Incidental Findings at Surgery—Part 1

Incidental Findings at Surgery—Part 1 Incidentalomas of the Liver Finding incidental liver lesions is a regular occurrence. Although many are benign, a specific diagnosis is necessary. Table 1 outlines the differential diagnosis of the commonly occurring incidentalomas of the liver.

Cystic Lesions of the Liver Simple cysts of the liver are very common incidental findings. In most cases they are small (usually ⬍5 cm), but they may be quite large, up to 20 cm in diameter. They are more common in women between 40 and 60 years of age and usually appear as thin-walled, well-circumscribed cystic lesions that usually contain clear fluid. Histologic examination of the wall demonstrates cuboidal epithelium and fibrous stroma. Occasionally, spontaneous hemorrhage or infection may occur, but these situations are more likely related to previous percutaneous intervention. Treatment is reserved for symptomatic cases. Thus when found incidentally, no treatment is necessary. Options for treatment include laparoscopic or open de-roofing. Percutaneous aspiration and sclerotherapy may be an option, but cyst recurrence is a common problem when this approach is taken.1,2 Polycystic liver disease is a rare, autosomal dominant condition that is usually found in association with polycystic kidney disease (Fig 1). Advanced disease may cause chronic pain symptoms, sometimes requiring surgery for de-roofing. Liver failure may rarely develop over time or after resection and liver transplantation is occasionally required, although usually for the debilitating symptoms associated with massive liver enlargement.3 Another cystic liver lesion that can be encountered is biliary cystadenoma. This is an uncommon tumor but considered to be a premalignant condition. Cystadenocarcinoma is its malignant form. Biliary cystadenoma is more common in women, usually seen in the third to fifth decade. It is commonly a multiloculated cystic lesion with a thickened wall and appears quite different from a simple cyst. Histologically, the cyst is lined with biliary epithelium. If there are polypoid projections of epithelium into the lumen, cystadenocarcinoma should be suspected. Biliary cystaCurr Probl Surg 2008;45:325-374. 0011-3840/2008/$34.00 ⫹ 0 doi:10.1067/j.cpsurg.2008.01.004

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TABLE 1. Incidental liver lesions Parenchymal Fatty liver disease Cirrhosis Benign Simple and complex cysts Hemangioma Hepatic adenoma Focal nodular hyperplasia Nodular regenerative hyperplasia Focal fatty change Angiolipoma Malignant Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Metastases

FIG 1. Operative photograph of a liver explant, demonstrating polycystic liver disease, from a patient undergoing a liver transplant for intractable pain.

denoma in itself is a premalignant lesion and should be resected or enucleated, regardless of symptoms. However, if there is any suspicion of cystadenocarcinoma from preoperative imaging, a formal liver resection is the appropriate treatment. When encountered in the operating room, 326

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biopsy or cyst drainage should probably not be attempted outside of the hands of a liver surgeon. Follow-up should include imaging such as magnetic resonance imaging (MRI) or multislice computed tomography (CT), so surgical excision may be planned.4,5

Solid Liver Lesions Benign Tumors. Hemangioma of the liver is essentially a benign tumor of the blood vessels. It appears as a dark-purplish lesion that may often be visible on the liver surface. It is easily compressible and may be spongy to palpation. Size varies from 1 cm to 20 cm or larger. “Giant hemangioma” refers to lesions larger than 5 cm in diameter. Histologically, these tumors are made up of vascular channels lined with endothelial cells. They have no malignant potential and are usually asymptomatic, and when encountered in the operating room there need be no immediate concern or treatment required. Biopsy is generally not recommended as bleeding may occur. Spontaneous bleeding from even very large hemangiomas is extremely rare. Pain is the usual indication for surgery, but this occurs in fewer than 5% of cases. An unusual clinical entity associated with giant hepatic hemangioma is Kasaback-Merritt syndrome, characterized by thrombocytopenia and disseminated intravascular coagulopathy (DIC), and may be triggered by a surgical procedure.6 Hemangiomas can be followed up by MRI if there is any concern about the diagnosis, as they have very characteristic bright signal intensity on T2-weighted images with early peripheral enhancement after IV contrast. Ultrasound is also useful in the diagnosis and is a less expensive option. Some hemangiomas may have estrogen receptors and stopping oral contraceptives is recommended. Subsequent follow-up imaging is recommended by some to demonstrate stability. Giant hemangiomas may require closer follow-up and may occasionally require surgical resection. Indications for treatment include large symptomatic lesions or atypical lesions not confirmable as hemangioma by imaging, and options include surgical enucleation or standard resection. Transarterial embolization has been reported anecdotally, although data supporting this approach are limited.7,8 Focal nodular hyperplasia (FNH) appears as an irregular firm lobulated mass that is paler than the liver parenchyma. It can sometimes be difficult to differentiate FNH from other tumors by visualization. It is usually on or near the liver surface and often small, but any size may be encountered. They are commonly encountered in women of childbearing age and are associated with the use of oral contraceptives. If excised and bisected, Curr Probl Surg, May 2008

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there is often central scarring, which is regarded as a classic finding. Microscopically, sheets of normal hepatocytes and bile ductules, with inflammatory infiltrates and abnormal vasculature, are present. There are usually fibrous bands radiating from the central fibrous scar. Focal nodular hyperplasia is not a premalignant condition and observation over a period of time to demonstrate stability is usually all that is required. Asymptomatic FNH does not require resection. If found incidentally, intraoperative consultation with a liver surgeon and/or biopsy should be performed. In up to 40% of cases, however, a biopsy is nondiagnostic, but should rule out malignancy. Imaging by an experienced MRI radiologist may confirm the diagnosis, but if there is doubt resection may rarely be required to rule out malignancy. Follow-up imaging to determine stability is an alternative option.1,2,9 Hepatic adenoma (HA) is a benign proliferation of hepatocytes encountered more commonly in women of childbearing age. There is a strong association with the use of contraceptives. Other risk factors include anabolic steroid use and glycogen storage diseases. They are smooth, round, well-circumscribed, pale yellow lesions. Hepatic adenoma is often single but may be multiple, sometimes containing hemorrhagic or necrotic areas. They also vary in size and often have large subcapsular vessels. Rarely, a condition called adenomyosis (⬎10 adenomas) may present (Fig 2). It is important to differentiate this condition from multifocal hepatocellular carcinoma (HCC) or metastases. Microscopically these lesions are composed of plates of normal hepatocytes, without ductules as in FNH, and few Kupffer cells. They are hypervascular tumors, commonly subcapsular in location, and are at a definite risk of spontaneous hemorrhage. The other important feature of hepatic adenoma is the risk of malignant transformation to HCC. The risk of rupture is between 15% and 30% and associated with increasing size.9 The exact risk of malignant transformation is unknown but has been demonstrated even in tumors that regress.10 In cases of adenomyosis, tumors may be numerous and resection may be impossible. Because of the risk of increased rupture and malignant transformation in these cases, liver transplantation may occasionally be indicated.2,11 When encountered incidentally in the operating room, biopsy should help with the diagnosis, although it is sometimes difficult to differentiate adenoma from welldifferentiated HCC. All patients should be seen by a liver surgeon. Because of the risks, the gold standard treatment is surgical resection for large tumors, if this can be performed safely. With small tumors (⬍5 cm) conservative management may be considered. Stopping oral contraception and serial ultrasounds can be performed for follow-up.1,9 For tumors 328

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FIG 2. Hepatic adenomyosis. This picture is taken from a young girl with unresectable multiple hepatic adenomas with rupture. Following evaluation, continued growth and intrahepatic hemorrhage ultimately led to liver transplantation. The picture demonstrates classic multifocal adenomas.

with active hemorrhage, hepatic artery embolization should be used for initial treatment with planned resection to follow later.4 Nodular regenerative hyperplasia (NRH) is a benign condition characterized by nodular proliferation without cirrhosis. Because this condition can be diffuse, NRH can resemble a cirrhotic liver. However, pathologically bridging fibrosis with microscopic nodule formation is absent and the nodules are made up of hyperplastic hepatocytes without fibrosis. They can be difficult to differentiate histologically from HA but NRH is multifocal and HA is usually only a single tumor site or several discrete nodules. Biopsy of the lesion is advisable, especially if there is concern for cirrhosis. Most patients are asymptomatic, but a few may develop compression of the portal vein and symptoms of portal hypertension. Patients with these symptoms need appropriate treatment by a hepatic specialist.1,12 Von Myenberg’s complexes are bile duct hamartomas and are extremely rare. They are characterized histologically by disorganized bile ductules surrounded by fibrous stroma. They can be confused with Curr Probl Surg, May 2008

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FIG 3. Operative photograph demonstrating hepatocellular carcinoma (HCC; arrow) in a noncirrhotic liver. This patient underwent successful hepatic resection.

metastatic disease on gross visualization. If there is diagnostic uncertainty, biopsy should be considered and is usually diagnostic.13 Focal fatty change is an area of discrete fatty change within the liver. Focal fatty change is usually seen as a wedge-shaped area and is different from steatosis because of its focal nature (Fig 3). It can be associated with obesity and/or diabetes. There is usually no treatment or follow-up required. Angiolipomas are rarely observed in the liver, but they can be confused with HCC and can pose a diagnostic challenge.14 If there is concern, any suspicious lesion should be biopsied. In unusual circumstances large symptomatic tumors may require surgical resection. Malignant Lesions. Hepatocellular carcinoma (HCC) in the setting of a normal liver usually appears as an irregular mass that may be adherent to the surrounding diaphragm or other structures (Fig 4). It may resemble HA or on the surface FNH, so differentiation from these lesions is necessary. Hepatocellular carcinoma more commonly develops in the presence of cirrhosis, usually associated in approximately 80% of cases. However, differentiation from a regenerative nodule, a dysplastic nodule, or HA may be difficult. If HCC is suspected either in a cirrhotic or noncirrhotic patient, the nontumor liver should also be biopsied. In the postoperative period, all patients should have hepatitis serologies as330

