Intraductal Growth Research Articles

Cholangiographic Spectrum of Intraductal Papillary Mucinous Neoplasm of the Bile Ducts

To propose a cholangiographic classification for intraductal growth type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor, collectively termed intraductal papillary mucinous neoplasm of the bile ducts (IPMN-B). For the extensive clinicopathologic variations of IPMN-B, a detailed characterization of cholangiography for IPMN-B is beneficial for determining the optimal therapeutic strategy. A total of 124 patients with cholangiography-available and pathologically proven IPMN-B were retrospectively studied. Numbers of IPMN-B type 1, type 2, type 3, and type 4 were 33, 17, 15, and 59, respectively. A cholangiographic classification was proposed based on the presence of hepatolithiasis, mucobilia, neoplasia localization, and concomitant malignancies. The demographics, histologic grading, management, and survival were also analyzed. All 33 IPMN-B type 1 and 12 of 17 IPMN-B type 2 displayed cholangiographic pattern IA demonstrating hepatolithiasis-related biliary stricture. The remaining 5 IPMN-B type 2 displayed cholangiographic pattern IB or IC, which demonstrated mucobilia without discernible neoplasia. Seven of 15 IPMN-B type 3 and 52 of the 59 IPMN-B type 4 displayed cholangiographic pattern IIA or IIB, which demonstrated overt intraductal neoplasia. Seven IPMN-B type 3 or 4 displayed cholangiographic pattern IIIA or IIIB, which demonstrated IPMN-B and concomitant malignancies. For those presenting with cholangiographic pattern IA, IC, IIA, IIB, and IIIA, straightforward hepatectomies for the diseased lobes were performed. For those with pattern IB, surgical resections were performed only when there was emergence of mucin-producing neoplasia. For those with IIIB, the concomitant malignancies were considered inoperable. No disease-related death occurred in IPMN-B type 1and 2. The mean survival rates of IPMN-B type 3 and type 4 were 55.5 +/- 17.1 months and 36.9 +/- 6.3 months, respectively. The presented cholangiographic classification facilitates the management for IPMN-B. Significant survival discrepancy at the various stages warrants a more aggressive surgical strategy.

Sonographic Findings of an Intraductal Mucinous Carcinoma

Cystic lesions of the breast are commonly seen on mammographic images. Although simple cysts are very common, intracystic tumors are rare. Intracystic growth is typically a finding associated with papillary carcinoma; however, to our knowledge, the literature does not show an association with mucinous carcinoma of the breast. We report a case of a mucinous carcinoma with an unusual intraductal growth and show sonographic and macroscopic findings.

Intraductal Papillary Mucinous Neoplasm: Is It Safe to Watch and Wait?

Intraductal Papillary Mucinous Neoplasm: Is It Safe to Watch and Wait? Mohammad Al-Haddad, Hugo Bonatti, Surakit Pungpapong, Kyung W. Noh, Seth A. Gross, Massimo Raimondo, Timothy A. Woodward, Michael B. Wallace Introduction: Intraductal papillary mucinous neoplasms of the pancreas (IPMN) are increasingly recognized in clinical practice. They represent a unique clinicopathologic entity that is characterized by mucin production, cystic dilation of the pancreatic ducts, and intraductal papillary growth. Published literature suggests that up to 45% of IPMN are malignant and should be resected however these data are based on larger, primarily symptomatic lesions. The risk of malignancy and need for surgical resection in smaller, lower risk lesions is not known. Aim: To identify predictors of a benign natural history in patients with IPMN. Methods: Patients with cystic lesions of the pancreas suspicious for IPMN were evaluated for known and potential clinical predictors of malignancy. Surgery was advised for those with a ‘‘high risk’’ features (mass, mural nodule, malignant cytology or CEA O 200 ng/ml on EUS-fine needle aspiration or pancreatic symptoms). Other patients were managed with serial imaging (CT or MRI) and clinical follow up. Potential predictors were compared to a gold standard of surgical pathology or long term clinical follow up without progression. Results: Sixty five patients with IPMN were included. Fortyfour patients IPMN were followed conservatively and were compared to 21 patients who underwent surgical resection based on high-risk features. Cancer or dysplasia was found in 9/21 (43%) of resected patients. None of the conservative group developed cancer during a median follow up of 7 months (2-52 months). The presence of a mass on EUS, main duct involvement and younger age were all predictors of malignancy (Table 1). Although there was an observed difference between the 2 groups in regards to presence of symptoms and mural nodules, it did not reach statistical significance. None of the other factors were found to be significant in predicting malignancy. Conclusions: 1Conservative management of IPMN with no features of malignancy is probably safe 2. This study confirms the previously described predictors for development of malignancy in IPMN including main pancreatic duct involvement and presence of masses. We found an unexpected inverse association with age that requires further studies to evaluate.

