James L. Zehnder, MD

• Professor of Pathology and Medicine, Pathology Department, Stanford University School of Medicine, Stanford

https://profiles.stanford.edu/james-zehnder

The affected duct may rupture treatment ketoacidosis cheap cyklokapron 500mg free shipping, or the duct epithelium may exhibit degenerative change medicine 4 you pharma pvt ltd buy cyklokapron 500mg with amex. The native ducts may be absent or obscured by lymphoid aggregates or collections of foamy macrophages medicine x ed discount 500mg cyklokapron mastercard. Any combination is referred to as overlap syndrome treatment quietus tinnitus discount cyklokapron 500mg mastercard, and the pathology evaluation frequently determines the dominant process (Floreani et al symptoms throat cancer cheap cyklokapron 500 mg with mastercard, 2014) treatment 3rd nerve palsy purchase cyklokapron line. Florid duct lesions and granulomas may continue to exist where native bile ducts have not been completely destroyed. Canalicular cholestasis with bile plugs may be seen in the late stage and is regarded as a sign of poor prognosis. Characteristic features include concentric, "onion-skin" periductal fibrosis; however, this merely indicates chronic biliary obstruction of any cause and thus is not pathognomonic. Careful evaluation of explant livers for occult cholangiocarcinoma with thorough sampling of all hilar tissue is recommended. Iron deposition initially occurs in zone 1 (periportal) hepatocytes, with a decreasing gradient toward the centrilobular area. Kupffer cell clusters, or siderotic nodules, are common, and usually little to no significant portal and/or lobular inflammation is evident. When cirrhosis develops, it is typically micronodular with portal to portal bridging and retention of the terminal hepatic venules. Hepatocytes in cirrhotic nodules also are iron loaded and may exhibit a periseptal distribution pattern. Secondary iron overload in the liver is a common finding in a variety of nonbiliary conditions, including hepatic necrosis and cirrhosis (Limdi & Crampton, 2004). Iron deposition in these conditions is usually mild and rarely exceeds 2+ when a semiquantitative histologic score of 1 to 4 is used. Iron granules may be found in hepatocytes, Kupffer cells, and endothelial cells of the sinusoids or large vessels. It has been suggested that these patients are less likely to respond to venesection therapy and are also more prone to fibrosis and cirrhosis (Bonkovsky et al, 2003). Wilson Disease Wilson disease is an autosomal recessive inherited metabolic disorder of copper metabolism. Any young to middle-aged patient with unexplained cirrhosis or chronic or fulminant liver disease should be investigated for Wilson disease (Merle et al, 2007), particularly when neuropsychiatric symptoms are involved. Morphologic features in the liver vary as widely as the different clinical stages. In later stages, atypical lipofuscin, canalicular cholestasis, and Kupffer cell iron accumulation may be noted. Periportal hepatocytes may contain glycogenated nuclei and Mallory-Denk bodies, and cirrhosis is usually micronodular. Alternatively, the absence of stainable copper in a noncirrhotic liver does not exclude the diagnosis of Wilson disease. Currently, plasma-based genetic testing has not yet become practical for clinical diagnosis due to the number of genetic mutations that may result in this disease. Cryptogenic Cirrhosis In approximately 10% to 15% of patients with cirrhosis, no clinically or pathologically identifiable cause of cirrhosis is identified. In addition, several authors have shown that many of these patients have type 2 diabetes, obesity, or both, compared with patients with cirrhosis of other etiologies (Caldwell et al, 1999; Poonawala et al, 2000; Sakugawa et al, 2003; Sanjeevi et al, 2003). An autoimmune etiology also has been proposed based on clinical and histopathologic findings (Ayata et al, 2002; Kaymakoglu et al, 1998), but autoantibodies may no longer be detectable in these cases (Carpenter & Czaja, 2002). Finally, the possibility of an as yet unknown viral infection or metabolic condition cannot be excluded in cryptogenic cirrhosis. Evaluation of patients with unexplained cirrhosis should include careful review of all prior liver biopsy specimens, especially those from several years prior. The histopathologic hallmark of the disease is the presence of eosinophilic globules of varying sizes in zone 1 hepatocytes in patients older than infants. Cirrhosis developing from 1-antitrypsin deficiency can be micronodular, macronodular, biliary, or mixed in pattern. The etiopathogenetic mechanisms leading to portal hypertension in these conditions, the clinical presentation, and the prognoses vary widely (Khanna & Sarin, 2014). Venous Outflow Obstruction in Budd-Chiari syndrome (see Chapter 88) is secondary to posthepatic vein obstruction and may have an acute or subacute clinical course with liver failure. Portal hypertension associated with infiltrative amyloid or hematologic disorders, such as leukemia, mastocytosis, and Gaucher disease, is believed to occur primarily at the intrahepatic sinusoidal level. Precirrhotic alcoholic hepatitis also may cause portal hypertension because of hepatocyte swelling, sinusoidal fibrosis, and central sclerosis, which may be more insidious clinically. The histopathologic features of several selected entities associated with noncirrhotic portal hypertension are discussed briefly. Obstruction of hepatic venous outflow (posthepatic obstruction) increases sinusoidal pressure and results in subsequent portal hypertension. Etiologic possibilities include congestive heart failure, narrowing or occlusion of large hepatic veins (Budd-Chiari syndrome; see Chapter 88), or obliteration of the terminal or sublobular hepatic veins. The lesion known as "sinusoidal obstruction syndrome" (or venoocclusive disease) that occurs in bone marrow transplant recipients is not included, however. Liver injury caused by congestive heart failure is characterized by zone 3 sinusoidal dilation (also known as congestion) and, when severe or