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FIG 4. Operative photograph of an intrahepatic cholangiocarcinoma (arrow). The gross appearance does not distinguish a primary liver tumor from secondary malignancy.

sessed, MRI, and tumor markers. These patients, regardless of the presence or absence of cirrhosis, should be managed in a specialized liver center. In a noncirrhotic liver, the differentiation of HCC from a secondary malignancy or primary cholangiocarcinoma may not be possible without biopsy. The importance of differentiating primary versus secondary in the noncirrhotic liver is that if the lesion is a metastasis, the primary must be located. If a suspicious lesion is discovered during laparotomy for another indication, and the primary tumor is not obvious, a positron emission tomographic (PET) scan combined with gastroscopy and colonoscopy is advised in the postoperative period. Patients with HCC should be managed in a specialist center, because treatment options range from resection to embolization to liver transplantation under selected circumstances. The indication for a specific treatment depends on not only the stage of the malignancy but also the presence or absence of cirrhosis. Cholangiocarcinoma may be present in 1 of 2 types: hilar infiltrating tumors that usually manifest with obstructive jaundice, or intrahepatic cholangiocarcinoma, usually manifesting as a mass lesion in the liver without biliary obstruction or jaundice (Fig 5). Sometimes associated lobar atrophy is present and usually implies vascular involvement. Curr Probl Surg, May 2008

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FIG 5. Focal fatty change demonstrated here (arrow) is of no consequence and need not be biopsied.

Management should include detailed imaging, tumor marker assessment (eg, CA19-9, carcinoembryonic antigen [CEA], alpha feto protein), elimination of occult distant metastases, followed by resection if appropriate or oncological referral if surgery is not an option. Metastatic tumors usually have the appearance of an irregular mass if they are on the surface of the liver. They may be single or multiple. They range from subcentimeter surface nodules (usually peritoneal deposits on the liver surface) to large, 10- to 15-cm, irregular tumors. The most common tumor to metastasize to the liver is colorectal cancer, but any tumor can theoretically metastasize here. Clearly, the correct management is the main issue if an incidental malignancy is found. Differentiation of primary versus secondary malignancy is necessary so an occult primary is not missed. Biopsies should be taken when a suspicious lesion is discovered in the operating room. If the abdomen is open, a full laparotomy should be performed to search for a possible primary, with or without an intraoperative consult from a liver surgeon. Postoperatively, the patient should be evaluated from a primary and secondary perspective, with a triphasic CT and consideration of PET imaging to look for an occult primary with or without gastroscopy and 332

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colonoscopy depending on the results of the PET. Tumor markers may also help locate a potential source for the primary tumor.

Liver Conditions Encountered Incidentally Nonalcoholic fatty liver disease (NAFLD) covers a progressive spectrum of liver pathology, from hepatic steatosis where there is accumulation of lipid within the liver, to inflammation and fibrosis characteristic of nonalcoholic steatohepatits (NASH), which may progress to cirrhosis. Hepatic steatosis is the accumulation of lipid within the liver. It often accompanies weight gain and obesity. Other causes include excessive alcohol use, hepatitis C infection, and hepatotoxin exposure. Although the pathogenesis is not fully elucidated, it is thought that steatosis induces a proinflammatory state, which can result in steatohepatitis and progression to fibrosis. Grossly the liver appears pale and yellow (Fig 6) if severe, and if milder disease is present when the liver parenchyma is compressed, the presence of fat can often be appreciated. In the operating room, a core biopsy should always be taken in the stable patient if this is suspected. If the extent of steatosis is mild, the primary care physician should be made aware. If severe, however, referral to a hepatologist for long-term management is advised. This includes dietary modification and exercise programs. For those with severe disease and morbid obesity, bariatric surgery has been shown to reduce the amount of steatosis present. However, because of the lack of randomized trials, there is some debate about the effectiveness of reversing fatty liver disease, especially when steatohepatitis or fibrosis is present. Nonetheless, follow-up is necessary in the majority of cases.15-19 Cirrhosis is a state of hepatic architectural and vascular disarray that is a common endpoint of many pathological processes. The cirrhotic liver functions less efficiently, resulting in a low tolerance for any traumatic insult such as surgery. The parenchyma is transformed into nodules of hepatocytes surrounded by fibrous connective tissue. It is never focal and proceeds through varying degrees of fibrosis. Cirrhosis appears as a diffusely nodular liver, with a micro- or macronodular appearance. Incidental cirrhosis at surgery implies that the patient is well compensated and probably in Child’s class A. If the patient is not having liver surgery, then a liver biopsy should be performed. Some nonliver surgeons may be concerned about liver biopsy if the international normalized ratio (INR) is elevated, but bleeding is usually easily controlled with cautery. The type of surgery in the face of cirrhosis must also be considered. The Child-Turgott Pugh (CTP) classification and the model for end-stage liver disease (MELD) scoring systems have both been used as Curr Probl Surg, May 2008

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FIG 6. Hepatic steatosis seen here in a donor liver after total hepatectomy. The yellowish appearance is clearly seen.

predictors of mortality after surgery. In patients of Child’s class A, mortality rates of between 8% to 16%, and up to 84% to 100% in Child’s class C, have been reported. Model for end-stage liver disease (MELD) scores greater than 14 are said by some to correlate to Child’s class C and therefore surgery in these patients should be avoided. However, the patients in whom cirrhosis is found incidentally are usually well compensated but still have an increased mortality risk and this must be taken into account if occult cirrhosis is found.20-26 For example, a colon resection with a colostomy can be a disaster in the face of cirrhosis if the patient develops ascites postoperatively. Thus when unsuspected cirrhosis 334

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FIG 7. Algorithm for the management of an incidental liver lesion. FNH, focal nodular hyperplasia; NRH, nodular regenerative hyperplasia.

is found, careful consideration must be given to the surgery being planned. Clearly, if cirrhosis is an incidental finding and the patient is due to have a liver resection, the surgery should be reconsidered unless it is a minor nonanatomic resection and performed in the hands of an experienced liver surgeon. Postoperatively, any patient with cirrhosis should be monitored carefully in the perioperative period for signs of decompensation. Avoidance of hepatotoxic medications and consultation or follow-up with a hepatologist should be initiated. An algorithm for the management of the hepatic incidentaloma is presented in Figure 7.

Incidentalomas of the Pancreas Although incidentalomas have been routinely recognized and managed in other organs, the earliest formal report of a pancreatic incidentaloma was published only as recently as 2001.27 However, any lesion of the pancreas, whether it be malignant or benign, cystic or solid, primary or metastatic, can be identified in asymptomatic patients, and there are numerous case reports in the literature to this effect. Malignancies include pancreatic adenocarcinoma, cholangiocarcinoma, ampullary or duodenal malignancies, adenosquamous carcinoma, pancreatic neuroendocrine tumors (PNETs), gastrointestinal stromal tumors (GISTs; Fig 8), and metastatic renal cell, melanoma, or breast cancers. Benign entities include Curr Probl Surg, May 2008

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FIG 8. Gastrointestinal stromal tumor (GIST). A 4.5 ⫻ 7.0-cm lesion with hyperenhancing and necrotic elements and prominent peripancreatic lymphadenotathy was discovered incidentally during an evaluation for hepatitis C infection. Esophagogastroduodenoscopy demonstrated a bulging submucosal mass just distal to the ampulla of Vater. Aspiration biopsy at that time revealed “atypical” cells. An uneventful pancreatoduodenectomy was performed. Final pathology revealed a GIST with 0/14 nodes positive and 7 mitoses/50 high-powered field. The patient has been referred for consideration of adjuvant imatinib (Gleevac) therapy, given the diagnosis of a tumor with borderline features of malignancy.

nonmalignant neuroendocrine tumors, accessory splenules (Fig 9), duodenal diverticulae, chronic pancreatitis, focal fatty infiltration of the pancreas, and rare retroperitoneal masses. Cystic entities of the pancreas are more commonly recognized in this fashion and include cystadenomas (both serous [Fig 10] and mucinous), cystadenocarcinomas (Fig 11), intraductal papillary mucinous neoplasm (IPMN), solid pseudopapillary tumors, malignant adenocarcinoma and neuroendocrine tumors with cystic components, pseudocysts, inclusion cysts, and retroperitoneal cysts (misidentified as being derived from pancreatic parenchyma). The largest published series on this subject helps us understand the overall scope of the problem from a renowned pancreatic surgical specialty unit.28 Over a recent 8-year period, 118 patients undergoing pancreaticoduodenectomy at Johns Hopkins University presented with an incidental finding of a periampullary or pancreatic mass. This comprised 6% of the total of 1944 cases performed during this period, the rest of which manifested with symptoms. Of the incidentalomas, 31% were frankly malignant. By contrast, 76% of the nonincidentaloma 336

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FIG 9. Accessory splenule. This lesion was incidentally found during an evaluation for lower abdominal pain. Its cystic appearance with calcification on this computed tomographic scan was worrisome for a mucinous cystic neoplasm, pseudocyst, or teratoma situated within the pancreatic parenchyma. An endoscopic ultrasound-guided biopsy aspirate was nondiagnostic. On surgical exploration, a 4 ⫻ 5-cm purple lesion was identified to be separate from the pancreatic tail and within the transverse mesocolon. Final pathology revealed accessory splenic tissue with focal fibrosis, cystic degeneration, and calcification (all highly atypical of this fairly common entity).