Selected Aspects of Molecular Diagnostics of Constitutional Alterations in BRCA1 and BRCA2 Genes Associated with Increased Risk of Breast Cancer in the Polish Population

ObjectivesThis study was undertaken to determine: 1) Type and prevalence of founder mutations BRCA1 and BRCA2 genes in Polish families with strong aggregation of breast and/or ovarian cancer. 2) Risk of breast and/or ovarian cancer depending on type of BRCA1 gene mutation. 3) Prevalence of BRCA1 mutation and of other alleles presumably linked with predisposition to breast cancer in unselected Polish patients with breast cancer. 4) Risk of breast cancer in patients with 5972C/T polymorphism that alters the BRCA2 protein structure.Summary of the results1. Among 66 families from several regions in Poland with a strong aggregation of breast/ovarian cancer, founder mutation of the BRCA1 gene were disclosed in 34 families and of the BRCA2 gene in on family. Altogether, seven different mutations were disclosed. Five mutations were found in at least two families in this group. The most frequent mutation was 5382insC (18 families), followed by C61G (7 families) and 4153delA (4 families). 2. Among 200 families representative for Poland with strong aggregation of breast/ovarian cancer, mutation of the BRCA1 gene were found in 122 families (61%) and of the BRCA2 gene in seven families (3,5%). 119 out of 122 mutations of the BRCA1 gene (97,5%) were repeatable. Three recurrent mutations of the BRCA1 gene (5382insC, C61G, 4153delA) characteristic for the Polish population were disclosed in 111 families representing 86% of all pathogenic sequences of this gene. 3. The risk of ovarian cancer in carriers of the three most frequent recurrent mutation of the BRCA1 gene in Poland is similar (OR 43.6 for 5382insC and 50 for 4153delA). The risk of breast cancer is significantly different for 4153delA (OR 1) and for other mutations (OR 10.9). 4. Among 2012 unselected breast cancers diagnosed in hospitals of nine Polish cities, mutations of the BRCA1 gene (5382insC, C61G, 4153delA) were disclosed in 2.9% patients. CHEK2 alternation (1100delC, IVS2+1G>A, I157T) was discovered in 8.1% and NBS1 mutation (657del5) in 0.8% of the patients. The changes were more frequent in the study than the control group. However, the risk of breast cancer was significantly higher for only three of them. Two changes, namely 5382insC and C61G of the BRCA1 gene revealed a high penetrance (OR 6.2 and 15.0, respectively), while I157T of the CHEK2 gene was associated with a low risk of breast cancer (OR 1.4). Mutations of the BRCA1, CHEK2 and NSB1 genes were significantly more frequent in patients with breast cancer diagnosed prior to 50 years of age. The mean age at diagnosis was 47.2 years for carriers of the BRCA1 mutation, 50.7 years for NBS1 and 54.2 for CHEK2. The mean age at diagnosis in the group of patients without any if the mutations described above was 56.1 years. When breast cancer patients with the diagnosis before and after 50 years of age were compared, the greatest difference in the frequency of mutation was revealed for the BRCA1 gene (5.5% vs 1.5%).BRCA1 mutations were significantly more frequent I familial aggregates of the tumor (10.8%), but were also present in sporadic cases (1.8%). For the CHEK2 and NBS1 genes, there was no correlation between frequency and family history of cancer in probands. 5. A higher frequency of heterozygous carriers of 5972C/T polymorphism of the BRCA2 gene was demonstrated for breast cancer prior to 50 years of age (OR 1.4). the risk of breast cancer prior to 50 years of age was particularly high in 5972T/T homozygote (OR 4.7). This polymorphism was associated with breast cancer notable for intraductal growth.Conclusions1. Efficient molecular diagnostics of genetic predisposition to breast/ovarian cancer in Poland could be based on relatively simple tests disclosing some of the most frequent recurrent mutations of the BRCA1 gene. 2. The risk of breast cancer seems to be only slightly higher in carriers of some BRCA1 gene mutations. This finding should be taken into account during work on prevention schemes for carriers of the BRCA1 mutations. 3. 5382insC and C61G mutations of the BRCA1 gene are linked with high risk of breast cancer. Changes in the CHEK2 and NBS1 genes appear to be linked with a higher risk of breast cancers, particularly at young age. However, penetrance in this case is low. All patients with breast cancer should be tested for BRCA1 gene mutations because the percentage of mutations is also high in patients older than 50 years of age or without familiar aggregation of breast/ovarian cancer. 4. Polymorphic changes in the BRCA2 gene sequence previously regarded as non-pathogenic may nevertheless predispose, homozygotes in particular, to breast cancer. Apparently, the recessive character of these changes is responsible for the negative family history in most cases. The use of DNA tests is the only way to disclose increased risk of breast cancer in carriers of the 5972T/T mutation.