acute, extravasation of red blood cells into the space of Disse, displacing hepatocytes from the hepatic cords. Hepatocellular necrosis is uncommon unless accompanied by systemic hypotension and hypoperfusion. The portal tracts are typically unremarkable and devoid of significant inflammatory cell infiltration. In long-standing cases, zone 3 hepatocytes exhibit atrophic change and are often no larger than a small nucleus, with markedly attenuated cell plates. Lipofuscin pigment and sinusoidal lining-cell iron may accrue, and perivenular fibrosis and bridging fibrosis also may develop. Rarely septal formation, reverse lobulation, and cardiac cirrhosis occur in refractory cases. Budd-Chiari syndrome results from obstruction at any level of the hepatic venous system between the liver and the inferior vena cava or the right heart atrium. It may result from a variety of thrombotic and nonthrombotic causes, among which hypercoagulable states secondary to myeloproliferative disorders are the most common (Menon et al, 2004). The histopathologic features of Budd-Chiari syndrome are similar to those of congestive heart failure, but acute onset also may give rise to a hemorrhagic appearance within zone 3, with extravasation of red blood cells into the space of Disse replacing hepatocytes within the cords, and significant hepatocyte loss. If unrelieved, Budd-Chiari syndrome results in cord atrophy, replacement by fibrosis, and eventual cirrhosis. The pathogenesis is unclear, but may involve intrahepatic portal venous thrombosis, leading to a microcirculatory disturbance in the liver that causes localized ischemia with atrophy and compensatory hepatocyte hyperplasia. The liver may be normal sized or enlarged when associated with a hematologic disease. On cut surface, the liver is diffusely nodular in appearance, with nodules ranging from 0. Nodular regenerative hyperplasia differs from cirrhosis in that fibrosis, if present, is minimal, and the portal tract architecture is usually unaltered. These characteristic features may be shown more easily on a wedge biopsy specimen and may be difficult to appreciate on a needle biopsy specimen. This connective tissue stain highlights the lesions of venoocclusivedisease(sinusoidalobstructionsyndrome). Congenital Hepatic Fibrosis Congenital hepatic fibrosis is a developmental disorder of the ductal plate predominantly seen in children and only rarely seen in adults. It is inherited in an autosomal recessive or, less commonly, autosomal dominant fashion and may be part of the spectrum of polycystic kidney and liver disease (Kamath & Piccoli, 2003). The affected patient may initially come to medical attention with portal hypertension, and the liver is usually enlarged and firm. Microscopically, the portal tracts are expanded by mature fibrous tissue and may show portal-toportal bridging fibrous bands that do not have the characteristic features of septa described earlier. Inspissated bile may be noted in these ductal lumina, and portal vein branches may be hypoplastic or actually decreased in number, but the hepatic artery branches may be hypertrophic and abnormally numerous (Desmet, 1992), suggesting arteriovenous anastomosis. This process affects the distal sinusoids, the intrahepatic portion of the hepatic venous system, and the terminal hepatic and sublobular veins. It has been stressed that the injury in this process is to the sinusoidal lining cells and surrounding hepatocytes. Oxaliplatin-based chemotherapy is increasingly recognized as a cause of marked damage to the sinusoids, with the subsequent risks of nodular regenerative hyperplasia, perisinusoidal and outflow vein fibrosis, and potentially liver failure (RubbiaBrandt et al, 2004) (see Chapters 71 and 100). Bridging fibrosis, cirrhosis, or nodular regenerative hyperplasia may ensue in recovery. Drugs and Toxins Chronic liver injury attributable to drugs or toxins may cause extensive fibrosis and cirrhosis, leading to portal hypertension. Well-known examples include methotrexate toxicity, long-term exposure to arsenic or vinyl chloride, and chronic hypervitaminosis A, resulting in hepatic stellate cell hypertrophy, hyperplasia, and activation. Drugs and toxins also induce noncirrhotic portal hypertension via different mechanisms, such as via venoocclusive disease, Budd-Chiari syndrome, and nodular regenerative hyperplasia. Herbal medicines are recognized as hepatotoxic agents in recent years (Stedman, 2002). A classic example found in a variety of herbal medicines is pyrrolizidine alkaloids, which can cause venoocclusive disease and portal hypertension. Schistosomiasis In endemic areas, infestation by Schistosoma japonicum or Schistosoma mansoni is a frequent cause of portal hypertension (Bica et al, 2000). The mechanism involves ova deposition in the portal venules, which incites a granulomatous inflammatory response and extensive, so-called clay pipe stem fibrosis, leading to hemodynamic disturbance. Definitive diagnosis can be made by showing the presence of schistosomal ova (see Chapter 73). Idiopathic Portal Hypertension As the name implies, idiopathic portal hypertension, also known as hepatoportal sclerosis or noncirrhotic portal fibrosis, is a rubric for disorders of unknown etiology, characterized by splenomegaly, long-standing portal hypertension in the absence of cirrhosis, and patent extrahepatic portal veins (Khanna & Sarin, 2014). Subtle histologic differences may exist among these terms, however, which may reflect different underlying etiologies. Although the etiology is obscure, there is a common association of idiopathic portal hypertension with other autoimmune disorders; immunologic disturbance is thus thought to be involved in pathogenesis. Bacterial infection leading to repeated stimulation also has been proposed as a candidate mechanism, but this remains speculative. In addition, some authors (Hillaire et al, 2002; Nakanuma et al, 2001) suggest that prothrombotic disorders and thromboembolism play a role in etiopathogenesis. A recent review suggests it is a combination of recurrent infections and thrombotic