Papillary Proliferation Research Articles

Hepatobiliary and pancreatic: Papillary cholangiocarcinoma

Papillary neoplasms of the bile duct are rare. Benign disorders include solitary biliary papillomas and multiple papillomas, either at the same time or at different times (biliary papillotomatosis). Both disorders are thought to be premalignant with the potential for evolution from adenoma to carcinoma. Carcinomas with papillary proliferation in the duct lumen are usually called papillary cholangiocarcinomas. These carcinomas have a distinctive appearance within the bile duct and, in contrast to typical cholangiocarcinomas, rarely show mutations in K-ras or p53 or aberrant expression of matrix metalloproteinase-2 or b-catenin. In addition, biliary papillary tumors appear to share pathological features with intraductal papillary mucinous neoplasms of the pancreas. The most common presenting symptoms are jaundice and pruritis. At endoscopic retrograde cholangiography or magnetic resonance cholangiography, the typical appearance is a dilated bile duct with extensive soft tissue expansion, often involving the common hepatic duct and intrahepatic ducts. A minority of patients have a mucus-filled papilla. Most patients are treated surgically with resection of the affected area, often including a partial hepatectomy. The prognosis is better than that of typical cholangiocarcinomas with a 5 year survival rate ranging from 35% to 60%. The patient illustrated below was a 64-year-old man whose liver function tests had become increasingly abnormal over the previous 2 years. He described fatigue and pruritis over the preceding 2 months. Five years previously, he had an uneventful laparoscopic cholecystectomy for gallstones. Tumor markers including carcinoembryonic antigen and CA19.9 were within the reference range. A computed tomography cholangiogram showed soft tissue expansion of the left hepatic duct extending down to the common hepatic duct. There was marked dilatation of the left hepatic duct and atrophy of the left lobe of the liver (Figure 1). At endoscopic retrograde cholangiography, gelatinous material was noted in a widely-open papilla. Biopsies were taken from the common hepatic duct after which a biliary stent was inserted. Biopsies did not reveal definite evidence of cancer. At laparotomy, choledochoscopy demonstrated a dilated bile duct filled with mucin while the left hepatic duct contained mucin and prominent papillary mucosal projections. The patient was treated with a left hepatectomy, radical resection of the extrahepatic biliary tree and reconstruction by hepatojejunostomy. Histology revealed mucus and papillary fronds covered by predominantly dysplastic intestinal-type epithelium (Figure 2) as well as a small focus of adenocarcinoma.

Necrotic, ulcerated papules on a newborn male

A 1-day-old Hispanic boy presented to our department with truncal lesions that had been present since birth. The infant was born at term without prenatal or perinatal complications and was otherwise healthy. The physical examination revealed an afebrile patient with three 5-mm eroded papules with black eschars—one each on the right posterior axilla, left posterior axilla, and right buttock (Fig 3). Two 4-mm punch biopsy specimens were taken from two of the lesions. Histologic examinations of the ulcerated skin revealed an infiltrate of large, pleomorphic cells with oval to indented nuclei admixed with some neutrophils, eosinophils, and lymphocytes. Mitoses were readily identified (Fig 4). The infiltrate was heaviest in the papillary dermis, with focal epidermotropism and extension into the reticular dermis. Immunohistochemical stains were strongly positive for S-100 protein (Fig 5) and CD1a in the papillary dermal proliferation. 6.What is the most likely diagnosis? a.Congenital candidiasis b.Neonatal disseminated hemangiomatosis c.Langerhans cell histiocytosis d.Congenital leukemia e.Neonatal pustular melanosis 7.Immunohistochemical stains of this condition show that the cells demonstrate which of the following? a.S-100 b.CD1a c.Interferon-γ receptor d.Placental alkaline phosphatase e.All of the above 8.A higher degree of which of the following findings suggests a self-healing process as opposed to a multisystem disease? a.Necrosis b.Ulceration c.Dense infiltrate of eosinophils d.All of the above e.None of the above 9.Treatment of this condition when limited to the skin includes which of the following? a.Systemic chemotherapy b.Immediate excision of the lesions c.Long-term follow-up d.All of the above e.None of the above View Large Image Figure Viewer Download Hi-res image View Large Image Figure Viewer Download Hi-res image