顎下腺に発生したＳａｌｉｖａｒｙ Ｄｕｃｔ Ｃａｒｃｉｎｏｍａ例

Salivary duct carcinoma is an uncommon tumor and was first described by Kleinsasser et al. in 1968. Its histological features resemble ductal carcinoma of the breast. We experienced a 72-year-old male with salivary duct carcinoma of the submandibular gland with neck metastasis. The tumor was resected with the surrounding tissue and selective neck dissection was performed. Histological examination revealed that the tumor presented with cribriform and papillary patterns of the intraductal growth with comedo necrosis. Postoperative radiation of 50Gy and chemotherapy (CDDP, THP, CPA) were performed. The patient is alive without any evidence of recurrence at 30 months after surgery.

Endoscopic resection of benign tumors of the duodenal papilla without and with intraductal growth

Endoscopic papillectomy of benign papillary tumor is still not widely practiced. Intraductal growth has been considered a contraindication for endoscopic therapy. This prospective study evaluates endoscopic papillectomy for treatment of benign papillary tumors without and with intraductal growth. Monofilament snare and monopolar electrocoagulation were used for papillectomy. A 7F stent was placed in the pancreatic duct. Patients with distal intraductal growth underwent sphincterotomy and endoscopic resection after exclusion of more proximal growth. Between February 1985 and April 2004, 106 patients (109 lesions), 68 women, 38 men, median age 68 years (range 29-88 years) were included. Median tumor size was 2 cm (range 0.5-6 cm) with one session (range 1-8) required for removal. Nine patients had invasive carcinoma (8%). Surgery for incomplete removal or recurrence was performed in 12% of 75 patients without and 37% of 31 patients with intraductal growth (p < 0.01), respectively. Fifteen patients had recurrence (15%); but, only 4 required surgery. Endoscopic resection was curative (median follow-up, 43 months) in 83% without and 46% with intraductal growth (p < 0.001). Endoscopic papillectomy is safe and effective, and may be feasible in cases of intraductal growth. Surveillance and, if required, re-treatment are mandatory because of the risk of recurrence.

Intraductal Papillary Mucinous Tumors of the Pancreas

Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) are increasingly recognized in clinical practice. They are a unique clinicopathologic entity that is characterized by mucin production, cystic dilation of the pancreatic ducts, and intraductal papillary growth. Histologically, they may demonstrate a spectrum of cellular atypia ranging from minimal mucinous hyperplasia to frank invasive carcinoma. Similar to invasive ductal adenocarcinoma of the pancreas, patients with IPMN generally present in the seventh or eighth decade of life with the head of the gland being the predominant disease site. The majority of patients are symptomatic at presentation with abdominal pain, weight loss, and diarrhea being the predominant symptoms. Traditionally, the diagnosis was made following an endoscopic retrograde cholangiopancreatography. However, a cross-sectional imaging study such as a computed tomography or magnetic resonance imaging is now the radiological imaging studies of choice. Current thinking suggests that at best IPMN represents a premalignant condition and, as such, surgical intervention should be recommended. The aim should be to resect all gross disease while attempting to achieve a negative surgical margin, which in the majority of cases can be achieved by a partial pancreatectomy. The disease seems to be somewhat indolent with resection of noninvasive disease being curative in the majority of patients with 5- and 10-year actuarial survival rates of 75% and 60% reported. However, up to 50% of cases will have invasive cancer, and for this cohort the prognosis is more guarded. The role of adjuvant therapies is unclear, and further studies are required in this area.