disorders that results in the condition (Khanna & Sarin, 2014). Idiopathic portal hypertension is essentially a diagnosis of exclusion; thus morphologic examination of liver tissue is imperative to rule out the presence of cirrhosis or other known etiology of portal hypertension, for instance, schistosomiasis. The pathologic changes in idiopathic portal hypertension are believed to represent the effects of long-standing portal venous insufficiency, which may or may not be related to the initiating factors (Nakanuma et al, 2001). Macroscopically, the liver may have a reduced mass, and the surface may be irregularly undulant or finely wrinkled, owing to subcapsular parenchymal atrophy (Krasinskas et al, 2005). The cut surface may show portal and perivascular fibrosis, dilation and wall thickening of the veins, and unusual distribution and approximation of the portal and outflow vascular structures. Microscopically, the normal relationship between the portal and central areas is distorted. The portal tracts are either abnormally approximated to each other or widely separated. The terminal hepatic vein may be eccentrically located in the lobule adjacent to a portal tract, and sometimes multiple ectatic tributaries (angiomatous lesions) are seen in a single lobule. Conspicuous fibrosis usually is present in the portal tracts, which may extend into the periportal areas and the lobules in a pericellular, perisinusoidal fashion. Common presentations include esophageal varices with variceal bleeding, portal hypertensive gastropathy, congestive splenomegaly with hypersplenism, and ascites with spontaneous bacterial peritonitis. Portal hypertension also contributes to the development of hepatic encephalopathy and hepatorenal syndrome. In general, portal hypertension secondary to a noncirrhotic etiology has a better prognosis than portal hypertension caused by liver cirrhosis because of maintained synthetic function in the former. Pathologic recognition of the characteristic morphologic features of many commonly encountered disorders underlying cirrhosis and noncirrhotic portal hypertension can aid in clinical management of patients with portal hypertension with and without cirrhosis. Hepatic Cirrhosis, Portal Hypertension, and Hepatic Failure Chapter 76 Cirrhosis and portal hypertension: pathologic aspects1160.

Arnon R: Life span of parasite in schistosomiasis patients treatment research institute cheap cyklokapron 500 mg otc, Isr J Med Sci 26:404 symptoms type 2 diabetes cheap 500mg cyklokapron with mastercard, 1990 medications or drugs cheap cyklokapron express. Augustine P medicine chest generic 500mg cyklokapron, et al: Recurrent pyogenic cholangitis (Oriental cholangiopathy) in Kerala treatment 7th feb cardiff buy cyklokapron once a day, J Gastoenterol Hepatol 3:515 treatment for vertigo discount 500mg cyklokapron with amex, 1988. Ballingall G: Practical observations on fever, dysentery and liver complaints as they occur amongst the European troops in India, Edinburgh, 1818, Balfour and Clark. Kong F, et al: Ascaris infestation of biliary tree mimicking gallbladder cancer, Dig Liver Dis 47:e3, 2015. In Guerrant R, et al, editors: Tropical infectious diseases: principles, pathogens, and practice, ed 2, Philadelphia, 2006, Elsevier, p 967. Sotoudehmanesh R, Yoonessi A: Diagnosis of Fasciola hepatica by endoscopic ultrasound, Endoscopy 35:1038, 2003. Wiwanitkit V: Amebic pericarditis: a summary of Thai cases, Anadolu Kardiyol Deg 8:305, 2008. Hydatidosis infects a large number of wild and domestic animals and humans, and the larval stage of the disease develops into a hydatid cyst (Brunetti et al, 2010). The life cycle of Echinococcus requires a definitive host, which is often a dog, and an intermediate host, which is commonly sheep. Humans become accidental intermediate hosts when they become infected after ingesting ova passed in dog feces. During the natural history of hydatid cysts in the liver, several complications may occur, the most frequent and severe of which are secondary infection of the cyst cavity, biliary fistula causing jaundice and cholangitis, and rupture of the cyst into the peritoneal or pleural cavity. Increasing migration and world travel require that clinicians, radiologists, and surgeons in developed countries have a clear understanding of the diagnosis and treatment of hydatid disease. In recent years, laparoscopic surgery has been used for uncomplicated cysts located in anterior liver segments. Percutaneous treatment techniques represent an important therapeutic advance in the treatment of hydatid disease. Medical treatment alone for univesicular cysts, and in conjunction with surgical and percutaneous techniques, is effective in selected patients. The characteristics of these four Echinococcus species are summarized in Table 74. Echinococcus has two developmental stages in its life cycle: the adult tapeworm, which is the sexual stage, and the cystic or infiltrative larval metacestode that reproduces asexually (Thompson & Jenkins, 2014). The eggs contain an embryo that is called an oncophere or hexcanth, which has three pairs of lancet-shaped hooklets. The adult tapeworm lives in the intestine of the dog, which is the most common definitive host for E. Worms release large numbers of infected eggs that pass out in the dog feces and contaminate soil, water, and plants. The eggs are ingested by the intermediate host (humans are accidental intermediate hosts); the eggs hatch and the embryo migrates through the intestinal wall into the portal system. Metacestodes, the larval forms of the parasite, may develop in almost any organ, including liver, lung, spleen, kidney, brain, and bone. Solitary cysts are localized to the liver in four of five patients and to the lung in one of five. The liver/lung ratio may vary from 2: 1 to 7: 1 or more (Larrieu & Frider, 2001). In the liver, the parasite develops into the larval stage, the hydatid cyst, which is filled with fluid and contains hundreds of protoscolices. For the life cycle to be complete, a canine host must ingest the hydatid cyst or its contents, which