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FIG 10. Serous cystadenoma. A healthy 52-year-old woman was evaluated for hematuria. Imaging revealed this 2.2 ⫻ 2.0-cm cystic lesion in the tail of her pancreas. Fine detail analysis of the internal features, demonstrated on both this scan and magnetic resonance imaging, show a “ground-glass” or “cluster of grapes” appearance indicative of a microcystic serous cystadenoma. She will be followed with serial imaging to ensure stability of the lesion. (Color version of figure is available online.)

patients had malignant pathology. Furthermore, almost one half of the incidentaloma group had premalignant disease (47%), with only 22% being benign. The 3 most common diagnoses were: IPMN (30%), cystadenoma (17%), and pancreatic ductal adenocarcinoma (10%). Operative complications were more frequent in the incidentaloma cohort, largely because of significantly more pancreatic fistulae. Most importantly, those patients in the incidentaloma group who had malignant disease had superior long-term survival (median, 30 months) compared with those patients in the symptomatic group. Details show that 73% of the cases were identified by abdominal imaging, 18% by biochemical testing, and 9% by endoscopy. Baseline clinical demographics were similar between incidentally and symptomatically identified disease. Cancers that were discovered incidentally demonstrated more favorable histologic features with significantly lower TNM staging levels (31% in stage I). IPMNs identified incidentally were earlier lesions with 93% (vs 67%) being either benign, stage 0, or stage I cancers. There were no deaths from the Whipple operation in the incidentaloma group, but morbidity was significantly greater (55% vs 43%), with the pancreatic and biliary fistula rates being increased at 18.4% versus 8.5% 338

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FIG 11. Mucinous cystadenocarcinoma. This 18-cm cystic mass was initially identified by chest computed tomographic scan for left-sided chest pain in a 76-year-old woman. An endoscopic ultrasound ensued and demonstrated a large multiloculated cyst in the tail of the pancreas with septae and solid components. Cyst aspirate analysis revealed an amylase level of 18 IU/L and a carcinoembryonic antigen tumor marker level of 32,909 ng/mL— highly suggestive of a mucinous neoplasm. Cytology was negative for malignancy. A distal pancreatectomy was performed and final pathology demonstrated pancreatic adenocarcinoma within a mucinous cystic neoplasm (cystadenocarcinoma). Lymph nodes were positive, and there was evidence of perineural and microvascular invasion, but the margins of resection were negative. She was referred for consideration of adjuvant chemoradiation therapy.

and 6.1% versus 2.4%, respectively. Median survival for all patients was markedly different favoring the incidentaloma group (82 vs 33 months). When breaking this down by benign and malignant disease, overall survival was equivalent in both cohorts when dealing with benign diagnoses (approximately 80% at 5 years). However, for invasive cancer, the incidentaloma cohort outlived the symptomatic group by 9 months (30 vs 21 months). For the diagnosis of pancreatic ductal adenocarcinoma specifically, the survival advantage was even greater (28 vs 18 months). The investigators conclude that approximately three quarters of these incidentally found lesions are malignant or premalignant and are amenable to definitive surgical resection. Furthermore, when malignancy is identified in this scenario, long-term oncologic survival is improved in comparison to those patients whose disease presents symptomatically. This may be explained by more favorable pathology, possible lead-time bias, and early intervention on disease before lethal transformation. The high percentage of true invasive malignancy identified (31%) in this study, not to mention the enormous proportion of premalignant lesions, underscores the difference between pancreatic incidentalomas and Curr Probl Surg, May 2008

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incidental lesions found in other organs (usually below 10%). A limitation to this study is that it focuses only on lesions identified in the proximal aspect of the gland, whereas overall the majority of pancreatic incidentalomas are situated in the neck, body, or tail of the pancreas, and are more frequently cystic rather than solid lesions. This represents the only study in the literature that describes solid pancreatic incidentalomas beyond the case report level. Solid incidentalomas of the pancreas, being much more likely to be malignant or premalignant in nature, will more routinely be operated on with both diagnostic and therapeutic objectives. However, the same cannot be said for cystic lesions of the pancreas. Although cystic lesions of the pancreas harbor malignant potential or frank cancer far more often than cysts in other organs (kidney, liver, brain, etc.), there are many instances of simple, benign cysts of the pancreas. Given the high perioperative morbidity (30% to 60%), defined mortality rates (5% or less), and long-term physiologic sequelae (eg, diabetes, exocrine insufficiency) attributed to pancreatic surgery, it is necessary to understand these pancreatic cystic conditions better.

Contemporary Understanding It is evident that cystic lesions with malignant potential, in particular mucinous cystic neoplasms (MCN) and IPMN, are the most frequently encountered pancreatic incidentalomas. The aforementioned reports provided the impetus for developing a consensus management approach for these pancreatic cystic processes. These particular pathologies must be better understood to appreciate the importance of pancreatic incidentalomas. Therefore, an international consensus meeting convened in July 2004, during the Eleventh Congress of the International Association of Pancreatology in Sendai, Japan. Nine acclaimed pancreatologists met as a working group to develop clarity regarding the categorization, diagnosis, and management of these distinct cystic entities. The resulting manuscript is a landmark contribution to the field.29 Two types of IPMN with different levels of aggressiveness are now segregated. According to the literature, main-branch IPMN involving the main pancreatic duct is far more likely to harbor malignancy (70%; range 57% to 92%) than is the side-branch variant (approximately 25%; range 6% to 46%). These can be reliably distinguished by numerous radiographic modalities, but the most definitive classification can only be made on histologic grounds. Distinction between the 2 is imperative for determining an accurate prognosis. 340

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FIG 12. Side-branch intraductal papillary mucinous neoplasm (IPMN). A 1.3-cm cystic lesion was incidentally identified by computed tomographic scan in a patient being followed for treatment of early-stage bladder cancer. This magnetic resonance cholangiopancreatography was obtained and shows features in line with a side-branch IPMN in the uncinate process with direct communication with the main pancreatic duct, which is otherwise morphologically normal. Images were also suggestive of enhancing septae and nodularity within the cyst. The patient elected surgical resection (Whipple’s resection) for this presumed premalignancy. Pathology demonstrated a “borderline malignant” IPMN.

MCNs can be reliably distinguished from their mucinous cousins IPMN on histologic grounds by the presence of “ovarian-type” stroma, and as opposed to IPMNs, MCNs are solitary and do not recur following resection. MCNs do not demonstrate communication with the pancreatic ductal system as do side-branch IPMN (Fig 12). However, not all side-branch IPMNs will demonstrate this communication on radiographic means alone. Again, only pathologic analysis provides definitive understanding. Given their lower frequency of malignancy, all side-branch IPMNs need not be resected when originally diagnosed. The likelihood of malignancy in small cysts (⬍3 cm) without mural nodules, or asymptomatic cysts, is low enough to espouse serial radiographic follow-up over immediate surgery. Conversely, the evidence suggests that no combination of clinical or radiographic parameters can accurately predict malignancy in main-duct IPMN, and resection is advocated for suitable patients given the extremely high prevalence of cancer. All MCNs should be resected. This entity usually affects young to middle-aged women and is situated in the distal pancreas. Given the high propensity for these to progress to carcinoma, and the long expected life span for those afflicted, it is sensible to undertake a segmental or distal pancreatectomy with a reasonable risk profile. Curr Probl Surg, May 2008

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Due to the inability to accurately predict invasive malignancy preoperatively, standard resections with lymph-node clearance should be favored rather than limited resections, although limited resections, with their ability to spare endocrine and exocrine function, may be appropriate for some select IPMNs and MCNs. Multifocal side-branch IPMN may not require total pancreatectomy de facto. Given the lack of understanding of the natural history of these lesions, it may be more reasonable to resect dominant disease and observe the remaining pancreas to prevent the morbidity of the apancreatic state. If serial follow-up of a cyst is the chosen management strategy over resection, high-resolution CT, magnetic resonance cholangiopancreatography (MRCP), and/or endoscopic ultrasound (EUS) should be used to assess changes in cyst size, pancreatic duct characteristics, or the development of mural nodules. An interval of follow-up should be yearly if the lesion is smaller than 1 cm, every 6 to 12 months for cysts between 1 and 2 cm, and 3- to 6-month surveillance for those cysts larger than 2 cm. The interval can be lengthened after 2 years of no obvious change. Overt changes of these characteristics should prompt consideration for surgical resection, as should the development of new symptoms in the follow-up period. Post-resectional follow-up of these lesions is, so far, poorly defined. Benign MCNs do not require any further analysis. Malignant MCNs have a distinct chance of local and distant recurrence and should be followed every 6 months with imaging. The chance of recurrence of benign IPMNs is actually definable (at least 7%). The authors suggest yearly radiographic follow-up at least for a few years. On the other hand, patients with invasive IPMNs have a significant risk of recurrence and should be followed at least every 6 months. There is no obvious value to tumormarker (CEA and/or CA19-9) analysis in this process. Patients with IPMN, but not MCN, have a high prevalence (up to one third) of synchronous or metachronous malignant lesions in other organs. Most common among these are stomach, colon/rectum, lung, breast, and liver. Attention should therefore be paid to assessing these organs preoperatively, as well as in follow-up. The overall effect of this consensus statement has been a respect for precise definitions and a newfound temperance with regard to the resect-first mentality for pancreatic cysts that predominated in the 1990s. The guideline with the most impact has been the idea that all IPMN are not the same, and that there are defined predictors of malignancy in side-branch disease that can guide decisions regarding an aggressive surgical approach versus a more measured surveillance program. Despite these guidelines, however, the presence of symptoms and/or the anxiety 342

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of level of the patient who must live with a presumed premalignant process still greatly influence the decision for surgical resection.