Malignant pleural mesothelioma: Clinicopathology of 16 extrapleural pneumonectomy patients with special reference to early stage features

The earliest pathological events in the development of malignant pleural mesothelioma (MPM) are not understood. The aim of the present study was to elucidate the early histopathological features of MPM. A total of 16 extrapleural MPM pneumonectomy patients were investigated. Early stage mesothelioma was arbitrarily defined as a tumor < or =5 mm in thickness regardless of the nodal status or other organ involvement. Eight of these patients (six with epithelioid, two with biphasic) had early stage mesothelioma by this definition. Macroscopically there was no visible tumor, but the parietal and visceral pleura were thickened and there was focal adhesion between them. Microscopically, the mesothelioma lesions were multifocal and discontinuous on the pleura. In extremely early cases of epithelioid mesothelioma, tumor cells were generally arrayed in a single layer, but papillary proliferation was observed elsewhere. In sarcomatoid mesothelioma, mesothelioma cells proliferated, forming multiple small polypoid nodules on the pleura. Epithelial membrane antigen was helpful to distinguish reactive from neoplastic mesothelium, but glucose transporter-1 was not. Mesothelioma cells disseminate diffusely throughout the parietal and visceral pleura and mediastinal fat tissue before becoming visible. Stage Ia mesothelioma (neoplasm limited to the parietal pleura) would not be observed in daily practice.

Tumor-like lesions of the urinary bladder

Tumor-like lesions of the urinary bladder are reviewed emphasizing those that are most diagnostically challenging for the pathologist and may result in serious errors in patient care if misinterpreted. The first category considered, pseudocarcinomatous proliferations, represents an area of bladder pathology only recently appreciated as being particularly treacherous because of the extent to which irregular islands of benign epithelial cells may seemingly penetrate the lamina propria and cause confusion with carcinoma. Somewhat orderly proliferations of this type have been known for years, von Brunn's nests, and are rarely a challenge for the experienced, but proliferations of an irregular nature such as may be seen most often as a result of prior radiation therapy, but sometimes due to chemotherapy or even ischemia, represent a challenging interpretation. The clinical history may be very important in arriving at the correct diagnosis as is the appreciation that the morphology, although architecturally problematic, is different from that of any of the familiar patterns of invasive carcinoma. Florid epithelial proliferations in fibroepithelial polyps are also briefly noted. Within the category of glandular proliferations, emphasis is placed on the wide spectrum of morphology of nephrogenic adenoma including its pseudoinfiltrative pattern and occasional propensity for tiny tubules to be misconstrued as signet-ring cells. The spectrum of müllerian glandular lesions including the relatively recently described mucinous variant, endocervicosis, is reviewed. The reactive papillary proliferation, papillary–polypoid cystitis, is then discussed. This entity has long been known but has recently been re-emphasized. Other non-neoplastic papillary lesions include florid papillary forms of nephrogenic adenoma. The past 25 years has seen a great expansion of knowledge concerning non-neoplastic spindle cell proliferations, including those related to a prior procedure, the postoperative spindle cell nodule and those without such a history, variously designated inflammatory pseudotumor, pseudosarcomatous myofibroblastic proliferation, or even other terms. The morphologic spectrum is explored and it is recommended that the two categories be retained.