commonly occurs when infected sheep are slaughtered and organs containing hydatid cysts are fed to dogs. The disease occurs principally in sheepgrazing areas, especially where dogs are allowed to stray and eat uncooked viscera. Humans are accidental hosts and play little part in the transmission of the disease, making them so-called "dead-end hosts. Definitive host (adult form of tapeworm, Echinococcus granulosus) Outside the host (protoscolex) Outside the host (oncosphere or egg) (Richards, 1992; Watson-Jones & Macpherson, 1988). This domestic intimacy results in many of the population becoming infected when very young (Morris, 1992). In endemic areas, indigenous people are the primary high-risk group; however, aid workers and tourists are also at risk of infection, but less frequently. Human infection results from eating raw vegetables infected by the feces of dogs or by direct contact with dogs, mostly through the close contact of children with their pets. Some professions are particularly exposed: workers in slaughterhouses, veterinary, stock breeders, shepherds, tanners, and butchers. As a result of slow growth, cysts usually become symptomatic a few years after infection, in adolescence or early adulthood. Host immunity may overcome infection, resulting in a nonviable echinococcal cyst without the person ever becoming symptomatic.

This is notably better than the outcome obtained in the cited Italian multicenter study for the subgroup of medically treated patients (median overall survival of 86 months) symptoms 4 days post ovulation purchase cheap cyklokapron on line. Nevertheless symptoms diarrhea best purchase cyklokapron, the actual benefit of resection should be evaluated only in the light of the long-term results treatments buy 500mg cyklokapron fast delivery. We have found a very favorable 25% disease-free survival 10 years after resection medications journal safe cyklokapron 500mg, which emphasizes that only a curative resection has the ability to provide long-term disease-free survival treatment xanthoma purchase cyklokapron uk. In the modern era medications qid buy discount cyklokapron 500mg, and as for other oncologic disease, a multidisciplinary approach involving surgeons and medical oncologists should be advocated to "tailor" the appropriate therapy for the single patient. Zerbi A, et al: Pancreatic metastasis from renal cell carcinoma: which patients benefit from surgical resection Molino C, et al: Pancreatic solitary and synchronous metastasis from breast cancer: a case report and systematic review of controversies in diagnosis and treatment, World J Surg Oncol 12:2, 2014. Their cellular origin has been debated, but it is likely that these tumors arise from pluripotent stem cells in the pancreatic ductal/acinar system and not from the pancreatic islets themselves (Schimmack et al, 2011; Vortmeyer et al, 2004). These tumors are classified as functional, if they cause a specific hormonal syndrome, or nonfunctional. Homozygous deletion of the gene is lethal in mouse embryos (Bertolino et al, 2003, J. The most commonly mutated genes in this group of tumors are the tumor suppressors p53 (95%) and Rb (74%) (Yachida et al, 2012, J. Most patients are diagnosed between the ages of 60 to 80 years (Fraenkel et al, 2012). It is the most widely used grading system and the method used by most surgical pathology laboratories. Grade is determined either by the mitotic index or Ki-67 index (Bosman et al, 2010). Ki-67 labeling tags neoplastic cells with an antibody and then reports the percentage of cells that stain positively (Jamali et al, 2008) (Table 65. In addition to grade and the presence of distant metastases, age at diagnosis can also help stratify patients into prognostic categories, as an older age at diagnosis correlates with impaired survival (<55 years, 67. Endocrine Tumors Chapter 65 Pancreatic neuroendocrine tumors: classification, clinical picture, diagnosis, and therapy 999 of tumors. It is generally recommended that these patients be treated with chemotherapy, as their survival is poor, unless they have localized disease (Strosberg et al, 2010). The surgical management of these tumors is complex and discussed in greater detail later (see Chapters 66 and 67). The diagnosis can be confirmed by drawing plasma glucose, insulin, C-peptide, and proinsulin levels during a 72-hour fast. Malignant insulinomas tend to produce higher levels of insulin and proinsulin and thus more severe symptoms due to the fact that their metastases also secrete these hormones. To perform this test, the right and left hepatic veins are catheterized via a femoral puncture. Calcium is injected successively into the gastroduodenal, proximal splenic, superior mesenteric, and proper hepatic arteries. After each injection, venous blood is sampled from the hepatic veins at 30, 60, and 120 seconds, and a positive localization corresponds to a twofold increase in hepatic vein insulin levels (Doppman et al, 1993). Gastrinoma In 1955, Zollinger and colleagues published their case series detailing the clinical courses of two patients with gastric acid hypersecretion, severe peptic ulceration, and pancreatic tumors. The syndrome would be named for these authors, and the tumors would eventually be known as gastrinomas. The extraordinarily high levels of gastrin secreted by these tumors are the cause of the recurrent peptic ulcers, diarrhea, and reflux esophagitis experienced by most patients and also cause the thickened mucosal folds in the stomach that are a hallmark of the disease (Anlauf et al, 2006, Kulke et al, 2010). The majority of gastrinomas are considered malignant (60%) and have spread to regional lymph nodes by the time they are diagnosed. Liver metastases are often associated with gastrinomas that arise in the pancreas (Anlauf et al, 2006). Laboratory diagnosis of the disease requires demonstration of hypergastrinemia and abnormal gastric acid secretion. If the gastrin level is 10 times normal and the gastric pH is less than 2, the diagnosis is confirmed (Ito et al, 2012). If results are equivocal, a secretin or glucacon stimulation