Practical Approach to the Pancreatic Incidentaloma Initial Considerations. Given the scope and consequences of this dilemma, the practitioner who encounters an incidentally found pancreatic lesion should embrace a multidisciplinary team approach that relies on specialists in radiology, gastroenterology, interventional gastroenterology, medical pancreatology, pancreatic surgery or surgical oncology, and in some cases medical oncology. Attention should initially be focused on analyzing and addressing the source of the patient’s original complaint. Since most pancreatic incidentalomas have a nonurgent clinical course, there is no need to have their evaluation interfere with perhaps more pressing problems (eg, diverticulitis, peptic ulcer disease, pneumonia, renal stones, etc.). However, 1 diagnosis that should give the practitioner pause is overt evidence of biliary tract disease. It is first necessary to understand if cysts discovered in this setting may indeed be related to biliary stone disease (eg, pseudocysts from gallstone pancreatitis), or conversely, if biliary obstruction is a result of the pancreatic pathology. Alternatively, if the pancreatic lesion is such that it warrants an operative intervention, it might be prudent to combine the biliary and pancreatic procedures together in a single operation, unless urgent circumstances of the biliary disease, such as acute cholecystitis, force the matter. Beware, however, of the patient with acute relapsing pain flares with associated biochemical elevations in the absence of obvious risk factors for pancreatitis, as they may in fact be associated with the newly discovered lesion in the pancreas. Remember that pancreatic incidentalomas can obstruct the pancreatic duct through an external compression mass effect (eg, PNETs, cystadenomas; Fig 10) or intraluminal impaction (IPMN) and still be asymptomatic, as opposed to obstruction due to malignant stricture, which more often will cause pain. The bottom line is that it is exceedingly unusual to diagnose a pancreatic pseudocyst in a totally asymptomatic patient. Care should be taken to thoroughly probe for a remote history of pain, or risk factors. Next, review all and any available imaging of the abdomen. Quite often, patients will have had a CT scan or MRI for another cause within the last few years, or even more distant than that. Obtain the actual films for your personal review, not just the written report. This has proven invaluable on some occasions, when a lesion was actually previously present, by providing a means for comparison and establishing a “pace” of the Curr Probl Surg, May 2008

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process. Although in some instances the lesion will be recognized in hindsight, more often retrospective analysis of the imaging shows only a hint or suggestion of the problem. This is usually attributable to inferior sensitivity of imaging techniques from prior eras, or poor quality investigations (eg, single-phase), and not from diagnostic oversight by the original radiologist. Imaging Approaches. Most incidental lesions of the pancreas are first identified through either axial imaging or general abdominal ultrasound studies, which are no better than “screening” examinations. The first principle is then, from the initial imaging, to determine if the lesion is primarily solid, cystic, or mixed in nature. Although much of the literature emphasis has so far been on cystic lesions, solid lesions are quite common, and are actually more anxiety provoking since pancreatic adenocarcinoma, neuroendocrine tumors, and other malignancies prevail in this category. Solid lesions are best defined by CT scan, whereas cystic lesions are characterized more completely by MRI. In reality, most patients with pancreatic incidentalomas ultimately receive both forms of axial imaging because they are complementary. If the original imaging (whatever type) suggests a solid mass in the pancreas, a dedicated triple phase “pancreatic protocol” CT scan should be performed. This includes noncontrast, arterial and venous phases (achieved by appropriately timed contrast boluses) and can be digitally reformatted to recreate the pancreas in 3 dimensions (including peripancreatic vasculature and even the pancreatic ductal system). This dedicated protocol allows for full staging of the suspected tumor to assess for local (vascular encroachment), regional (lymphadenopathy), as well as distant features (metastases), which will govern subsequent treatment strategies. On the other hand, cystic lesions should preferentially be assessed with MRCP. This test allows for clarity of both the cystic lesion as well as the pancreatic and biliary ductal systems, but is less valuable at assessing the pancreatic parenchyma than is CT. It is particularly good at identifying side-branch communication (or lack thereof) to the main pancreatic duct, as well as mural nodules, other solid components, and/or enhancement of cysts. The functional capacity of the pancreas can also be ascertained by the administration of secretin during MRCP. This “dynamic” investigation allows for an understanding of the overall “horsepower” of the parenchyma, as well if the ductal system is obstructed when stressed. This is helpful for demonstrating the effects of chronic pancreatitis on the ductal system, and can further clarify if there is indeed side-branch communication with the main duct. It also can be a provocative test in that 344

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pain or discomfort may be elicited directly after the secretin bolus, thus implicating any vague symptoms with the pancreatic lesion itself. Endoscopic retrograde cholangiopancreatography (ERCP) is reserved for those cases in which MRCP cannot demonstrate a side-branch communication and where that information is critical in determining management (ie, delineation of MCN versus IPMN). Note that even this test may not always illustrate a side-branch communication in IPMN due to ductal obstruction with mucus or papillary ingrowth. It is less sensitive than MRCP for this. Endoscopic retrograde cholangiopancreatography is more valuable in confirming suspected main-duct IPMN by delineation a classic fish-mouth papilla, intraluminal defects, and extent of gross involvement of the main duct (Fig 13). However, ERCP comes with the price of a significant (realistically up to 10%) chance of inducing periprocedural pancreatitis, which can delay accurate diagnosis and therapy. ERCP is clearly indicated in cases of obstructive jaundice from pancreatic lesions, but incidentalomas, by definition, do not fall into this category. Solid Lesions. Identification of a solid lesion, anywhere in the pancreas, should first and foremost lead to suspicion of a malignant process. This is particularly true in the body and tail, where development of symptoms (eg, pain, nausea, anorexia) is a very late manifestation of the disease. Malignant processes to consider are led by pancreatic adenocarcinoma due to its aggressiveness, although it rarely manifests as an incidentaloma. This is best identified as a hypodensity on the venous phase of a CT angiogram (on account of the paucity of tumor cells to stroma, 1:9 ratio). Mild pancreatic or biliary ductal dilation may be appreciated on the imaging studies. Although most solid tumors can be classified on radiographic grounds alone, current approaches at most specialty centers are using EUS-guided fine-needle aspirates to confirm malignancy in equivocal cases. This is particularly useful in those cases in which the patient is extremely elderly and/or at significant operative risk for morbidity, allowing the surgeon to proceed with certainty that the process is malignant. However, the opposite scenario is just as relevant where, in the case of a young patient, morbidity of a major operation can be avoided through the diagnosis of a benign or innocuous condition. This test is more dependable for solid lesions than it is for cystic fluid analysis (see below) in terms of diagnostic certainty. Reports of “consistent with malignancy” or “suspicious for malignancy” on aspiration is highly predictive, but specificity falls off as “atypical” or “indeterminate” diagnoses are rendered. Unless definitive benign diagnoses are reported, current recommendations are to Curr Probl Surg, May 2008

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FIG 13. Main-branch intraductal papillary mucinous neoplasm (IPMN). An 80-year-old woman presented to the emergency room with pain after a fall with abdominal trauma. There was evidence of recent onset diabetes mellitus (A) A computed tomographic scan discovered an incidentally finding of a dilated pancreatic duct (1.2 cm) throughout its entire course, which was suspicious for main-duct IPMN. (B) Endoscopic retrograde cholangiopancreatography ensued and showed a classic “fishmouth” ampulla of Vater with mucous secretion. (C) A pancreatogram displays a widely dilated duct with intraluminal opacification consistent with either mucous plugging or a papillary excrescence. The common bile duct was normal. (D) Pathologic analysis following a Whipple’s resection revealed IPMN with low-grade dysplasia in papillary growths, no malignancy, normal lymph nodes, and a clean margin. (Color version of figure is available online.) 346

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FIG 13. Continued

proceed to surgical exploration for solid pancreatic incidentalomas. In some cases of uncertainty, diagnostic laparoscopy with ultrasound guided biopsy has been helpful in securing the diagnosis before a definitive open operation takes place.30 Most solid lesions require partial pancreatectomies following appropriate oncologic principles of regional lymphadenectomy. Curr Probl Surg, May 2008

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FIG 14. Side-branch intraductal papillary mucinous neoplasm (IPMN). A typical finding of a 2.5-cm septated cystic lesion of the body of the pancreas (arrows) is illustrated in this computed tomographic scan performed in the evaluation of acute cholecystitis. Endoscopic ultrasound– guided cyst aspirate revealed “string-like” fluid consistent with mucous. Cytology was “nondiagnostic.” The amylase level was 7 IU/L and the carcinoembryonic antigen level was uninterpretable due to the aspirate viscosity. Magnetic resonance imaging revealed side-branch communication with the main pancreatic duct. After extensive counseling, this 60-year-old patient opted for a definitive surgical resection (distal pancreatectomy) rather than long-term radiographic follow-up. Pathology showed a side-branch IPMN with low-grade dysplasia. (Color version of figure is available online.)