Serious Renal Hemorrhage in Masson Tumor

Intravascular papillary endothelial hyperplasia (IPEH; Masson tumor) is a vascular lesion of blood vessels, first described in 1923 by Masson, who termed it “hemangioendotheliome vegetant Intravasculaire.” This lesion consists of an exuberant, usually intravascular, proliferation of normal endothelial cells and is considered to be a reactive vascular proliferation after traumatic vascular stasis. The disease frequently occurs in skin and subcutaneous tissue; occurrence in solid organs is rare. We report a rare case IPEH that recurred as a possible consequence of an acute hypertensive arterial crisis in a patient with chronic kidney failure after kidney transplantectomy. Thirty days after transplantectomy, a 49-year-old white man receiving hemodialysis had pain in the left abdominal flank and acute anemia with serious hypovolemia after a hypertensive arterial crisis. An emergency non–contrast enhanced abdominal computed tomographic scan showed a massive retroperitoneal hemorrhage. A left nephrectomy was performed for evidence of a native kidney breach with toilette of the abdominal cavity. Histologic analysis revealed that the renal lesion had several important distinguishing characteristics that confirmed the diagnosis of IPEH. This lesion is considered to be an usual form of thrombus organization that is marked by excessive papillary endothelial proliferation. In rare cases, it is present in a solid organ of the abdominal cavity especially the kidney. Intravascular papillary endothelial hyperplasia is a benign lesion but can be dangerous. Clinical, radiologic, and histologic diagnosis of IPEH is difficult.

Well-differentiated papillary mesothelioma of the tunica vaginalis: A case report with aspirate cytologic, immunohistochemical, and ultrastructural studies

A case of a well-differentiated papillary mesothelioma of the tunica vaginalis testis in a 70-year-old man, who presented with a 1-month history of scrotal swelling with hydrocele, is described. Fine needle aspiration cytology of the hydrocele demonstrated a papillary cluster of uniform round cells with minimal atypia, reminiscent of mesothelial cells. Macroscopically, the lesion was characterized by a solitary, well-circumscribed papillary soft tumor measuring 1.2×1.2×1.0 cm 3. Histologically, the tumor exhibited papillary or tubulopapillary proliferation of predominantly bland cuboidal cells. No cellular pleomorphism, mitotic figures, necrosis, or stromal invasion was noted. Immunohistochemically, the tumor was positive for CAM5.2, epithelial membrane antigen, vimentin, calretinin, and D2-40, but negative for carcinoembryonic antigen. Ki-67 index was less than 1%. Ultrastructurally, the tumor cells showed numerous microvilli, mitochondria, rough endoplasmic reticulum, microfilaments, and desmosomes. The patient is alive with no evidence of disease at 18 months after right radical orchiectomy. Ki67 may be potentially a good maker for differentiating low-grade from high-grade mesothelioma.

The prevalence and distribution of human papillomavirus genotypes in oral epithelial hyperplasia: proposal of a concept

Evidence is accumulating for the aetiological role of human papillomavirus (HPV) in the pathogenesis of potentially malignant oral mucosal lesions and squamous cell carcinomas. Paraffin tissue sections from 49 patients with 'white patches' of the oral mucosa were investigated histologically, by broad-spectrum PCR followed by genotyping and chromogenic in situ hybridisation (CISH). Histologically, 33 flat hyperplasias and 16 papillary hyperplasias were diagnosed. Twenty-two of 28 samples studied (78.6%) were positive for HPV DNA by PCR and six were negative. The following HPV types were detected in decreasing order of prevalence: HPV 35, HPV 6, HPV16, HPV 53, HPV 18, HPV 51 and HPV 55. Seventeen samples (60.7%) contained high-risk HPV DNA. Using CISH, >or= 1 HPV signals were detected at least in a few epithelial cells in 95% of cases studied. All but one case were positive with the high-risk HPV probe and all HPV infections contained low viral load. Concordant positive results both by PCR and CISH were detected in 14 of 19 cases (73.7%) analysed. The high prevalence of HPV infection in hyperplastic 'white patches' of the oral mucosa supports the putative role of HPV at an early stage of oral carcinogenesis. These results further indicate that the majority of white oral mucosal lesions - flat, exophytic, wart-like or papillary proliferations - could be considered as the clinical manifestations of oral HPV infection. This finding has clinical relevance regarding therapy and patient management and may help in elucidating the role of HPV infection in oral carcinogenesis.