test can be performed, as gastrinomas frequently express both of these receptors and respond by secreting abnormally large amounts of gastrin to the injected reagent (Kulke et al, 2010, Shibata et al, 2013). In the rare Glucagonoma Only about 400 cases of glucagonomas have been reported in the literature (Sahoo et al, 2014). The syndrome may include glucose intolerance, cholelithiasis, weight loss, diarrhea, steatorrhea, or anemia. These tumors may arise either in the pancreas (56%) or duodenum and may be more aggressive if intrapancreatic (Nesi et al, 2008). If discovered in this context, they are less likely to be malignant (Williamson et al, 2011). Patients may present with intermittent abdominal pain, pancreatitis (Kuo et al, 2008), and some patients may develop glucose intolerance (Maxwell et al, 2014). The apex is at the junction of the cystic duct and common bile duct, the inferior aspect lies at the junction of the second and third parts of the duodenum, and the medial extent lies at the junction of the head and body of the pancreas. Rates calculated from single institutions may be lower due to a referral bias for functional tumors at academic medical centers. The most common symptoms of the disease are glucose intolerance, migratory necrolytic erythema, and weight loss (Kulke et al, 2010). If not properly identified and treated, patients will eventually succumb to renal failure secondary to hypovolemia (Fabian et al, 2012). Chromogranin A levels have been shown to correlate with tumor burden, and posttreatment decreases correlate with favorable outcomes, whereas rising levels may suggest recurrent or progressive disease (Kanakis et al, 2012). Its sensitivity for tumors greater than 2 cm is 80% to 100% (Kuo et al, 2014), although it is more sensitive for hepatic metastases than it is for primary tumors (Chiti et al, 1998; Sundin et al, 2009). Arterial phase of a contrast-enhanced computed tomography of the abdomen showing an early enhancing pancreatic neuroendocrine tumor in the head and uncinate process of the pancreas (white arrow), with a necrotic node medially (red arrow). These lesions will wash out in the venous and delayed phases (Bushnell et al, 2011). It has a sensitivity of 79% to 82% (Rosch et al, 1992) and can detect tumors as small as 2 to 3 mm (Kuo et al, 2014). In many centers, these small tumors are observed with serial imaging and resected if they show signs of progression. Nine percent of the operative group had positive nodes and a median tumor size of 2. Thus a reasonable number of these small tumors may progress beyond the point of being able to offer a patient curative surgery. A, Intraoperative view of a pancreatic neuroendocrine tumor located in the body of the pancreas. Therefore the optimal management of nonfunctional tumors less than 2 cm is unclear. In patients with significant comorbidities, tumors less than 1 cm without imaging findings suspicious for invasion or nodal metastases, or evidence of an increase in size over time, it seems reasonable to observe these tumors. In the series from Lee and colleagues (2012), 46% of the surgically treated patients had some sort of perioperative complication, the most common of which was development of a pancreatic fistula. As larger tumors commonly invade the splenic vein, splenectomy is often performed, although in cases where the tumors are small and do not invade the vein, splenic preservation should be considered. This may allow for preservation of the immunologic and hematologic function of the spleen. In the 2011 retrospective follow-up study at Massachusetts General Hospital of 158 patients who received the Warshaw procedure between 1986 and 2009, only 1. Diagram of key concepts in spleen-preserving distal pancreatectomy (Warshaw procedure). Top, the pancreas is mobilized by incising the retroperitoneum along the left inferior margin and opening the avascular plane behind it. Dissection is carried to the left, past the tip of the pancreas to isolate the splenic vascular pedicle. Bottom, the splenic artery and vein can be ligated and divided individually (as shown) or together, then body and tail of pancreas removed. To improve patient recovery, distal pancreatectomy may be performed laparoscopically. A recent meta-analysis examined 18 studies that included 1814 patients with pancreatic tumors amenable to resection via distal pancreatectomy. Forty-three percent of patients underwent laparoscopic resection, and the rest were approached with laparotomy. The laparoscopic group had a shorter length of stay, less blood loss, and fewer postoperative complications. Encouragingly, there was no difference in margin positivity, postoperative pancreatic fistula development, or mortality, although there did seem to be a trend toward fewer lymph nodes being sampled with the laparoscopic approach (Venkat et al, 2012). Some surgeons have begun performing robotic distal pancreatectomy, and although they anecdotally report good outcomes, insufficient evidence has been gathered to support the routine use of this modality in oncologic cases (Cirocchi et al, 2013). One argument against resection is that the patient is unlikely to obtain a curative (R0) resection and thus bears the risk of a large operation without the reward of improved survival. Vascular invasion or encasement on preoperative imaging should therefore not be considered as contraindicating resection. Hill and colleagues (2009) compared patients with all stages of disease who underwent surgical resection with those who did not. One must keep in mind that there is significant selection bias in each of these studies, and thus the benefit of resection cannot be assumed; however, the results are encouraging for operative resection, and it is unlikely that randomized trials will address these questions. B, Enucleation of a pancreatic neuroendocrine tumor located at the superior aspect of the neck of the pancreas. The tumor (circle) is mostly detached at this point and rolled inferiorly over the pancreas. In a retrospective analysis of the Surveillance Epidemiology and End Results database, Hill