Takahiko Funabiki

K-ras point mutations in cancerous and noncancerous biliary epithelium in patients with pancreaticobiliary maljunction

Pancreaticobiliary maljunction (PBM), an anomalous union of the pancreatic duct with the common bile duct, has frequently been shown to be associated with biliary carcinoma. However, the mechanism of carcinogenesis is unknown.

Pancreaticobiliary maljunction and carcinogenesis to biliary and pancreatic malignancy

BackgroundIt is widely accepted that congenital choledochal cyst is associated with pancreaticobiliary maljunction (PBM). But, PBM is an independent disease entity from choledochal cyst. PBM is synonymous with “abnormal junction of the pancreaticobiliary ductal system”, “anomalous arrangement of pancreaticobiliary ducts”, “anomalous union of bilio-pancreatic ducts”, etc. Cases with PBM not associated with biliary duct dilatation are often found, and these cases are frequently complicated gallbladder cancer. The Japanese Study Group of Pancreaticobiliary Maljunction was started in 1983, and defined diagnostic criteria and nationwide registration system of PBM cases was started. PBM is defined as a union of the pancreatic and biliary ducts which is located outside the duodenal wall. Bile and pancreatic juice reflux and regurgitate mutually.Biliary carcinogenesisThe most bothersome problem is biliary carcinogenesis. Gallbladder cancers arise in 14.8% and bile duct cancers arise in 4.9%. The incidence of the gallbladder carcinoma of PBM without bile duct dilatation is 36.1%. Many investigators have tried to clarify the carcinogenic process, from various aspects. The biliary epithelia are injured by harmful substances, and in the course of repair, multiple alterations of oncogenes and tumor suppressor genes are followed, and they lead to carcinoma through multistage interaction. In the biliary epithelia of PBM, incidence and degree of hyperplasia are characteristic. K-ras gene mutations are observed in the cancerous as well as noncancerous lesions of biliary tract of PBM patients. Mutations of p53 gene and overexpression of p53 protein are also found in the cancerous and noncancerous lesions. These changes are called “hyperplasia–carcinoma sequence”.TreatmentTotal excision of the extrahepatic bile duct with gallbladder followed by hepaticojejunostomy, Roux-en-Y, or end-to-side hepaticoduodenostomy are treatment of choice, even for cases with not dilated bile duct, because the incidence of cancer in the nondilated bile duct is not negligible, and genetic changes are seen in a nondilated bile duct.

Multifocal pancreatic serous cystadenoma with atypical cells and focal perineural invasion

SummaryA case of multifocal pancreatic serous cystadenoma with atypical cells is reported. The patient was a 72-yr-old female who complained of jaundice. The distal common bile duct was obstructed, and the proximal bile duct was remarkably dilated on cholangiography. The main portal vein was obstructed and collateral vessels had developed on portal angiography. Total pancreatectomy was performed. The resected specimen contained one tumor in the head of the pancreas, five in the body, and one in the tail. The tumors of the head and body were morphologically the same. Microscopically, both contained spongelike multilocular cysts on their cut surfaces. These cysts were covered with low cuboid epithelium containing clear cystoplasm and abundant glycogen.Neural invasion was also found. The tumor cells exhibited an increased N/C ratio, variable nuclear size, irregular nuclear margins, and coarse nuclear chromatin. These tumors had aneuploid nuclear DNA with a DNA index of 1.9 and a proliferation index of 0.28. We feel that it is necessary to reconsider the biological concept of serous cystadenoma.

Psoas abscess and cellulitis of the right gluteal region resulting from carcinoma of the cecum

Although retroperitoneal or psoas abscess is an unusual clinical problem, the insidious and occult characteristics of this abscess sometimes cause diagnostic delays, resulting in considerably high morbidity and mortality. In particular, psoas abscess caused by perforated colon carcinoma is uncommon. We report a case of psoas abscess caused by a carcinoma of the cecum. A 72-year-old Japanese woman was admitted to our hospital, with pain in the right groin and buttock. The pain had appeared 6 months before admission, and the symptoms had then been relieved by oral antibiotics. On March 25, 1999, inflammatory signs in the right buttock indicated localized cellulitis, and incision and drainage was performed at a local hospital. The patient was referred to our hospital on the same day. On admission to our hospital, computed tomography (CT) scan revealed a thick right-sided colonic wall and enlargement of the right ileopsoas muscle. Barium enema and colonofiberscopy revealed an ulcerated tumor occupying the entire circumference of the cecum. A retroperitoneal abscess and fistula had been formed by the retroperitoneal perforation of cecum carcinoma: surgical resection was performed after remission of the local inflammatory signs. Operative findings indicated that the cancerous lesion and its surrounding tissues were firmly attached to the right iliopsoas and major psoas muscle, and en-bloc resection, including adjacent muscular tissue, was performed. The fact that carcinoma of the colon could be a cause of psoas abscess and cellulitis in the gluteal region should be considered when an unexplained psoas abscess is diagnosed.