Evaluation of Novel Scoring System Named 5-5-5 Exacerbation Grading Scale for Allergic Conjunctivitis Disease

The objective of this study is to evaluate the practical usefulness of a scoring system using the 5-5-5 exacerbation grading scale for allergic conjunctivitis disease (ACD). Subjects were 103 patients with ACD including 40 patients with vernal keratoconjunctivitis (VKC), 20 patients with atopic keratoconjunctivitis (AKC), and 43 patients with allergic conjunctivitis (AC). The 5-5-5 exacerbation grading scale consists of the following 3 graded groups of clinical observations: the 100-point-grade group (100 points for each observation) includes active giant papillae, gelatinous infiltrates of the limbus, exfoliative epithelial keratopathy, shield ulcer and papillary proliferation at lower palpebral conjunctiva; the 10-point-grade group (10 points for each observation) includes blepharitis, papillary proliferation with velvety appearance, Horner-Trantas spots, edema of bulbal conjunctiva, and superficial punctate keratopathy; and the 1-point-grade group (1 point for each observation) includes papillae at upper palpebral conjunctiva, follicular lesion at lower palpebral conjunctiva, hyperemia of palpebral conjunctiva, hyperemia of bulbal conjunctiva, and lacrimal effusion. The total points in each grade group were determined as the severity score of the 5-5-5 exacerbation grading scale. The median severity scores of the 5-5-5 exacerbation grading scale in VKC, AKC and AC were 243 (range: 12-444), 32.5 (11-344), and 13 (2-33), respectively. The severity score of each ACD disease type was significantly different (P < 0.001, Kruskal-Wallis test). The severity of each type of ACD was classified as severe, moderate, or mild according to the severity score. The 5-5-5 exacerbation grading scale is a useful clinical tool for grading the severity of each type of ACD.

Intravascular Papillary Endothelial Hyperplasia Associated with Venous Pool Arising in the Lower Lip: A Case Report

Intravascular papillary endothelial hyperplasia is a benign nonneoplastic vascular lesion that consists of endothelial cells with abundant vascular tissue with papillary proliferation. An adult female had a painless growing dark red nodule on the left side of the lower lip and often touched and gnawed at it for more than 4 years. The lesion was a tender, smooth mass approximately 1 cm in diameter without discoloration reaction. Magnetic resonance imaging of the lesion showed specific findings. She was diagnosed clinically as having mimicked hemangioma, and the lesion was totally excised under local anesthesia. Histopathological examination revealed that papillary proliferated endothelial cells with venous pool, and the lesion was diagnosed as intravascular papillary endothelial hyperplasia associated with venous pool. There has been no recurrence for more than 1 year. Despite the benign nature of this lesion, it could have been mistaken for a malignant tumor because of its clinical course and radiologic findings.

The role of immunohistochemistry in the differential diagnosis of breast lesions

Immunohistochemistry may be helpful in the diagnosis of various breast lesions. It can be used to assist in distinguishing benign and malignant conditions, or to clarify the histological subtype of invasive carcinomas. There are several markers relatively frequently utilised. Myoepithelial markers (p63, alpha-SMA, smooth muscle myosin heavy chain, and others) are useful to highlight myoepithelial cells. They are employed to verify myoepithelial cell lining in intraductal papillary lesions, or to recognise peripheral myoepithelial cells for non-invasive carcinoma, although their staining results are not always excellent. High molecular weight cytokeratins (CK5/6, CK14, 34betaE12) typically show a mosaic-like pattern of expression in benign papillary/hyperplastic lesions, and are mostly negative in ductal in situ carcinoma, but some exceptions exist. Neuroendocrine differentiation (confirmed by anti-chromogranin A or synaptophysin) suggests malignancy in solid and papillary intraductal epithelial proliferations. The significance of immunohistochemical evaluation of apocrine lesions is still controversial. Negative E-cadherin staining is used for making confirmative diagnosis of lobular carcinoma, with a specificity and sensitivity of approximately 90%. Cytokeratins, especially the antibody 34betaE12, are of value to differentiate spindle cell carcinoma from phyllodes tumour. There are some other useful markers for characterising certain histological subtypes. Nevertheless, for accurate diagnosis, it is essential to correlate the immmunohistochemical staining results with the histological findings.