Clinicopathological Factors Predicting Long‐term Overall Survival after Hepatectomy for Peripheral Cholangiocarcinoma

Peripheral cholangiocarcinoma (PCC) is clinically challenging because patients typically do not present until the disease is relatively advanced. Three-year to 5-year survival rates even with resection thus remain dismal. This study aimed to determine the clinicopathological factors for predicting overall survival longer than 5 years in PCC patients treated with hepatectomy. From 1977 to 1997, the clinicopatholgical features of 11 PCC patients who underwent hepatectomy with long-term overall survival (group A) were reviewed. Comparison was made with the clinical features and factors influencing the outcome of 70 PCC patients who survived less than 5 years after hepatectomy (group B). Of 81 PCC patients undergoing hepatectomy, 11 (13.6%) were 5-year survivors. The 81 PCC patients comprised 32 men and 49 women, with a mean age of 56.0 years (range: 34-83 years). Univariate analysis showed that female gender, absence of physical findings, a higher percentage of presence of mucobilia, early staged tumor, intraductal papillary tumor growth, and curative hepatic resection were more frequent in group A patients than group B patients. However, multivariate logistic regression analysis showed that absence of physical findings, presence of mucobilia, early staged tumor, and curative hepatic resection were the four independent factors differentiating group A from B patients. The 1-, 3-, 5-, and 10-year survival rates of the group A patients were 100%, 100%, 100%, and 40%, whereas those of the group B patients were 46.0%, 9.5%, 0%, and 0%, respectively. Absence of physical findings, presence of mucobilia, early staged tumor, and curative hepatectomy could independently predict PCC patients with long-term overall survival after hepatectomy.

Intraluminal brachytherapy without stenting in intrahepatic papillary cholangiocarcinoma: A case report

A 46-year-old female patient, with mild cholestasis by a large papillary cholangiocarcinoma involving the left hepatic duct, received intraluminal brachytherapy (50 Gy at 1 cm from the source axis) with the aim to relieve biliary obstruction without stent positioning. The patient presented with haemobilia and vegetant lesions in the left main biliary duct, and thus she had a high risk of early stent obstruction. Eighteen months after the treatment the patient presented tumour progression in the controlateral hepatic lobe, but had a patent left hepatic duct, without signs of cholestasis and/or cholangitis. Based on this and other published reports, intraluminal brachytherapy may be tested in a setting different from standard setting with the aim to safely palliate jaundice in patients with intraductal tumour growth in the biliary tract.

Intestinal‐type mucinous adenocarcinoma arising from the prostatic duct

We present a case of mucinous adenocarcinoma of intestinal type arising from the prostatic duct in a 72-year-old Japanese man. The patient presented with macroscopic hematuria. Cystourethroscopy exhibited a mucus deposit at the 5 o'clock position of the verumontanum portion. A transurethral biopsy specimen revealed mucinous adenocarcinoma. A radical retropubic prostatectomy was performed. In the prostatectomy specimen, the cancer lesion mainly showed intraductal growth in the prostatic ducts with scattered mucin lakes in the prostatic stroma. There were no abnormalities in the urethral epithelium. The cancer cells resembled the intestinal epithelium rather than either the prostatic duct or the acinar epithelium, which showed diffusely positive immunohistochemical staining for carcinoembryonic antigen, but showed negative staining for prostate-specific antigen. Therefore, these findings suggest mucinous adenocarcinoma of intestinal type arising from the prostatic duct. A number of cases with mucinous adenocarcinoma arising from the prostatic urethra resembling the present case have been reported, but this is the first known case of carcinoma arising from the prostatic duct.