and colleagues (2009) demonstrated that overall survival of pancreatic neuroendocrine tumor patients can be improved if surgical resection of the primary tumor can be performed. Patients in whom surgery was recommended, but not performed (including palliative procedures), had median survival on par with patients in whom surgery was not offered. Much debate exists as to how to treat these tumors surgically, as biochemical cure is rare and recurrence is frequent. Endocrine Tumors Chapter 65 Pancreatic neuroendocrine tumors: classification, clinical picture, diagnosis, and therapy 1005 gastrinomas (Sugg et al, 1993). Patients were followed for a median of 32 months (range, 4 to 110 months), and none that had undergone resection developed metastatic disease (Libutti et al, 2000). Although curative resection is rarely achieved, surgical reduction of hepatic tumor burden may diminish symptoms related to functional tumor syndromes and also delay liver failure secondary to hepatic replacement (Niederhuber et al, 2006). Thus it is generally accepted that surgical debulking of hepatic disease is prudent for patients in whom it is estimated that an 80% to 90% reduction of metastatic burden can be made. The gold-standard cytoreductive technique is formal segmental resection (Mayo et al, 2010; Norton et al, 2003; Sarmiento et al, 2003), although wedge resection, enucleation, and ablation (radiofrequency or microwave ablation, hepatic artery embolization) (see Chapter 30) are also valuable techniques and have the advantages of preserving a maximal amount of normal liver parenchyma, with lower complication rates. Ablative techniques are best used for small metastases (<5 cm) and can be used to treat many lesions in one setting (Elias et al, 2009; Eriksson et al, 2008; Zappa et al, 2012). Because most patients with liver metastases have large, multiple tumors, hepatic artery embolic therapy is often the most rational approach.

Although it is reasonable to check bile cytology if the patient needs to undergo endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography treatment tinnitus cheap 500mg cyklokapron, for the reasons stated earlier medicine escitalopram cheap cyklokapron 500mg overnight delivery, a deliberate attempt to make the diagnosis this way is unwarranted medications with sulfur buy line cyklokapron. Sensitivity of bile cytology has been reported to be approximately 75% (Akosa et al medicine to increase appetite purchase cheap cyklokapron online, 1995; Arora et al treatment 02 academy buy cyklokapron 500 mg lowest price, 2005; Mohandas et al treatment as prevention order on line cyklokapron, 1994; Naito et al, 2009). It utilizes tumor depth (T), nodal status (N), and the presence of metastases (M) to place patients into four stages based on pathologic and radiographic findings. T1a tumors invade the lamina propria of the gallbladder; T1b tumors invade the muscular layers. T2 tumors spread through the muscular layers into, but not beyond, the connective tissue layers. Anatomically, this translates to spread into the gallbladder serosa or cystic plate, but not the liver parenchyma. T3 lesions spread through the gallbladder serosa and invade the liver, extrahepatic bile ducts, or perihepatic organs. T4 lesions invade multiple extrahepatic organs and/or major vessels and generally reflect locally unresectable disease. N1 nodes are lymph nodes adjacent to the cystic duct, bile duct, hepatic artery, and portal vein. The only polypoid lesions that have malignant potential and are associated with a significant rate of harboring malignancy are adenomatous polyps. Other benign lesions, such as fibromas, lipomas, hemangiomata, cholesterol polyps, inflammatory polyps, and adenomyomas, are not known to be associated with malignant potential. Adenomyomatosis, defined as extension of Rokitansky-Aschoff sinuses through the muscular wall, is common and often diagnosed by ultrasound criteria (Stunell et al, 2008). Cholesterol polyps are the most common gallbladder polyp but are not easily differentiated from other lesions of the gallbladder wall without pathologic analysis. The relevant clinical question is which lesions mandate a cholecystectomy in an asymptomatic patient. Numerous clinical reviews have identified factors associated with malignancy in gallbladder polyps. The most consistent predictors are single polyps, size greater than 1 cm, and age older than 50 (Shinkai et al, 1998; Yeh et al, 2001). Although some authors have recommended cholecystectomy for any patient with fewer than three polyps (Shinkai et al, 1998), we generally recommend cholecystectomy for any polyp greater than 1 cm because the risk of malignancy for polyps less than this size, regardless of number, is exceedingly low. Eighty patients underwent cholecystectomy, and a single patient had carcinoma in situ in a 13 mm gallbladder polyp. The exception to this recommendation of resection only for polyps larger than 1 cm is for those arising in the setting of primary sclerosing cholangitis. The prevalence of gallbladder cancer is higher in this patient population, and polyps beyond 0. For gallbladder polyps found in the context of abdominal symptoms, another cause of the pain should be sought. Most polyps are asymptomatic, and if no other cause is found to explain the abdominal symptoms, a cholecystectomy should be performed. Patients with polyps less than 1 cm who are asymptomatic should be followed with serial ultrasound to rule out the possibility of a growing adenomatous polyp. Long-term follow-up of stable polyps does not seem warranted according to a multiinstitutional registry of approximately 70,000 patients who had gallbladder ultrasound. They reported a prevalence of gallbladder cancer with polypoid lesions of the gallbladder equal to 0. Conversely, Kubota and colleagues (1995) reported that on periodic ultrasound 4 to 12 months after the original ultrasound, polyps grew 1. Thus our recommendation is for ultrasound follow-up at 12-month intervals for 2 to 3 years, then consideration of no additional imaging if the polyp is stable and there are no