A Consideration of Papillary Squamous Cell Carcinoma of the Gingiva: A Case Study Involving the Immunohistochemistry of Proliferative Activity

Papillary squamous cell carcinoma (PSCC) is a rare variant of squamous cell carcinoma (SCC) having an exophytic papillary component. We report the case of a 60-year-old woman with oral PSCC of the gingiva. Histopathologically, the operative specimen was composed of exophytic papillary and invasive proliferations of atypical squamous epithelium, from which a pathological diagnosis of PSCC was made. On the Ki-67 labeling index, the exophytic area of PSCC (42.8%) was higher than the superficial area of SCC (20.7%) and papilloma (38.9%). The invasive area of PSCC (53.1%) was slightly higher than that of SCC (52.2%). The PSCC had high proliferative activity in both the exophytic and invasive areas, which reflected the PSCC characteristic features of papillary and invasive growths. Clinicians should check for the existence of PSCC in the oromaxillofacial region and provide treatment as they do for SCC.

Ependymoblastoma in a Japanese Black Heifer

An 18-month-old, Japanese Black heifer had ananastasia over a two-week period. The heifer was euthanized and necropsied. Grossly, a brown and soft mass was found in the left cerebellar hemisphere, which originated from the fourth ventricle in the pons. Multiple papillary masses were also found on the wall of the fourth ventricle. There was massive dilatation of the cerebral aqueduct, and also in the third and lateral ventricles. Histologically, the neoplastic cells formed numerous ependymoblastic rosettes and perivascular pseudorosettes. In the fourth ventricle, the normal ependymal cells were replaced by papillary proliferation of the neoplastic cells. Ultrastructually, the neoplastic cells had a feature differentiating to the ependymal cell showing a few basal bodies in the cytoplasm and connecting to adjacent cells with junctional complexes. We diagnosed the present case as ependymoblastoma with its origins in the fourth ventricle.

A Simple Ductal Mammary Papilloma in a Male Maned Wolf (Chrysocyon Brachyurus)

A 1-cm-diameter nodule was identified in the left inguinal mammary gland of a 9-year-old male maned wolf (Chrysocyon brachyurus). The mass was surgically excised and examined histologically. Microscopically, the neoplasm consisted of papillary proliferations of epithelial cells on well-defined fibrovascular stalks. A myoepithelial layer was located between the single layer of epithelial cells and the fibrovascular stalk. This histologic appearance was compatible with a diagnosis of simple ductal mammary papilloma. Immunohistochemical staining was positive for p63, cytokeratins AE1/AE3, and estrogen receptors. The clinical and histologic observations in the present case indicate that male maned wolves may develop mammary tumors that are similar to those observed in domestic dogs and humans.

Biliary Papillomatosis Coexisting with Hepatitis C: Report of a Rare Case with Review of the Literature

Biliary papillomatosis is a rare disease and is often fatal. It is characterized by diffuse papillary proliferations of bile duct epithelial cells. Patient may present with fever, abdominal pain and obstructive jaundice. The degree of biliary obstruction varies, ranging from almost asymptomatic to severe life-threatening illness with painful obstructive jaundice, vomiting, cholangitis, and pancreatitis. Preoperative diagnosis is very uncommon. Here, we describe an incidental finding of a case of biliary papillomatosis after liver transplant in a 65 year-old woman with end-stage liver disease secondary to Hepatitis C. Grossly, the mass is located at the posterior aspect of the right lobe, extending to the portal area, presenting as a white fibrotic area measuring 6.0 x 8.0 x 4.5 cm. Cut surface of this area is gray-white with multiple cysts ranging from 1.2 x 0.9 x 0.9 cm to 0.2 x 0.2 x 0.2 cm. Microscopic examination revealed glandular growth pattern of the epithelial cells with a stroma consisted of fibrovascular connective tissue. These epithelial cells have abundant cytoplasm with the nuclei arranged regularly close to the basement membrane. There is slight nuclear hyperchromatism, but there is no obvious atypia. The tumor cells contain mucin as shown by PAS stain, which is resistant to the diastase treatment. The negative immunohistochemical stains for CEA and Cytokeratin 20 did not support the possibility of metastatic tumor from lower GI tract, while the positive Cytokeratin 7 staining was compatible with an origin of intrahepatic bile duct. Based on above findings, she was diagnosed multifocal biliary papillomatosis in the background of florid bile ductule proliferation. The cirrhosis and chronic inflammation in her liver were consistent with the history of hepatitis C. She also had associated chronic cholecystitis and cholelithiasis. She was treated by liver transplantation. The patient is doing well now (eight years after the transplantation). In addition, the related literatures are reviewed, and the possible pathogenesis, treatment plan, and prognosis of biliary papillomatosis are briefly discussed.