Histopathological and Immunohistochemical Characteristics of Two Canine Lipid‐Rich Mammary Carcinomas

Clinicopathological and immunohistochemical findings of two uncommon canine lipid-rich mammary carcinomas are described. The predominant histological feature in both tumours was the presence of at least 80% of cells with intracytoplasmic vacuoles which stained positively with Sudan IV but not with alcian-blue periodic acid-schiff method. In both tumours, small groups of non-vacuolated cells were identified among the vacuolated cells. However, histological and immunohistochemical differences were also found between these tumours. Thus, one of them was composed of tumour cells with a large and single vacuole, which were arranged in lobular pattern, while the other neoplasm showed an intraductal growth of tumour cells with a fine vacuolated cytoplasm. Immunohistochemically, in the first tumour most vacuolated cells were positive for CK (cytokeratin)8-7, indicating a secretory epithelial immunophenotype while CK5 and CK8-7-expressing non-vacuolated cells were associated with luminal duct immunophenotype. However, in the second tumour the expression of CK14 in most of vacuolated cells and alpha-smooth muscle actin (alpha-SMA) in non-vacuolated cells, alone or in combination with CK5 suggested a myoepithelial immunophenotype for both cell types. These results suggest heterogeneity of the cell type and growth pattern for this type of canine tumour as has been described in women but not in dogs.

Tumours of the biliary system

Biliary hamartoma, bile-duct adenoma (BDA) and mucinous cystadenoma are the most common benign biliary tumours. Hamartomas occur sporadically or in association with polycystic liver disease. BDAs may represent a localized response to injury rather than true neoplasms. Cystadenomas are multilocular lesions lined by mucinous epithelium, often with cellular ovarian-like stroma. Cytologic atypia may suggest malignant transformation, but stromal invasion must be identified for diagnosis of cystadenocarcinoma. Cholangiocarcinoma (CC) is the most common malignant neoplasm. Risk factors include primary sclerosing cholangitis, liver flukes, hepatolithiasis and thorotrast exposure. The tumours show mass-forming, periductal-infiltrating or intraductal growth patterns. Intrahepatic CC presents as a hepatic mass and can be confused with hepatocellular carcinoma or metastatic adenocarcinoma. Immunohistochemistry and albumin in situ hybridization are helpful in this distinction. The diagnosis of extrahepatic CC can often be elusive due to the marked stromal desmoplasia, and multiple endoscopic biopsies and brushings may be required. Loss of p53 is common in mass-forming intrahepatic CC, and K-ras mutations in periductal-infiltrative extrahepatic tumours. Prognosis is poor, with 5-year survival of <20%. Lymph-node metastasis and surgical margin status are the most significant prognostic factors.

Cystic lesion of the pancreas

Cystic lesion of the pancreas

Endoscopic Resection of Benign Ampullary Tumors

Although benign tumors of the ampulla are uncommon, they present a difficult clinical problem. Endoscopic resection might not eradicate intraductal tumor growth, but surgical resection is associated with significant morbidity and mortality. To evaluate the safety and efficacy of endoscopic resection for benign tumors of the ampulla, investigators in Germany evaluated patient outcomes associated …

Carcinoma ex-pleomorphic adenoma: immunoprofile of the cytoskeleton proteins

Carcinoma ex-pleomorphic adenoma (CXPA) accounts for 5% to 15% of all salivary gland malignancies. They are considered high-grade tumors, except when carcinomatous component is enclosed within PA capsule, when a benign behavior is expected. In order to recognize which cellular component of PA develops in carcinoma, and how the progression of the lesion occurs, a panel of antibodies against cytoskeletal proteins (SMA; vimentin, and CK 7, 8, 13, 14, and 19), was applied to 13 cases of CXPA from major and minor glands, using the streptavidin-biotin method of immunohistochemistry. Two major kinds of CXPA were identified: those exhibiting only epithelial differentiation as seen in 10 cases from major glands (positive only to CK 7, 8, and 19) and those presenting myoepithelial component composed either by 2 cell types, luminal and myoepithelial, or with only myoepithelial cells (expressing SMA, vimentin, and CK 7 and 8). In CXPA with only epithelial differentiation, besides the area of PA, 2 other areas could be seen: intraductal carcinoma and/or invasive carcinoma, the latter regardless of being enclosed or not within PA capsule. In intraductal areas myoepithelial cells strongly expressing SMA, vimentin, and CK14 surrounded carcinomatous luminal cells. Invasive areas showed only carcinomatous epithelial cells without myoepithelial cells, indicating no more an intraductal or “in situ” localization of malignant cells. Based on these findings it is clear that the intracapsular CXPA can present in situ and/or in invasive areas. Thus, we recommend that the use of the term “in situ” should be restricted to tumors presenting only intraductal growth.

