 2.9 ± 0.5 in 1-80% tumor cells (p<0.001). ALK amplification was closely associated with chromosome 7 (EGFR) or 17 (HER2) polysomy (p<0.001). Out of 51 MELAD, 10 were ALK-rearranged (p=0.026) and only one amplified (p=0.009). No amplified tumors, either PSC or MELAD, expressed the relevant protein by IHC, while the 10 ALK-rearranged MELAD were strongly positive. TP53, KRAS and CTNNB1 mutations accounted for 30%, 22%, and 4% of cases, respectively, with no significant relationship with ALK amplification. No mutations for EGFR, HER2, BRAF or PIK3CA gene were observed. CONCLUSION ALK gene amplification is a nonrandom and clonally related event in a subset of PSC, but its biologic rationale deserves further investigation. KRAS mutation could represent a novel tool for therapy of such so deadly tumors with MEK inhibitors.

Immunohistochemical analysis of nestin and c-kit and their significance in pancreatic tumors.

The purpose of the present study was to clarify the difference of expression of two stem cell markers, nestin and c‐kit, among various pancreatic epithelial tumors and evaluate their utility. Immunohistochemistry was done for 99 surgically resected pancreatic tumor specimens, including 20 ductal adenocarcinoma (DAC), two undifferentiated carcinomas (UC), 31 intraductal papillary‐mucinous neoplasms (IPMN), six mucinous cystic neoplasms (MCN), five serous cystadenomas (SCA), six acinar cell carcinomas, two pancreatoblastoma (PB), eight solid‐pseudopapillary neoplasms (SPN), and 19 endocrine neoplasms (EN). Nestin was widely expressed in four SPN, one PB, one SCA, sarcoma areas in two UC, one MCN, and one DAC, and an area of oncocytic component in one IPMN. Some of these SPN, SCA and sarcomatous or oncocytic components in which nestin was expressed, also coexpressed c‐kit. Additionally, partial (scattered) expression of c‐kit was observed in ductal elements of 16 DAC, eight IPMN, five MCN, and one UC, one SCA, and three EN. The eight c‐kit‐positive IPMN included four of 23 adenoma‐to‐border lesions and four of eight non‐invasive‐to‐invasive carcinomas. The three EN were all carcinomas. These indicate that expression of two stem cell markers is different by tumor type, but the utility of judging direction or degree of differentiation and malignant grade on the basis of their expression status is suggested.

Possible Recruitment of Peripheral Blood CXCR3+ CD27+ CD19+ B Cells to the Liver of Chronic Hepatitis C Patients

It has been suggested that hepatitis C virus (HCV) infects not only hepatocytes but also immune cells, including B cells. HCV infection of B cells is the likely cause of B-cell dysregulation disorders such as mixed cryoglobulinemia, rheumatoid factor production, and B-cell lymphoproliferative disorders that may evolve into non-Hodgkins lymphoma. To clarify the effects of chronic HCV infection on B-cell dynamics, peripheral B cells from chronic hepatitis C patients (CHC) were characterized. We found that the frequency of CD27(+) B cells, that is memory phenotype, was significantly reduced in the peripheral blood of CHC. At the same time, the amount of IFN-gamma-inducible protein-10 (IP-10), a CXCR3 ligand, was markedly elevated in the plasma of CHC. Furthermore, the CD27(+) B-cell population was found to highly express CXCR3 in CHC, thus suggesting that the CD27(+) B-cell population was recruited from peripheral blood to the inflammatory site of the liver of CHC, where IP-10 is produced. Immunohistochemical analyses of intrahepatic lymphocytes indicated that CXCR3(+) B cells were infiltrated in the liver of CHC. Our results thus offer new insight into the role of memory B cells in the HCV pathogenesis.

Tumor dimension and prognosis in surgically treated lung cancer: for intentional limited resection.

Tumors with a maximum dimension of 3 cm are categorized as T1, whereas those greater than 3 cm are T2 by TNM classification. Some physicians suggest that early-stage peripheral lung cancer should have a maximum tumor diameter of 2 cm and that limited surgery (segmentectomy without lymph node dissection) is acceptable for the patients. In this study, the relationship between the tumor dimension and prognosis was analyzed in 207 patients with surgically treated primary non–small-cell lung cancer (SCLC). The 5-year survival rate of those with tumors 3 cm or less and without lymph node (LN) metastases was 86%, which was significantly higher than that of those with tumors more than 3 cm and without hilar and mediastinal LN metastases (65%) (p < 0.05). However, 33% of the patients with tumors 3 cm or less had LN metastases, and the 5-year survival rate did not differ between those with tumors 3 cm or less (60%) and those with tumors more than 3 cm (54%). Twenty-eight percent of patients with tumors 2 cm or less had LN metastases, and the 5-year survival rate of the patients with tumors 2 cm or less was 62%. The 5-year survival rate of those with tumors 2 cm or less and without LN metastases was 88%. Forty-six patients with tumors 2 cm or less included 5 cases with an intrapulmonary metastasis in the same lobe (11%). In conclusion, a size of 3 cm is an appropriate boundary as the T factor. Because those with tumors 2 cm or less have a relatively high percentage of LN metastases, intraoperative frozen sections of LN should be considered for those undergoing limited surgery for primary non-SCLCs 2 cm or less. Intrapulmonary metastases also should be considered for those undergoing limited surgery even if the maximum dimension of the primary tumor is less than 2 cm.