Intravascular Papillary Endothelial Hyperplasia

Intravascular papillary endothelial hyperplasia (IPEH) is a benign vascular proliferative process characterized by papillary proliferation of endothelial cells located within a vascular lumen. The lesions occur most commonly in the extremities and in the head and neck region. 1,2 Reports of the imaging findings of these masses are scarce. We report a rare case of IPEH occurring in a dorsal wrist vein with demonstration of the sonographic appearance and pathologic correlation.

Clinicopathological analysis of multifocal micronodular pneumocyte hyperplasia associated with tuberous sclerosis in Japan

This study investigated the clinical and pathological findings of lung disease in tuberous sclerosis complex (TSC) as previously reported in Japan. The clinical and pathological findings in 15 patients diagnosed as having multifocal micronodular pneumocyte hyperplasia (MMPH) with TSC were analysed. The majority of patients (80%) were women and the mean age was 37 years. Three patients had a family history of TSC. The radiological findings were small multiple nodular shadows with ground-glass opacity randomly distributed in the bilateral whole-lung fields in most patients. Differentiation from multiple atypical adenomatous hyperplasia or metastatic lung cancer was necessary in most patients. In 11 patients, the diagnostic method used to identify pulmonary lesions of MMPH with TSC was VAT. Among the complications of MMPH with TSC, lymphangioleiomyomatosis was recognized in 53% of patients. The prognosis was comparatively good because only one patient died of respiratory failure. The histological findings were papillary or tubular proliferation of type II pneumocytes without nuclear atypia lining the thickened alveolar septa and lymphocyte infiltration. Immunohistochemical staining for cytokeratin, and surfactant proteins A and B was positive in alveolar lining cells of all MMPH lesions. However, staining for HMB-45, alpha-smooth muscle actin, p53, carcinoembryonic antigen and hormonal receptor was negative in most patients. Surgical investigation and immunohistochemical staining for pathological markers are useful for diagnosing MMPH when the radiological findings indicate multiple micronodules with ground-glass opacity in patients with TSC.

546 POSTER Gl261 brain tumor cells: responses to single or fractionated x-irradiation with the avb3 integrin thyroxine receptor antagonist TETRAC (tetraiodothyroacetic acid)

Thyroid hormone (l-thyroxine, T4, or 3,5,3′-triiodo-l-thyronine, T3) treatment of human papillary and follicular thyroid cancer cell lines resulted in enhanced cell proliferation, measured by proliferating cell nuclear antigen (PCNA). Thyroid hormone also induced activation of the Ras/MAPK (ERK1/2) signal transduction pathway. ERK1/2 activation and cell proliferation caused by thyroid hormone were blocked by an iodothyronine analogue, tetraiodothyroacetic acid (tetrac), that inhibits binding of iodothyronines to the cell surface receptor for thyroid hormone on integrin alphaVbeta3. A MAPK cascade inhibitor at MEK, PD 98059, also blocked hormone-induced cell proliferation. We then assessed the possibility that thyroid hormone is anti-apoptotic. We first established that resveratrol (10 μM), a pro-apoptotic agent in other cancer cells, induced p53-dependent apoptosis and c-fos, c-jun and p21 gene expression in both papillary and follicular thyroid cancer cells. Induction of apoptosis by the stilbene required Ser-15 phosphorylation of p53. Resveratrol-induced gene expression and apoptosis were inhibited more than 50% by physiological concentrations of T4. T4 activated MAPK in the absence of resveratrol, caused minimal Ser-15 phosphorylation of p53 and did not affect c-fos, c-jun and p21 mRNA abundance. Thus, plasma membrane-initiated activation of the MAPK cascade by thyroid hormone promotes papillary and follicular thyroid cancer cell proliferation in vitro.