Aberrant expression of laminin gamma 2 chain and its prognostic significance in intrahepatic cholangiocarcinoma according to growth morphology

Laminin gamma 2 chain is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. We report altered expression and characteristic localization of this chain in a series of 105 cases of intrahepatic cholangiocarcinomas examined immunohistochemically. All tumors were grossly classified into the following three types: intraductal growth type (n=9), periductal infiltrating type (n=8) and mass-forming type (n=88). The tumors exhibited three distinct staining types: basement membrane staining, cytoplasmic staining and stromal staining. The basement membranous staining of laminin gamma 2 chain was more frequent in biliary dysplasia, intraductal growth and periductal infiltrating type than in mass-forming type. The cytoplasmic staining of carcinoma cells was observed especially at the cancer–stromal interface or at the invasive front of tumors. Stromal staining of laminin gamma 2 chain was essentially localized in the stroma around cancer cells at the invasive area, and the expression was significantly correlated with tumor aggressive factors and a poor prognosis in patients with intrahepatic cholangiocarcinoma. We conclude that laminin gamma 2 chain exhibits aberrant expression in a stepwise manner through different aggressive stages of tumor progression.

Condyloma acuminatum and condyloma-like lesions of the oral cavity: a study of 11 cases with an intraductal component.

We studied the clinicopathological features of 11 condyloma and condyloma-like lesions of the oral cavity with an unusual mixed pattern of exophytic and intraductal growth. The latter manifest as involvement of minor salivary gland ducts by the proliferative squamous lesions. This pattern of ductal involvement has not been previously described in oral condyloma. The clinical history was available for nine patients ranging in age from 17 to 73 years. Two were female and seven male. The buccal mucosa (five cases) was the most common site of occurrence, followed by the floor of mouth (two cases), lingual frenum (two cases), and hard palate (one case). All lesions exhibited exophytic and intraductal growth. The latter manifested itself as extension of the lesions into the excretory ducts of minor salivary glands. Underlying minor salivary glands, present in many of the excisional biopsy specimens, typically showed changes of obstructive atrophy. The exophytic components of all cases exhibited some degree of parakeratosis, and cryptic invaginations of parakeratin were typically present. Koilocytes were present in seven lesions and were equivocal in four. Mucous cells were present in the intraductal component of all cases and the intraductal component was never keratinized, but often papillary. A mild stromal-based, lymphocytic host response was present in three. A variably prominent neutrophilic infiltrate was present in the exophytic component of eight. Dysplasia was not present in any case. Five of 11 cases were positive with anti-human papillomavirus (HPV) and two of 11 cases were positive for in-situ hybridization probes directed against HPV 6/11. All cases were negative for HPV 16/18 and 13/33/35. Oral condyloma acuminatum may involve the excretory ducts of minor salivary glands. The diagnosis of oral condyloma acuminatum is difficult, as these lesions share considerable histological overlap with squamous papilloma. Finally, the relationship between these two lesions is incompletely understood.

Expression of matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 and -2 in intraductal and nonintraductal growth type of cholangiocarcinoma.

The intraductal growth (IG) type of cholangiocarcinoma has a better prognosis than the mass forming (MF) and periductal infiltrating (PI) types. Matrix metalloproteinase (MMP)-2 and MMP-9, regulated by tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-1, respectively, play important roles in the degradation of the basement membrane during tumor invasion. Alteration in MMPs and TIMPs may regulate the gross morphology of cholangiocarcinoma. MMP-2 and MMP-9 were analyzed in 35 cholangiocarcinomas and 4 normal livers with fresh tissue using zymography and real-time reverse transcription-polymerase chain reaction (RT-PCR), and expressions of MMP-2, MMP-9, TIMP-1, and TIMP-2 were evaluated in 76 cholangiocarcinomas by immunohistochemistry. Activity of MMP-2 and its active form were detected in 80% and 57% of cholangiocarcinomas respectively. The total MMP-2, active 62 kDa MMP-2, and MMP-2 mRNA increased 5.4 and 8.2 times, 4.4 and 10.9 times, and 2.9 and 5.8 times in the MF and PI types, respectively, compared to the IG type. The majority of MMP-9 was in the proform and active 82 kDa MMP-9 was detected in 9% of cholangiocarcinomas. MMP-9 revealed no significant difference in relation to the gross types. The balanced expressions of MMP-2/TIMP-2 and MMP-9/TIMP-1 were significantly decreased in the MF and PI types, compared to the IG type. In the normal and nonneoplastic livers, the expressions of MMP-2 and MMP-9 were very low without active forms. The activities of MMP-2 and loss of balanced expressions of MMP-2/TIMP-2 and MMP-9/TIMP-1 are suggested as playing important roles in invasive growth related to the gross type of cholangiocarcinoma.