Metastasis to the Forearm Skeletal Muscle from an Adenocarcinoma of the Colon: Report of a Case

Abstract While the liver and lung are primary targets for distant metastasis from colorectal carcinoma, metastasis in other distant sites is rarely found. We report herein an unusual case of metastasis to the skeletal muscle of the right forearm from an adenocarcinoma of the transverse colon. A 60-year-old man was originally admitted to our hospital for surgical treatment of an intestinal obstruction caused by a transverse colon carcinoma. Transverse colon resection along with lymph node dissection was performed and no evidence of distant metastatic foci was found. Angiography-enhanced computed tomography scanning done 14 months after the first operation revealed multiple hepatic metastases which were resected. A metastasis was subsequently detected in the right extensor carpi ulnaris muscle 2 years after the primary resection, and a major part of the right extensor carpi ulnaris and the extensor digiti minimi muscle were resected, warranting a sufficient margin of 5 cm of normal tissue from the tumor. Reattachment of the residual muscles into the ulna was performed. Metastases to bone and/or soft tissues from colorectal carcinomas are extremely rare and to our knowledge, only eight other cases have been reported in the world literature. This low incidence may be related to the anatomical characteristics and/or the biochemical environment of the skeletal muscle, but it is also possible that the true incidence is underestimated. Recent improvements in interventional radiological procedures may facilitate a diagnosis of skeletal muscle metastasis being made more frequently.

Multiple perforated ulcers of the small intestine associated with allergic granulomatous angiitis: report of a case.

Although allergic granulomatous angiitis (AGA) is occasionally associated with gastrointestinal lesions, multiple perforated ulcers of the gastrointestinal tract are uncommon. We report herein a case of AGA associated with multiple perforated ulcers that erupted in the small intestine during corticosteroid therapy. A 31-year-old Japanese man was admitted to our hospital with epigastralgia, edema of the bilateral lower extremities, and general malaise. He had a persistent high fever, abdominal pain, and watery diarrhea. Laboratory data showed remarkable eosinophilia. The abdominal pain became exacerbated after the administration of oral prednisolone. Physical examination indicated positive signs of peritoneal irritation in the entire abdomen, and abdominal computed tomography scanning showed intra-abdominal free air, suggesting generalized peritonitis due to intestinal perforation. Laparotomy revealed multiple perforated ulcers in the jejunum and ileum. Histological examination indicated remarkable eosinophilic infiltration in the surrounding area of the small arteries and arterioles located in the submucosal layer, which was compatible with AGA. Although the association of intestinal perforation with AGA is relatively infrequent, intensive perioperative management is essential to ensure a favorable clinical outcome, particularly during the period on corticosteroid therapy.

Biliary carcinogenesis in pancreaticobiliary maljunction

The coexistence of bile duct carcinoma in choledochal cysts is well known. With large number of cases of congenital bile duct dilatation and pancreaticobiliary maljunction (PBM), it is now apparent that gallbladder carcinoma is more frequent in PBM without bile duct dilatation. The incidence of Gallbladder cancer in choledochal cyst and bile duct cancer in PBM, regardless of the presence of bile duct dilatation is significantly higher than that in control patients with biliary cancer but without PBM. A recent survey shows that the incidence of bile duct cancer in PBM without dilatation is equivalent to that of gallbladder cancer and bile duct cancer in patients with choledochal dilatation. Pathology in PBM is a result of reflux of pancreatic juice and stasis of the mixture in the biliary system. Carcinogenic factors thus present in the biliary contents induce epithelial changes in the biliary tract. In the biliary contents, activated pancreatic enzymes and secondary or deconjugated bile acids are markedly increased and they irritate the biliary mucosa. Mutagens are proven to form in the bile of PBM. In the epithelia of PBM, hyperplasia, metaplasia, and dysplasia are often found, and proliferative activity is increased; furthermore, K-ras gene mutation and overexpression of p53 protein are demonstrated. As for treatment of PBM, whether it is symptomatic or not, an operative procedure, is necessary, to prevent carcinogenic changes in the gallbladder and bile duct. Regardless of whether dilatation is present or not, total excision of the extrahepatic bile duct, along with gallbladder, is the treatment of choice, followed by hepaticojejunostomy or hepaticoduodenostomy.