The exception is a clear-cut small PNET, which may be enucleated, or segmentally resected, if there is no evidence of multifocality. Cystic Lesions. Given their wider variety of biologic behaviors, and our lack of precise understanding, the management of cystic incidentalomas is less straightforward. Common cystic lesions of the pancreas, in descending frequency, include: pseudocysts, cystadenomas (both serous and mucinous), IPMN (main-duct and side-branch variants) (Figs 13, 14, and 15), solid pseudopapillary tumor (also known as Hamoudi, or Franz tumor), and cystadenocarcinomas (primarily mucinous). Rarer diagnoses include: congenital inclusion cysts, simple mucinous (nondysplastic) cysts, von Hipple-Lindau disease (a multicentric, systemic disease), and neuroendocrine, adenocarcinoma, or acinar cell carcinomas with cystic degeneration. Pathologic, imaging, and clinical features of the more common entities are described in detail elsewhere, but the more common diagnoses deserve some consideration here.31,32 Once the cystic incidentaloma has been initially discovered, a differen348

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FIG 15. Mucinous cystic neoplasm with nodule. A healthy 80-year-old lady had an incidental finding of a 2 ⫻ 1.6-cm unilocular cyst in the body of the pancreas identified through an evaluation for diarrhea. Endoscopic ultrasound showed a normal appearing pancreatic parenchyma with 2 ⫻ 4-mm nodular projection within an otherwise simple appearing cyst. Cyst aspirate was consistent with a mucinous neoplasm with a carcinoembryonic antigen level of 8933 ng/mL, and an amylase level of 7 IU/L. Cytology was “nondiagnostic.” Given her advanced age and fear of surgery, she opted for close follow-up, despite the worrisome finding of a solid nodule. She will undergo repeat endoscopic ultrasound analysis in 6 months.

tial diagnosis is developed given the characteristic demographic, radiographic, and clinical features suggested above. Delineation of the cyst as being either neoplastic or benign is the first consideration. As stated above, an initial priority is to rule pseudocyst disease in or out. Another diagnosis, which can be simply ruled out by imaging alone, is an asymptomatic duodenal diverticulum, some of which are situated within the pancreatic parenchyma. A cystic space with an air/fluid level or oral contrast within is diagnostic for this benign process. Once these diagnoses are excluded, it is pretty straightforward with larger cysts, since few larger than 5 cm in size are nonneoplastic (a major exception is serous cystadenoma). However, with current imaging detecting many more cysts smaller than 2 cm in size these days, this initial distinction is far more difficult now (see above discussion of the contemporary literature). Curr Probl Surg, May 2008

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Endoscopic ultrasound cyst analysis with aspiration is useful in determining the nature of the fluid, and is commonly used for pancreatic incidentalomas. Details on cyst morphology such as the presence of nodules, septae, debris, and wall thickness can be acquired. Cyst multiplicity and positioning in the pancreas can also be assessed. Cyst fluid can be sent for cytology, tumor markers, amylase, and molecular analysis.32 The most helpful parameter for clinical decision making is cyst-aspirate (not serum) CEA level. A level of 200 ng/mL or greater is highly predictive of a mucinous pathology, which has greater odds for malignancy than for serous lesions. It is a common mistake, however, to equate a high aspirate CEA level directly with malignancy. Unfortunately, to date, there is not a good marker to delineate benignity versus malignancy. CA19.9, a carbohydrate tumor marker highly suggestive of pancreaticobiliary malignancy when measured via the serum, has been very inconsistent in predicting malignancy when aspirated directly from cysts. Sensitivity and specificity for determining the diagnosis of cancer from EUS-acquired aspirates is quoted at 69% and 90%, respectively. However, determination of premalignant lesions by cyst aspirate cytology falls off to 56% sensitivity and 81% specificity.33 Even the sensitivity of cytologic analysis of cyst aspirates in predicting malignancy is a dubious 48%34 (Fig 11). Most pancreatic specialty centers now have EUS expertise and are using cyst aspiration in decision making as well as academic protocols. Some, however, do not perform this test, preferring to rely on quality imaging for distinguishing the lesions. The decision to operate on cystic lesions is predicated largely on the odds of malignancy. As demonstrated above, cyst size over 3 cm, mural nodules, enhancing components, thickened walls, high serum CA19.9 levels, or overt malignancy or atypia by cytology are all strong predictors of cancer, and represent triggers for immediate operative intervention in suitable candidates. Fortunately, only a distinct minority of these cysts will demonstrate these features. Unfortunately, for the rest, uncertainty remains. In that most of these lesions have malignant potential, some patients are uncomfortable with the idea of harboring any cyst, much less premalignant lesions. Also, the idea of long-term radiographic follow-up (ie, years) is unappealing to many patients (young and old), may expose patients to risk as well (cumulative radiation exposure from repetitive CT scans), and is costly (Fig 14). Common sense also is in play, since innocuous or borderline lesions in very elderly, or physiologically frail, patients probably will not be the source of their demise. An accurate risk/benefit analysis should be presented to the patient on diagnosis so that informed consent can be obtained for whatever approach is chosen. 350

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In the end, the decision to operate to remove a cystic lesion largely comes down to philosophy— both on the part of the patient and the surgeon.

Conclusions This clinical problem of incidentalomas is both exciting and vexing for physicians dedicated to the pancreas. Despite the explosive identification of pancreatic incidentalomas recently, much remains to be understood about the natural history of these lesions. More than in any other organ system, malignancy is of utmost concern due to its frequency and aggressiveness. In particular, we need to: (1) identify parameters that will allow for safe monitoring and observation; (2) determine how long serial surveillance should be performed; and (3) further refine indications for operative intervention— giving this high-stakes endeavor greater therapeutic yield. This insight will be best accomplished through multiinstitutional cooperative trials, which will require multidisciplinary approaches and years, perhaps decades, of patient accrual and observation. No doubt, this will be aided by future advances in imaging, molecular diagnostics, and less-invasive therapeutics.

Incidental Gallstones According to the 1992 NIH Consensus Statement, approximately 10% to 15% of the adult population, or approximately 20 million people, have gallstones. Complications of gallstone disease account for a significant number of hospitalizations and substantial health care costs.35 Currently, the standard treatment of symptomatic gallstones is laparoscopic cholecystectomy. Before the advent of laparoscopy an open cholecystectomy was associated with significant morbidity, which precluded this as a viable option to treat asymptomatic gallstones. However, laparoscopy has transformed the cholecystectomy to a predominately ambulatory procedure associated with a low morbidity and mortality rate. This has brought to the forefront the question of whether a laparoscopic cholecystectomy should be performed for incidental gallstones. One can argue that there are benefits of operating in an elective fashion for asymptomatic disease, rather than in an emergent situation in a symptomatic patient, if a procedure can be performed with ease and a low rate of complication. Additionally, one could argue that it is better to operate on a younger, healthier individual than to risk waiting until a patient is symptomatic, when other medical comorbidities arise that increase the risk of the operation. The ensuing section will illustrate the natural history of gallstone disease and management options for asymptomatic gallstones explored for various Curr Probl Surg, May 2008

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clinical situations and subsets of populations to aid in the decision-making analysis.

Natural History of Gallstone Disease Gallstones are prevalent in the population. Several factors contribute to an increased incidence of gallstones, including advanced age, female gender, family history, obesity, and various medications. Although by age 75 approximately 35% of women and 20% of men have gallstones, the majority of those individuals will remain asymptomatic. Data accumulated by the 1992 NIH Consensus Conference report that 10% of patients with diagnosed asymptomatic gallstones become symptomatic in the first 5 years, and 20% are symptomatic by 20 years.1 However, once an individual develops mild symptoms from gallstone disease, the risk of developing complications of gallstones is increased. Among those individuals with symptomatic gallstones, 6% to 8% per year require an operation.36,37 There have been several studies reported in the literature that have enhanced our understanding of the natural history of gallstone disease. Gracie and Ransohoff followed 123 Michigan faculty members for 15 years after being diagnosed with gallstones after routine screening. At the 5-year follow-up period, 10% of individuals became symptomatic, and 18% at 15 years. The rate of development of biliary pain was 2% per year.38 Friedman and colleagues followed 123 patients in a health maintenance organization with asymptomatic cholelithiasis for a 25-year period. Complications from gallstones occurred approximately 1% per year. During each 5 years after diagnosis of gallstones approximately 4% of patients developed symptoms. Additionally, the probability of developing symptoms decreased with increasing time.39 Zubler and colleagues performed a retrospective analysis identifying 32 patients found to have asymptomatic gallstones as diagnosed by routine patient care in a rural family practice office. Twenty-five percent of patients developed symptoms over a mean 5-year follow-up period. The average time to develop symptoms was 3 years and 5 months. Twenty-two percent of patients required cholecystectomy.40 Complications of gallstone disease, although relatively uncommon (incidence of less than 1% per year), can cause significant morbidity. The majority of patients who develop symptomatic cholelithiasis present with biliary colic. The more serious complications, such as acute cholecystitis, gallstone pancreatitis, cholangitis, gangrenous cholecystitis, gallstone ileus, and Mirizzi syndrome are less common.41 The mortality rate from complications of asymptomatic gallstones is rare, occurring more com352

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monly in the elderly. Despite the low incidence of complications, the impact to the health care system is significant. This, contrasted with the low complication rate from laparoscopic cholecystectomy (1% to 5%), raises the issue of whether asymptomatic gallstone disease should be treated with elective laparoscopic cholecystectomy to prevent infrequent, but potentially serious complications of gallstone disease. Thus, the management options for asymptomatic gallstones include expectant management, selective laparoscopic cholecystectomy, or incidental cholecystectomy in conjunction with another abdominal operation.42

Management of Asymptomatic Gallstones Healthy Patients. There are no definable predictive factors of who will develop serious complications from gallstone disease. However, most patients present with an episode of biliary pain before a more serious complication, thus allowing a window of opportunity to perform an elective cholecystectomy. The complication rate of laparoscopic cholecystectomy is low, but the potential complications have serious adverse outcomes, such as injury to the common bile duct (1%), bile leak (3%), or bowel or vascular injuries. The overall mortality rate from laparoscopic cholecystectomy is 0.6%, but it increases with advanced age. In addition, emergent operations are associated with increased morbidity, mortality, length of hospitalization, and conversion to open procedures. Therefore, in otherwise healthy patients an elective laparoscopic cholecystectomy is not indicated for asymptomatic cholelithiasis and would result in a high rate of overtreatment for asymptomatic individuals.42 Patients with Diabetes Mellitus. Historically diabetes mellitus was thought to be an independent risk factor for increased morbidity in patients undergoing any operative procedure. However, several studies found no independent increased risk associated with the presence of diabetes mellitus. Walsh and colleagues examined the results of cholecystectomy in diabetic and nondiabetic patients.43 The morbidity and mortality rates were similar among diabetic and nondiabetic patients, but morbidity and mortality were greatest among patients with vascular or renal disease, independent of the presence of diabetes mellitus. Hjortrup and colleagues performed a retrospective study including 224 patients with diabetes mellitus matched with 224 nondiabetic patients. Complication rates were the same (21%) among the 2 groups, as well as mortality rates.44 Hjortrup and colleagues also performed a retrospective analysis of diabetic and nondiabetic patients undergoing abdominal surgery to evaluate morbidity. Seventy-nine diabetic patients were matched with 79 nondiabetic controls. Morbidity was similar between the 2 groups (25% vs Curr Probl Surg, May 2008