new or suspicious clinical symptoms. For polyps mandating cholecystectomy (>1 cm) without obvious evidence of malignancy on imaging, it has been considered controversial whether to perform an open or a laparoscopic cholecystectomy. Our practice is to perform a laparoscopic cholecystectomy for polyps greater than 1 cm when there is no obvious ultrasound concern for malignancy, with the caveat that all such lesions must be examined by frozen-section histology. There is a low threshold to convert to an open procedure, and that definitive resection will be performed if invasive cancer is suspected intraoperatively. The reasons for this policy include (1) the overall low risk of malignancy, (2) simple cholecystectomy is curative for T1a tumors, and (3) laparoscopically resected early-stage tumors do not appear to have a worse outcome if a definitive resection is performed subsequently and there is no perforation of the gallbladder (Fong et al, 2000). Every patient undergoing a cholecystectomy for polyps should be carefully counseled as to the risk of malignancy and the possibility of needing a liver resection and lymph node dissection at the same sitting. Gallbladder Carcinoma Incidentally Discovered During or After Routine Cholecystectomy Gallbladder cancer is found in 0. If the diagnosis of gallbladder cancer is made by frozen section in the operating room, the surgeon should prepare for a curative resection, with possible liver and portal lymph node dissection. If the surgeon is not comfortable with this extent of surgical resection, no further dissection should be performed, and the patient should be transferred to an experienced hepatobiliary surgeon. Malignant Tumors Chapter 49 Tumors of the gallbladder 797 primary curative resections (Fong et al, 2000). However, these findings are subject to significant selection bias because the majority of patients diagnosed with gallbladder cancer after routine cholecystectomy have early-stage tumors. Ouchi and associates (2002) reported on 498 patients diagnosed with gallbladder cancer after laparoscopic cholecystectomy and found 34% had T1a tumors, 14% T1b, 41% T2, 8% T3, and 2% T4 tumors. Once the diagnosis is made, all patients should undergo a complete staging workup, as described previously. If patients have resectable disease with no contraindications to additional surgery, a second operation should be considered. With T1a tumors, if margins are negative, standard cholecystectomy cures 85% to 100% of patients, with the majority of reports showing cure rates closer to 100% (Shirai et al, 1992a; Yamaguchi & Tsuneyoshi, 1992). In the past, there was controversy regarding the optimal surgical management of T1b tumors. Principe and colleagues (2006) demonstrated a 50% 1-year survival in patients with T1b gallbladder cancers after simple cholecystectomy (Shirai et al, 1992a). Other series, however, report overall survival rates for T1b tumors that range from 30% to 75% at 5 years (Hari et al, 2013; Kang et al, 2007). Most recent series, however, show an incidence of residual carcinoma associated with T1b tumors that supports routine reoperation and definitive resection in most of these patients. When a patient who has undergone a noncurative cholecystectomy is referred, careful workup is required. Reviewing the precholecystectomy ultrasound (or any other imaging) is prudent to try to locate the location of the tumor. It is also wise to discuss the case personally with the operating surgeon to assess the specific intraoperative findings. The specimen should also be carefully re-reviewed pathologically to assess T stage and margins (specifically the cystic duct margin). Given the results previously discussed, re-resection is recommended for all patients who are medically fit with T1b or greater level of invasion. Although the role of re-resection in patients with T1b tumors has been controversial, data from several centers now support reoperation and definitive resection in this setting. Routine resection of the bile duct has not been associated with improvements in survival but is generally required for a complete resection in patients with a positive cystic duct stump margin (Pawlik et al, 2007; Sakamoto et al, 2006). If there is concern regarding the cystic duct stump margin, the stump can often be examined with frozen section, which avoids the need for bile duct resection. In a series reported by Butte and colleagues (2014), patients with incidental gallbladder cancer undergoing definitive resection, T stage at initial cholecystectomy was the only independent predictor of residual disease (T3, 70%; T2, 48. The presence of residual disease was associated with significantly reduced disease-free and disease-specific survival. A multiinstitutional study of 115 patients reported residual disease at any site in the abdomen during re-resection for 38% of T1, 57% of T2, and 77% of T3 tumors (Pawlik et al, 2007). Residual invasion of the liver parenchyma in the gallbladder bed was found in 0% of T1, 10% of T2, and 36% of T3 tumors. The benefits of discovering occult metastases at laparoscopy compared with laparotomy are obvious and include less pain, less morbidity, quicker hospital discharge, more rapid resumption of normal activity, and earlier start of other therapies. The yield for staging laparoscopy for initial evaluation of gallbladder cancer is high, and this examination should be used routinely. Of 44 patients in whom staging laparoscopy was used, Weber and colleagues (2002) reported a 48% yield, and all these patients were spared laparotomy. Despite this high yield, the examination still missed an additional 15 patients, suggesting room for further improvement in detecting unresectable disease. In a subsequent study evaluating patients undergoing reexploration for definitive resection of incidentally found gallbladder cancer, Butte and colleagues (2011a) found a 4% yield of staging laparoscopy. Factors that increased the yield of staging laparoscopy included poor tumor grade, positive cholecystectomy margin, and increasing T stage. Extent of Resection by Stage An early