Autopsy cases of fulminant-type bacterial infection with necrotizing fasciitis Group A beta hemolytic Streptococcus pyogenes versus Vibrio vulnificus infection

Two autopsy cases of fulminant‐type infection associated with necrotizing fasciitis were analyzed clinicopathologically. Both cases involved 57‐year‐old alcohol abusers. The former was a woman with group A (beta) hemolytic Streptococcus pyogenes infection, and the latter was a man with Vibrio vulnificus infection. The sudden onset of shock with high fever resulted in sepsis, decreased clotting, and hepatorenal symptoms, followed by death within a few days. Post‐mortem examination showed widespread congestion and bleeding, and alcoholic liver cirrhosis was observed. Necrotizing fasciitis was identified in both cases. Bacteria from the pharynx or intestinal tract invaded the blood, and marked bacterial proliferation produced sepsis, resulting in necrotizing fasciitis. Despite the presence of sepsis, bilateral pulmonary congestion and bleeding were observed without pneumonia. Due to the rapid progression of sepsis, there was no time for granulocyte migration from the bone marrow. It seems that almost all mature granulocytes which had already existed in the bone marrow accumulated at the focus of necrotizing fasciitis because the bone marrow had few mature granulocytes and lacked hypercellularity. The cause of death in each case was circulatory collapse due to septic shock. It was difficult to distinguish the type of infection on histopathology. Cultures were necessary to determine the bacterial agents involved.

Outcome Following Surgery for Primary Lung Cancer with Interlobar Pleural Invasion

PurposeTo determine whether interlobar pleural invasion into the adjacent lobe (interlobar P3) should be assessed as T3 according to the tumor-node metastasis classification.MethodsSurgically treated patients with primary lung cancer (n = 322) were analyzed.ResultsTumors with interlobar P3 had a significantly lower incidence of mass screening detection, a higher occurrence rate of squamous cell carcinoma, and a larger tumor diameter than tumors without interlobar P3. The lymph node metastatic rate did not differ between the patients with and without interlobar P3. The 5-year survival rate of patients with interlobar P3 was 63% and the rates of other patients were 56% with T1 disease, 57% with T2, 31% with T3, and 19% with T4. The survival rate for patients with interlobar P3 was higher than for those with T3 without interlobar P3 (P < 0.05). The 5-year survival rate of the patients with interlobar P3 was lower in adenocarcinoma (39%) than in squamous cell carcinoma (69%, P < 0.01). The results were similar when the analysis was restricted to patients without lymph node metastasis. In adenocarcinoma, the survival rate for interlobar P3 was between the rates for T2 (53%) and T3 (13%) without interlobar P3, whereas in squamous cell carcinoma, the survival rate for interlobar P3 was between the rates for T1 (88%) and T2 (54%) without interlobar P3.ConclusionTumors with interlobar P3 should be classified as T2 only in squamous cell carcinoma.

Multiple Carcinomata Associated with Anomalous Arrangement of the Biliary and Pancreatic Duct System

Two rare cases of multiple neoplasms occurring in association with anomalous arrangement of the pancreatobiliary duct system (PBD) are reported. Ultrasonography, computed tomography and endoscopic retrograde cholangiopancreatography revealed cholecystic tumor in the first case, and multiple choledochocholecystic tumors in the second case. In the first case, pancreatic tumor was discovered two years after cholecystectomy. In the second case, a pancreatic tumor was discovered incidentally in the removed pancreatic head after the operation. The histology of all of these biliary and pancreatic tumors revealed papillary adenocarcinoma in both patients, and additionally small pancreatic endocrine tumors were found in the first case. Postoperative prognosis was comfortably favorable in both patients. In a literature survey, two other cases of double carcinomata associated with anomalous PBD were found, in which the tumors showed the same histology of papillary adenocarcinoma and the postoperative prognoses were also good. These mutual clinicopathological features appear to suggest that this abnormal condition acts as a carcinogenetic risk factor in the pancreatic duct and the biliary duct system, and may finally cause multiple carcinomata in the PBD. Acta Pathol Jpn 40: 755‐763, 1990.