Cardiac metastasis from squamous cell carcinoma of gallbladder

A 65-year-old woman was admitted to our hospital with the diagnosis of gallbladder tumor. Right extended hepatic lobectomy plus lymph node dissection of the hepatoduodenal ligament and left hepaticojejunostomy with Roux-en-Y reconstruction was performed in July, 1993. The gallbladder tumor was histologically proven to be squamous cell carcinoma. Seventeen months later, the patient experienced dyspnea and pitting edema of the lower legs and was admitted, in December 1994, with a diagnosis of heart failure. Despite intensive cardiac support, she died 12 days after the second admission. Autopsy revealed multiple cardiac tumors in the left and right ventricles, left atrium, left coronary artery, and left diaphragm. Histologically, these tumors were shown to be squamous cell carcinoma, considered to have metastasized from the primary gallbladder carcinoma. As neither local recurrence of the gallbladder carcinoma. As neither local recurrence of the gallbladder carcinoma nor any lymph node metastasis was found, the cardiac metastasis of the gallbladder carcinoma may have occurred via the hematogenous route. Although rare, this route of cardiac metastasis of gallbladder carcinoma may be an important aspect of distant metastasis, which should be monitored for during follow-up after resection of the primary tumor.

Some considerations on the biology of pancreatic serous cystadenoma.

SummaryFive cases of pancreatic serous cystadenoma were examined pathologically, and their nuclear DNA ploidy patterns were determined. Four were unifocal tumors, and one was a multifocal tumor. The four unifocal tumors were typical serous cystadenomas. However, the multifocal tumor exhibited an increased N/C ratio, irregular nuclear margins, various-sized nuclei, coarse nuclear chromatin, and neural invasion. All tumor cells were stained with antiCA19-9 but none with antiCEA. In the antiCA19-9 staining, the four unifocal tumors and the tumors of the pancreatic tail in the multifocal case were positive only on the apical membrane, whereas the tumor cells of the pancreatic head in the multifocal case were positive within the whole cytosol. The unifocal tumors were diploid with a DNA Index (DI) of 1.0 and proliferation indices (PI) from 4.9 to 20.9% with a mean of 14.4%. In the multifocal case, the tumor in the pancreatic head was aneuploid (DI = 1.9) and had a PI of 27.8%. The multifocal sites in the pancreatic body were aneuploid (DI = 1.9) with a PI of 22.4%. We suggest that the biological property of serous cystadenoma should be revisited.

Intrahepatic sarcomatous cholangiocarcinoma

A 77-year-old man, diagnosed with a liver tumor, was referred to our hospital. Abdominal ultrasonography demonstrated a low echoic mass in the liver S2 region, and abdominal CT confirmed the presence of a round low-density mass 7 cm in diameter. Enhanced angio-computed tomography (CT) showed a ring-like form with a pale periphery. In the delayed phase of angio-CT, the inside of the mass was enhanced, showing septal stricture. Abdominal magnetic resonance imaging (MRI) revealed a heterogenous low intensity area in T1-weighted images, with a clear high intensity border becoming apparent in T2-weighted images. Stretching of the hepatic artery was evident on the arterial phase of angiography, while an avascular area was apparent in the lateral segment of the liver in the portal phase. Lateral segmentectomy was performed. The size of the tumor was 6×6×5 cm. On macroscopic cross section, it was white and clearly demarcated from the surrounding tissue. Microscopic observation of H&E-stained specimens did not show any glandular formation. The tumor consisted of an irregular fascicular arrangement of spindle-shaped and round cells with poor intercellular adhesion. While there was no region containing differentiated epithelial components, silver impregnation staining revealed structures resembling regenerating bile ducts. The tumor cells were positive for wide-keratin, and for vimentin staining. Tumor cells were carcinoembryonic antigen (CEA)-positive and alpha-feto protein (AFP)-negative. From the above findings, the tumor was judged to have originated from epithelium rather than from mesenchymal elements. The final diagnosis was intrahepatic cholangiocarcinoma with secondary sarcomatous transformation, rather than hepatocellular carcinoma.