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23%) and types of complications were also similar.12 These studies support the claim that diabetes mellitus is not an independent factor for increased operative morbidity.44,45 Morbidity rates for urgent cholecystectomy for acute cholecystitis in patients with diabetes are significantly higher than for nondiabetics. Hickman and colleagues reported a 39% morbidity rate among diabetics, compared with 21% among nondiabetics who required an urgent operation for acute cholecystitis. The infection rate among diabetics was 3-fold higher, and the death rate among diabetics was 4% versus no deaths among nondiabetics. These data support the recommendation to operate once symptoms develop, before the development of complications such as acute cholecystitis, which may result in increased morbidity.46 The recent literature illustrates diabetes mellitus as a less threatening risk factor for operative risk in elective situations. The rates of complications and mortality are similar among those with and without diabetes mellitus. Therefore, the management choice for asymptomatic gallstones among diabetic patients should be expectant management. However, once an individual becomes symptomatic, an urgent cholecystectomy is advocated.42 Transplant Patients. Management of asymptomatic cholelithiasis among potential transplant patients is controversial. Several factors contribute to this issue. Gallstones are more prevalent among transplant patients; there is an increase infectious morbidity and biliary complications secondary to immunosuppression; and an increased morbidity and mortality associated with emergent or urgent surgery in this population. Risk factors for gallstone formation include immunosuppressive medications, which increase cholesterol levels, rapid weight change, gallbladder dysmotility, and development of diabetes mellitus in the transplant population. The prevalence of stone formation after transplantation has been reported at up to 55%. The reported prevalence of gallstones pretransplant is 17% for cardiothoracic transplants and 10% for pancreas or kidney transplants. In follow-up studies after transplantation the rate of development of symptoms was 35% to 55%, which is substantially higher than in the nontransplant population. The mean time to development of symptoms is shorter in transplant patients, which has been reported as 2 to 11 months.42,47-49 A major concern is that gallstones may be more likely to become symptomatic after transplantation. The literature reports 35% to 55% of transplant patients will have symptomatic disease.47 However, prophylactic pretransplant cholecystectomy for asymptomatic gallstones must be considered with hesitation. The mortality rate in this population is 8%, which is much greater than the 1% mortality rates found in nontransplant patients. 354

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This is contrasted with morbidity and mortality rates of post-transplant cholecystectomy patients. The morbidity and mortality of urgent cholecystectomy in heart transplant patients is 44% and 37%, respectively, and 33% and 6%, respectively, for renal transplant patients.42,48,50 Prevalence and morbidity data are limited due to small population sample sizes. One study by Melvin and colleagues found that in renal transplant patients 8% required a cholecystectomy. Post-transplant cholecystectomy was associated with low morbidity (12%), no mortality, and high graft survival—98% at 1 year, 85% at 5 years.50 Decision analysis schemes have also been created providing estimates of mortality that can aid in the evaluation of treatment options. These models have determined that expectant therapy is the preferred management option for patients who have undergone renal/pancreas transplant. This was associated with 2 deaths per 1000 patients as compared with 5 deaths per 1000 patients for prophylactic cholecystectomy.48 Data from a retrospective review by Jackson and colleagues also support expectant management among renal transplant patients. In this review 38% underwent preoperative cholecystectomy for asymptomatic disease without complications. The remainder of the study population was managed expectantly. During the mean follow-up of 6 years, all remained asymptomatic.51 Variable outcomes are reported for cardiac transplant patients. It is known that the prevalence of cholelithiasis is high, but the timing of treatment is controversial. The preferred management for asymptomatic gallstones in cardiac transplant patients is prophylactic post-transplant cholecystectomy. The decision model found 80 deaths per 1000 patients for pre-transplant cholecystectomy, 5 deaths per 1000 patients for prophylactic post-transplant cholecystectomy, and 44 deaths per 1000 patients for expectant management. The risk of death for an emergent cholecystectomy was 63%.48 Patients with Abdominal Aortic Aneurysms. Management of cholelithiasis in a patient undergoing abdominal aortic aneurysm repair is not straightforward. The concern for the prevention of graft infection is paramount among vascular surgeons. However, not effectively treating gallstone disease can lead to high morbidity and mortality for vascular patients postoperatively. This was illustrated in the historical paper by Ottinger, who described the outcomes of patients who developed acute cholecystitis during the postoperative period of a prior operation, including aortic reconstruction. The overall mortality in this group of patients was 47%. Sixty percent of the cases in this study were complicated by gangrenous gallbladder, gallbladder perforation, or cholangitis. Fever, dehydration, anesthesia, fasting, and narcotic use can all contribute to bile Curr Probl Surg, May 2008

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stasis, gallstone formation, and outflow obstruction, which can progress to symptomatic cholelithiasis. The complications of symptomatic cholelithiasis in the postoperative period can have high morbidity.52 Despite the startling data revealing high mortality rates for reoperation for acute cholecystitis, there is no measure to predict who will develop symptomatic gallstone disease. Therefore, an assessment of the safety and long-term results must be determined to accurately assess the risk-benefit ratio of performing a cholecystectomy in conjunction with abdominal aneurysm surgery. In California, the mortality rates of Medicare patients undergoing an abdominal aortic aneurysm (AAA) repair were calculated in relation to whether or not a cholecystectomy was performed. Patients who underwent an AAA repair without cholecystectomy (303 of 4468 patients) had a 6.8% mortality rate. Patients who had a ruptured AAA repair without cholecystectomy had a 47.8% mortality rate (469 of 981 patients). Patients who underwent simultaneous elective AAA repair and cholecystectomy (12 of 191 patients) had a 6.3% mortality rate.53 Data support that cholecystectomy is safe and indicated at the time of elective AAA repair when there are palpable gallstones once the closure of the retroperitoneum is complete. This does not result in high rates of graft infection or increased morbidity. However, mortality rates are similar with or without concomitant cholecystectomy, indicating that cholecystectomy can be performed selectively based on optimal patient and operative conditions. Patients Undergoing Other Gastrointestinal Operations. The clinical question occasionally arises of how to manage gallstone disease found incidentally either in the preoperative evaluation of a patient scheduled for another gastrointestinal operation, or gallstones found at the time of operation. Reports in the literature have found a high incidence (as high as 70%) of postoperative symptoms or complications related to cholelithiasis following an abdominal operation for another disease. Almost 40% of patients required a cholecystectomy within 1 year of the initial operation.42 A study by Juhasz and colleagues examined the morbidity and mortality of incidental cholecystectomy in conjunction with colorectal operations. During the study period 355 patients underwent colorectal surgery; of those, 195 patients had incidental cholecystectomy (64%). Patients were followed for a median of 6 years to determine which patients developed symptomatic cholelithiasis. Mortality for the nocholecystectomy group was 2.7%, and 3.6% for the cholecystectomy group. Biliary complications during the postoperative hospitalization for the no-cholecystectomy group was 2.7% (3 patients), with 2 patients requiring cholecystectomy in the same admission. Overall operative 356

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morbidity was the same in both groups (32%). Follow-up data revealed that 27% of patients who did not undergo cholecystectomy developed symptomatic disease, with an 18% probability of needing a cholecystectomy at 2 years’ follow-up and 31% probability at 5 years’ follow-up.54 Klaus and colleagues also found that performing incidental cholecystectomy during the time of laparoscopic antireflux surgery was safe and did not result in increased morbidity.55 Other reports in the literature support these findings and conclude that incidental cholecystectomy can be performed in conjunction with another abdominal procedure as long as the surgeon is comfortable with the procedure, exposure is adequate, and the additional procedure does not produce any significant increased risk to the patient.56,57 Patients with Chronic Liver Disease. Gallstones are present in 29% to 46% of individuals with cirrhosis compared with 10% to 20% of individuals in the general population. The increase in incidence of gallstone formation among patients with liver disease is not entirely understood, but the risk of developing gallstones is correlated with the severity of liver disease. Despite the high incidence of gallstone formation among individuals with liver disease, the majority remain asymptomatic. The overall mortality rate for patients with liver disease undergoing any operation is up to 12%.58 The morbidity of a laparoscopic cholecystectomy in this population has been reported at 21%, as compared with 8% in noncirrhotic patients. The meta-analysis of laparoscopic cholecystectomy in cirrhotic patients demonstrated that operating for symptomatic disease did not result in high mortality rates. The overall mortality rate was 0.5% in the meta-analysis, with a 21% morbidity rate.59 A study by Orozco followed the history of asymptomatic cholelithiasis found at the time of abdominal operation in cirrhotic patients.60 The data from the literature support expectant management for individuals with chronic liver disease; however, once symptoms occur a cholecystectomy should be performed expeditiously to avoid increased morbidity and mortality. Patients Undergoing Bariatric Surgery. The incidence of cholelithiasis among the obese is higher than in the general population. The risk of gallstone formation is increased with increasing level of obesity, as well as during the period of rapid weight loss. Fobi has reported prevalence data among bariatric patients undergoing Roux-en-Y gastric bypass (RYGB), which reveal 27% had asymptomatic gallstones at the time of surgery.61 Amaral, Schmidt, and Wudel all report similar data with incidence rates between 28% and 35%.62,63,64 These authors have also found an increase in new gallstone formation after RYGB from 28% to 71%. The exact reason for the high incidence of cholelithiasis following Curr Probl Surg, May 2008