description of a rational approach to the surgical treatment of gallbladder cancer was provided by Glenn and Hays in 1954. They recommended a wedge resection of the gallbladder bed and regional lymphadenectomy of the hepatoduodenal ligament. The late presentation and generally poor prognosis, compounded by the rarity of the disease, have resulted in significant controversy and confusion about the best surgical approach to gallbladder cancer since that time. For the same stage of disease, surgeons have recommended varying operations, from a simple cholecystectomy to combined major hepatectomy, bile duct resection, and pancreaticoduodenectomy. A survey of gastrointestinal surgeons from the early 1990s showed that 49% recommended lymph node dissection, and 64% recommended some form of liver resection for stage T2 to T4 disease (Gagner & Rossi, 1991). In recent years, however, much has been learned, and consistent approaches have been met with some success. Despite the lack of definitive evidence, a rational approach to gallbladder cancer can be devised and should depend on the stage of the disease, location of the tumor, margin status (if previous cholecystectomy), and whether a prior noncurative cholecystectomy has been performed. When considering extensive surgery, the morbidity must be weighed carefully against the long-term outcome data. Despite the confusion about the extent of resection for gallbladder cancer, strong evidence supports the use of liver resection and regional lymphadenectomy for T2 and T3 tumors without distant metastases. The modest improvements in survival over time probably reflect the better selected surgical resections applied to this overall minority of patients (Grobmyer et al, 2004). In a study from Toronto, two separate time periods were analyzed and showed improved survival (median survival increased from 9 to 17 months) in completely resected patients. In the second time period, there was increased use of liver resection and regional lymphadenectomy, and the authors attributed the improved survival to this strategy (Dixon et al, 2005). In general, we recommend the following principles based on the literature and our own data. T1b tumors, although associated with good long-term survival after simple cholecystectomy, are Staging Laparoscopy Staging laparoscopy is an important consideration with surgery for intraabdominal malignancy (see Chapter 23). A negative cystic duct margin must be ensured, and a bile duct resection, if required to obtain a negative margin for a T1 tumor, is recommended. If the tumor extent is such that there is documented or suspected invasion of hepatic inflow vascular structures, an extended right hepatectomy may be necessary to clear all tumor, and this is appropriate in a healthy patient with no evidence of distant disease. Additionally, in patients with involvement of right hepatic inflow, it is reasonable to consider systemic chemotherapy in advance, which not only allows time to assess response to treatment, but also allows for identification of disseminated disease in this high-risk group. A negative margin at the cystic duct should be assessed, and if necessary, a bile duct resection should be performed. It is important to stage the patient carefully at operation, and major resections should be abandoned if distant nodal (retropancreatic or celiac) or other metastases are found. Liver Resection It is now accepted that some degree of liver resection is appropriate to treat gallbladder cancers beyond the very early T1a stage. Recommendations have ranged from a limited 2-cm wedge resection of the gallbladder bed to a routine extended right hepatectomy. The goal of the liver resection is to ensure a margin of resection of approximately 1 to 2 cm because there is no serosal surface on the liver side of the gallbladder. Intraoperative ultrasound can be helpful in delineating vascular anatomy and guiding the resection. Major bleeding can occur from the distal branches of the middle hepatic vein, and these must be carefully controlled. This may be the case for large tumors invading the right portal pedicle or tumors of the lower end of the gallbladder encroaching on the porta hepatis. Again, these patients should be considered for neoadjuvant systemic chemotherapy because they are at risk for disseminated disease progression. Isolated invasion of local organs (stomach, duodenum, and colon) in the absence of distant metastases requires a local resection, which is reasonable to perform to ensure tumor clearance. In patients with a prior noncurative cholecystectomy, the preoperative ultrasound should be reviewed to find the tumor, which can guide the resection. In this series, 20% of patients had direct invasion of other organs and had concurrent en bloc resections. The principal finding of this analysis was that the stage of the tumor, rather than the extent of resection (given a margin-negative resection), was the overwhelming determinant of long-term survival. Thus current practice is to perform only the extent of hepatic resection necessary to achieve tumor clearance. Lymph Node Dissection Studies of the lymphatic drainage of the gallbladder have been performed and reviewed earlier in this chapter (Shirai et al, 1992c). As in the extent of liver resection, there has been wide variability in the recommendation for the extent of lymphadenectomy, ranging from excision of the cystic duct node to a complete portal clearance combined with pancreaticoduodenectomy (Matsumoto et al, 1992). Groups from Japan have reported some success for the treatment of extensive gallbladder cancer with hepatopancreaticoduodenectomy even in the face of extensive nodal metastases (Sasaki et al, 2002). The recommendation for these extensive procedures is based on the fact that early lymph node metastases to the retropancreatic/ interaortocaval nodes are common, and a pancreatic resection presumably improves the ability to clear these nodes. The more important question is whether the increased risk of such an approach is justified by the outcome.

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