Expression of integrins in intraductal papillary-mucinous tumors of the pancreas as an indicator of malignancy.

Intraductal papillary-mucinous tumors (IPMTs) of the pancreas are intraductal tumors with diffuse or segmental dilation of the pancreatic ducts and intraductal papillary growth with abundant mucous secretion. We examined clinicopathological features and immunohistochemical findings to investigate the malignancy of IPMTs. Between April 1994 and December 2002, 23 patients with IPMT underwent pancreatic resections at Nagoya City University Hospital, Japan. We immunohistochemically analyzed the expression of p53 protein, proliferating cell nuclear antigen, alpha6-integrin subunit, alpha5beta1 integrin, and interleukin-1 receptor type I in tumor specimens from the 23 patients with IPMT. The tumors were classified as intraductal papillary adenoma (n = 16), intraductal papillary adenocarcinoma and moderate dysplasia (n = 7). At a median follow-up of 42.9 months, 2 patients had died of this disease. The actuarial 5-year disease-free survival rate was 80.7%. Expression of the alpha6-integrin subunit was significantly strong in adenocarcinoma and moderate dysplasia tissues of IPMTs (P = 0.038). Our current results indicate that alpha6-containing integrin expression can be a significant marker of malignancy in IPMTs. We emphasize that immunohistochemical investigation of resected specimens is indispensable in cases of IPMT, so that appropriate postoperative treatments for malignant IPMTs are initiated to improve prognosis.

Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.

We retrospectively investigated the clinicopathologic features and outcome of 51 patients who underwent hepatectomy for intrahepatic cholangiocellular carcinoma (ICC) between 1991 and 2000, and we also analyzed the potential prognostic factors for long-term survival. There were 27 men and 24 women, with a mean age of 63.7 years. The surgical procedures were extended right or left hepatectomy (15 cases), right or left hepatectomy (19 cases), bisegmentectomy (3 cases), segmentectomy (7 cases), and subsegmentectomy (7 cases). The macroscopic findings of the excised tumor showed the mass-forming (MF) type (31 cases), the periductal-infiltrating (PI) type (13 cases), and the intraductal growth (IG) type (7 cases). The patients with the MF type had a significantly higher incidence of lymph node metastasis (44.8%), as compared to those with the PI or IG type (15.0%). Two patients who died of hepatic failure during their hospital stay were excluded from this survival study. The cumulative 1-, 3-, and 5-year survival rates in 49 patients who underwent liver resection were 68.2%, 44.1%, and 32.4%, respectively. The patients with the IG type had the best outcome, followed by those with the PI type and MF type. The survival rates with or without lymph node metastasis were 9.0% and 60.6% at 3 years, and 9.0% and 42.9% at 5 years, respectively ( P << 0.05). The 1-, 2-, and 3-year survival rates in the MF-type patients with lymph node metastasis were 25.4%, 16.9%, and 0%, respectively. Eight patients (15.7%) survived for more than 5 years after operation. The gross appearance of these tumors was the PI type in 5 patients, the IG type in 2, and the IG + MF type in 1. Except for one case with the PI-type tumor, lymph node metastasis was not observed. All of the 5-year survivors underwent curative resection and none of them had any positive surgical margin. Analysis of the clinicopathologic factors influencing the survival after surgical treatment showed that the macroscopic type, surgical curability, lymph node metastasis, tumor size, and cancer-free margin were the most predictive.