Intraductal papillary mucinous neoplasm of pancreas: a clinicopathologic and immunohistochemical study of 19 cases

To study the clinicopathologic features and diagnosis of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Nineteen cases of IPMN encountered during the period from 1999 to 2007 were studied by light microscopy and immunohistochemistry. IPMN occurred more often in males (68%). It affected patients in older age group (mean age = 59) and was located mainly in the head of pancreas (60%). The mean tumor size was 4.2 cm (range = 1 to 8 cm). The clinical presentation was epigastric pain (53%), weight loss (32%), diabetes (21%), pancreatitis (21%) and jaundice (10%). Pancreatectomy was performed in 18 cases. The remaining patient received bypass surgery only. Features of in-situ or invasive malignancy were present in 15 of the 19 cases (78%). Histologically, the tumor consisted of papillary proliferations protruding into and expanding the pancreatic ducts. Invasion into the surrounding pancreatic parenchyma was noted in 12 cases and chronic pancreatitis was present in 16 cases. Follow-up data (4 to 48 months) were available in 13 patients. Apart from 1 patient who died of other disease, all were still alive. Immunohistochemical study showed that p53 was positive in 6 cases, p16 in 5 cases and fascin in 8 cases. The expression of c-erbB-2 was all negative. Ki-67 index ranged from 1% to 80% (mean = 38%). Malignant changes are not uncommon in IPMN. The prognosis after surgical resection however is better than that of conventional pancreatic adenocarcinoma. The overexpression of p53, p16 and fascin may be related to tumor progression. The possibility of malignant transformation needs to be considered if the Ki-67 index is over 15%. Early recognition by radiologic examination (including ERCP) and pancreatic cytology would be helpful in early diagnosis. Surgical resection represents the mainstay of treatment and long-term post-operative follow up is needed.

Progression of Epididymal Maldevelopment Into Hamartoma-like Neoplasia in VHL Disease

Inactivation of the von Hippel-Lindau (VHL) gene and activation of the hypoxia-inducible factor (HIF) in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes. Areas of interest were genetically analyzed by tissue microdissection, immunohistochemistry for HIF and markers for mesonephric differentiation, and in situ hybridization for HIF downstream target vascular endothelial growth factor. Structural analysis of the epididymides revealed marked deviations from the regular anatomic structure resulting from impaired organogenesis. Selected efferent ductules were represented by disorganized mesonephric cells, and the maldeveloped mesonephric material was VHL-deficient by allelic deletion analysis. Furthermore, we observed maldeveloped mesonephric material near cystic structures, which were also VHL-deficient and were apparent derivatives of maldeveloped material. Finally, a subset of VHL-deficient cells was structurally integrated in regular efferent ductules; proliferation of intraductular VHL-deficient cells manifests itself as papillary growth into the ductular lumen. Furthermore, we clarify that that there is a pathogenetic continuum between microscopic tumorlets and formation of tumor. In multiple locations, three-dimensional reconstruction revealed papillary growth to extend deeply into ductular lumina, indicative of progression into early hamartoma-like neoplasia. We conclude epididymal tumorigenesis in VHL disease to occur in two distinct sequential steps: maldevelopment of VHL-deficient mesonephric cells, followed by neoplastic papillary proliferation.

Acute Hemobilia and Hemocholecyst in 2 Dogs with Gallbladder Carcinoid

Acute Hemobilia and Hemocholecyst in 2 Dogs with Gallbladder Carcinoid