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RYGB is not entirely known; however, rapid weight loss, malabsorption, or other physiologic factors related to the bypass are presumed to be contributing factors.65 Despite the data that suggest that cholelithiasis is more prevalent among this population, several authors have shown that the rate of symptomatic cholelithiasis is still relatively low. A study examining outcomes among the gastric banding population revealed only 6.8% of patients had symptomatic cholelithiasis over a median 4-year follow-up period and underwent elective cholecystectomy without complication.65 In the gastric bypass population, Swartz and Felix found that 14.7% of patients required cholecystectomy after RYGB, with low complication rates.66 Shiffman followed the natural history of gallstones in patients undergoing RYGB without simultaneous cholecystectomy.67 There was a 23% incidence of gallstones intraoperatively. Although at 12 months postoperatively 40% of patients had gallstones, only 11% of the study population developed symptomatic disease requiring subsequent cholecystectomy. The recent data illustrate that although cholelithiasis is more common among the morbidly obese and gallstone formation is increased during the postoperative period of gastric bypass surgery, incidental cholecystectomy is not warranted at the time of bypass. The immediate postoperative morbidity that has been described associated with open abdominal operations has not been present with laparoscopic gastric bypass surgery. Patients generally leave the hospital without complications of gallstone disease. Additionally, performing a cholecystectomy after a period of weight loss is technically less difficult and safer for the patient. The rates of symptomatic cholelithiasis in the long-term follow-up period are low, and complications are not severe, supporting the safety of routine elective cholecystectomy for symptomatic disease. Patients with Sickle Cell Disease. Gallstone formation is more prevalent in individuals with sickle cell disease compared with the general population. This is most revealing in the pediatric population, in which 15% of children with sickle cell disease under the age of 10 have pigmented gallstones. This rate increased to 40% of children between ages 15 and 18, and more than 80% of individuals over the age of 30.68,69 Although many individuals may remain asymptomatic, the diagnosis of acute cholecystitis or biliary colic can be difficult to discern from an acute sickle cell crisis due to vaso-occulsive crisis. Additionally, the mean number of hospitalizations and emergency room visits in individuals with sickle cell disease and cholelithiasis is double compared with individuals with sickle cell disease without gallstones.70,71 As a result, controversy 358

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exists whether individuals with sickle cell disease and asymptomatic cholelithiasis should undergo elective laparoscopic cholecystectomy. Despite earlier reports that individuals with sickle cell disease are at increased risk of having complications due to their disease, there have been reports of low morbidity and prevention of acute pain crises postoperatively with comprehensive perioperative management including aggressive hydration and preoperative exchange transfusion therapy. Data have also been published on laparoscopic cholecystectomy in infancy and childhood and have shown it to be a safe procedure even in this age group with planned perioperative management.72 The benefits of a planned perioperative approach to the individual with sickle cell disease is evident by the data in the literature that reveal a more than 2-fold increase in morbidity for an urgent cholecystectomy compared with an elective operation among this population.73 Therefore, the current recommendations support the treatment of asymptomatic cholelithiasis in infants and children with persistent calcified and pigmented gallstones secondary to chronic hemolysis. This allows for the opportunity for aggressive perioperative management aimed to prevent postoperative sickle cell crisis and acute chest syndrome, which can cause significant morbidity.69,74-76

Conclusion Gallstone disease is prevalent in the population. The majority of individuals, however, remain asymptomatic throughout their lifetime. The evolution of laparoscopy over the past 2 decades has made the cholecystectomy a safer procedure with low morbidity and mortality. As a result, some controversy exists about whether to treat patients with asymptomatic cholelithiasis with a laparoscopic cholecystectomy. Although complication rates are low, the types of complications of a cholecystectomy can be severe, and therefore the management decisions must be made cautiously. A review of the literature supports expectant management in the following subpopulations diagnosed with asymptomatic cholelithiasis: healthy individuals, individuals with diabetes mellitus, patients undergoing renal or pancreatic transplantation, patients undergoing gastric bypass surgery, and individuals with chronic liver disease. There is no contraindication to selective incidental cholecystectomy in patients undergoing another primary abdominal operation including gastrointestinal surgery and abdominal aortic aneurysm repair. Elective cholecystectomy for asymptomatic cholelithiasis is indicated after cardiac transplantation and for individuals with sickle cell disease (Table 2). The benefits and Curr Probl Surg, May 2008

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TABLE 2. Optimal management of asymptomatic gallstones Subpopulation of patients

Management decision

Healthy Expectant Diabetes mellitus Expectant Renal or pancreas transplant Expectant Chronic liver disease Expectant Undergoing gastric bypass Expectant Undergoing abdominal operation Selective incidental cholecystectomy Undergoing abdominal aortic aneurysm repair Selective incidental cholecystectomy Heart transplant Prophylactic post-transplant cholecystectomy Sickle cell disease Elective cholecystectomy

risks of surgery as compared with expectant management must be assessed for each individual encountered.

Incidentalomas of the Adrenal An incidental adrenal mass or “incidentaloma” is an adrenal mass, generally 1 cm or more in diameter, that is discovered on a radiological examination performed for indications other than adrenal disease. The traditional definition of incidentaloma excludes patients undergoing imaging procedures as part of staging and evaluation for cancer, as well as those in whom the diagnosis of a symptomatic adrenal-dependent syndrome was missed because of insufficient suspicion or investigation.77,78 The increased and widespread use of imaging modalities such as abdominal ultrasound (US), CT, and MRI has increased the number of incidentally detected adrenal masses since first described more than 20 years ago.79 Up to 5% of abdominal CT examinations performed for reasons unrelated to possible adrenal dysfunction will demonstrate an adrenal mass.78 Autopsy series have identified adrenal masses in up to 9% of patients who had no evidence of adrenal dysfunction before death.80 Adrenal incidentalomas may or may not represent clinically significant disease; the majority are asymptomatic and require no treatment. The differential diagnosis of an incidentally detected adrenal mass is extensive. One review of multiple series reporting on adrenal incidentaloma revealed the following pathologies: cortical adenomas, 41%; metastases, 19%; adrenocortical carcinoma, 10%; myelolipoma, 9%; pheochromocytomas, 10%; and other benign lesions such as adrenal cysts comprised the remainder.79 A more recent review of more than 2000 incidentalomas found the incidence of nonfunctioning adenoma to be 82%, pheochromocytoma, 5.1%; subclinical Cushing’s, 5.3%, aldosteronoma, 1.0%, adre360

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nocortical carcinoma, 4.7%, and metastatic disease, 2.5%.81 The differences between these large series probably reflect patient selection biases. Adrenal cortical carcinoma is a rare neoplasm, accounting for only 0.2% of all cancers and approximately 1 in every 4000 adrenal tumors. There is a bimodal age distribution with an increased incidence in children less than 5 years of age and in individuals in the fourth and fifth decades of life. Adrenocortical carcinomas may be functional or nonfunctional, producing cortisol in 30%, androgens in 20%, estrogens in 10%, aldosterone in 1% to 2%, or a combination of hormones in 35%. Even today its prognosis remains poor. Several series have demonstrated 5-year survival rates ranging from 32% to 48% in patients who underwent complete resection.82 The risk for carcinoma grows with tumor size, found in 2% of all tumors less than or equal to 4 cm in diameter, 6% of tumors 4 to 6 cm in diameter, and 25% of tumors larger than 6 cm. Benign nonfunctional adenomas comprise 65% of masses 4 cm or smaller and 18% of masses larger than 6 cm.77,80 Benign adrenal neoplasms are classified into those with increased adrenal hormone secretion and those without. Syndromes of hormone overproduction include Cushing’s (cortisol-producing adenoma), Conn’s (aldosteronoma), and adrenogential, all of which are of adrenocortical origin, and pheochromocytoma, which originates from the adrenal medulla. The adrenal gland is a site of metastatic spread for many tumors. Primary malignancies of the colon, lung, stomach, breast, and kidney, and melanoma and lymphoma have a propensity to spread to the adrenal glands.83 Three quarters of clinically inapparent adrenal masses among patients with a history of cancer are metastatic; in contrast, two thirds of lesions in patients with no cancer history are benign.78,84 When formulating an effective diagnostic and therapeutic plan to manage an adrenal incidentaloma, 2 major issues that must be addressed are whether the lesion is hormonally active and whether the lesion is benign or malignant.78,80 Proper evaluation of the patient with an adrenal incidentaloma requires an understanding of the imaging techniques employed, screening, epidemiology, natural history, biochemical profile of hyperfunctioning adrenal tumors, risk factors for malignancy, treatment, and follow-up of tumors. Because of the high mortality rate of adrenocortical cancer and the fact that complete surgical resection is currently the only potentially curative therapy for localized adrenal cortical carcinoma, early detection and treatment is crucial. Surgery is also generally recommended for all patents with functional tumors.80 Diagnosis and treatment strategies for patients with asymptomCurr Probl Surg, May 2008

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atic adrenal hormone excess are not always straightforward. Because even subclinical hormone overproduction by incidentalomas left untreated may be associated with increased morbidity and mortality, the threshold for treating these patients has been lowered over the last decade79 (Fig 16).

Imaging of the Adrenal Incidentaloma Improvements of both CT and MRI techniques have increased the reliability of these imaging methods in differentiating benign and malignant adrenal masses. Additionally, nuclear medicine studies using specific radiopharmaceuticals have the advantage of providing functional metabolic information for adrenal characterization. Positron emission tomography (PET)/CT using 18-F-fluorodeoxyglucose (18-FDG) allows malignant adrenal lesions to be characterized and gives detailed morphologic information. Currently, adrenal masses can often be characterized with high sensitivity and specificity by the use of these imaging techniques. Computed Tomography. The CT scan is the preferred primary modality in the assessment of adrenal masses. The CT is fast, readily available, accurate, and offers the highest spatial resolution.85 On CT, adrenal adenomas are generally small, homogeneous, well-defined lesions with clear margins. Nonspecific findings such as calcification, necrosis, and hemorrhage are uncommon. Large size, irregular shapes, vague contour, and invasion into surrounding structures are suggestive of malignancy. The morphologic features of metastases are nonspecific on CT. Studies that evaluated adrenal masses based on interpretation of various subjective CT criteria generally delivered poor test results.78,85 Although most lesions smaller than 4 cm are benign, size cannot be used to distinguish malignant from benign lesions with 100% accuracy. No size threshold has yielded both high sensitivity and specificity. As a result, alternate CT characteristics have been explored as predictors of malignancy. Attenuation values from unenhanced CT scans have been shown to be useful in differentiating adrenal malignancy metastasis from benign adenomas. Adrenal adenomas frequently contain a large amount of lipid, which allows a quantitative evaluation by measurement of the attenuation value of the lesions, conventionally expressed in Hounsfield units (HU). Benign adenomas usually have attenuation values of less than 18 HU on unenhanced CT. When the density of a lesion is less than 10 HU, further evaluation is often not required because this carries a sensitivity of 74% and a specificity of 96% for the diagnosis of a lipid-rich adenoma.86 Like primary adrenocortical cancer, adrenal metastases have attenuation values on unenhanced CT that are 362

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Curr Probl Surg, May 2008 FIG 16. Biochemical evaluation of the incidentally discovered adrenal neoplasm. 363

generally higher than those measured in patients with adenomas, although overlap has been observed.77,79,85 Magnetic Resonance Imaging. MRI, which provides imaging of the adrenals without radiation dose, is useful for patients with iodine contrast allergies, has excellent contrast resolution for tissue characterization, and is superior to CT to identifying invasion of adrenal carcinomas into adjacent organs. Ultrasound. Adrenal masses are increasingly discovered incidentally through the widespread use of US. US has little differential diagnostic utility for adrenal masses. Besides giving information on tumor diameter and solidity, US is operator dependent, has low sensitivity for detection of small adrenal masses (⬍1 cm), poorly detects extension into adjacent structures, gives no information on functional status, and provides little information about the malignant potential of a mass. US, however, is inexpensive and can be a simple, effective tool for follow-up. Rapid tumor growth suggests malignancy.85 Adrenal Scintingraphy. Nuclear scintingraphy provides a functional characterization of the adrenal glands based on uptake and accumulation of radiotracers. The radionuclide agent NP-59 (131I-6␤-iodomethyl-19norcholesterol) takes advantage of the fact that benign tumors with intact steroidogenesis show uptake of NP-59, whereas malignant and nonadenomatous lesions do not. Despite several reports demonstrating a high degree of accuracy for predicting benign lesions, there are several limitations to its widespread use. The radiopharmaceutical NP-59 is not readily available, and scanning requires 5 to 7 days. In addition, patients must be treated with potassium iodide before imaging, to block thyroid uptake of radioactive iodine.79,85 For the localization and identification of pheochromocytomas, the radiopharmaceuticals 123I-MIGB (metaiodobenzyl guanidine), 131I-MIGB, and 111 In-octreotide can be used. Any discrete uptake of 131I-MIGB after 24 to 72 hours of administration is suggestive of pheochromocytoma. 111In-octreotide is less sensitive but is able to visualize tumors that are undetected by MIBG studies. In the evaluation of the adrenal incidentaloma, the use of these agents should be limited to cases in which malignant or bilateral pheochromocytoma are suspected.85 Positron Emission Tomography. Malignant tumors usually show increased glycolytic metabolism with increased uptake of deoxyglucose than can be visualized by PET using 18F-2-fluoro-D-deoxyglucose (FDG). In a study designed to differentiate unknown adrenal masses in cancer patients, PET correctly distinguished benign lesions from metastatic lesions with 100% sensitivity and specificity. To date, the data are 364

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insufficient to justify the routine use of PET to evaluate clinically inapparent masses. PET may be useful in patients with a known history of cancer who have equivocal imaging on CT or MRI.78,79,85

Hormonal Evaluation of Adrenal Incidentaloma Adrenal neoplasms may arise from the adrenal cortex or medulla, and they may or may not be functional. Five percent to 10% of incidentalomas arise from medullary tissue; the remainder are of cortical origin among which only 12% to 15% are hormone secreting.87 In reviews covering more than 2000 patients, the frequency of hormone-secreting tumors was as follows: pheochromocytoma, 5.1%, Cushing’s syndrome, 5.3%, primary hyperaldosteronism, 1%, and sex steroid–producing adenoma, ⬍1%.81 Functional incidentalomas are frequently detected before a clinical manifestation of hormone overproduction, or there may exist only subtle physical or laboratory abnormalities that have been overlooked or ascribed to other disease processes.

Adrenal Biopsy Adrenal glands were not meant to be biopsied. For the operating surgeon, news that an adrenal biopsy has been performed is not cheering. It often will have produced periadrenal hemorrhage with associated inflammatory change and scarring. This leads to obliteration of the normal tissue planes, thereby increasing the difficulty of dissection and potential for surgical morbidity.88 Despite their retroperitoneal location that makes them easy targets for CT-guided percutaneous biopsy, the indications for adrenal biopsy are rare. Before such a procedure is considered in the evaluation of an adrenal incidentaloma, tumor functionality must be ruled out. Specifically, biochemical testing must be performed to exclude pheochromocytoma and subclinical Cushing’s syndrome. Needle biopsy of a pheochromocytoma has the potential for producing dire hemodynamic consequences, as well as adrenal hemorrhage.89 Nonetheless, in a series of 33 laparoscopic adrenalectomies for nonmalignant adrenal neoplasms, 3 patients with pheochromocytoma underwent biopsy and were diagnosed as such before a biochemical evaluation, and a fourth patient underwent adrenal biopsy after biochemical confirmation of catecholamine hypersecretion because she had a coincident lung nodule (unpublished data). If an adrenal neoplasm is identified radiographically in a patient with a previous history of malignancy, and the biochemical evaluation is negative, CT-guided biopsy is warranted to assess for possible metastatic Curr Probl Surg, May 2008

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disease. When a patient with no previous cancer history is found to have an isolated adrenal lesion that is nonsecretory, there is no role for biopsy because biopsy is rarely helpful in distinguishing a benign from malignant adrenal cortical tumor.88 Such patients should be managed based on the lesion size and imaging characteristics, and therefore undergo adrenalectomy when these criteria suggest the possibility of adrenocortical carcinoma.

Surgical Management of Adrenal Incidentalomas Decisions regarding the management of an incidentally discovered adrenal mass should be individualized according to the clinical circumstances, hormonal status, imaging characteristics of the mass, the patient’s age, and the patient’s preferences as summarized in Figure 17. Adrenalectomy is recommended for lesions that are found to be hormonally active or potentially malignant. Because of the risk of malignancy, most experts agree that adrenal masses larger than 6 cm should be removed.77-80 When a size threshold of 4 cm was used for incidentaloma removal, a benign-to-malignant ratio of 8:1 was demonstrated.90 Most centers of endocrine surgery now use 4 cm as the threshold for adrenalectomy for nonfunctional tumors. Decisions regarding surgical resection should also take into account the imaging phenotype of the mass, as well as the patient’s age and other medical conditions.78 Adrenal lesions with findings concerning for malignancy on imaging should be removed regardless of size. In patients with adrenal metastases, adrenalectomy can be considered for potential curative intent in patients with solitary adrenal metastases with a prolonged disease-free interval and palliative intent for large symptomatic lesions. Although the resection of isolated adrenal metastases remains controversial, retrospective studies demonstrate a median survival of between 20 to 30 months in highly selected patients who underwent resection of isolated adrenal metastases compared with 6 to 8 months in patients who did not undergo adrenalectomy.78,84

Adrenalectomy Since the first reported laparoscopic adrenalectomy in 1992, the use of minimally invasive surgery has become the preferred surgical approach for the treatment of benign functioning and nonfunctioning adrenal disorders.80,83,84 When compared with open adrenalectomy in nonrandomized studies, laparoscopic adrenalectomy has been associated with less pain, shorter hospitalizations and convalescence, less blood loss and need for transfusion, and fewer wound complications. Although the 366

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FIG 17. Mind-mapping technology is used to summarize the authors’ approach to adrenal incidentalomas. Situations highlighted (lightly) represent that adrenalectomy is indicated. Areas highlighted (darkly) emphasize the need for prolonged clinical, radiological, and biochemical follow-up.

technical difficulty of performing laparoscopic adrenalectomy increases as tumors increase in size (larger than 8 to 10 cm), resections of progressively larger adrenal neoplasms have been reported in association with improvements in laparoscopic techniques, equipment, and surgeon experience. A laparoscopic approach can be used for most incidentalomas, because the risk of a primary malignant adrenal tumor is low.84 Although controversial and once considered an absolute contraindication to a laparoscopic approach, potentially malignant primary tumors and adrenal metastases are now being removed laparoscopically in some centers. Successful laparoscopic resection of adrenal metastases has been reported by some authors.84 Although laparoscopic removal of larger adrenal tumors may be technically possible by the most proficient laparoscopic surgeons, it must be recognized that these lesions are more likely to be malignant. To ensure an oncologically correct operation that maximizes the chances of a margin-negative resection, avoids violation of the tumor capsule and tumor spillage, facilitates vascular control of the IVC, aorta, and renal vessels, and allows maximal exposure for en bloc resection of associated anatomic structures, open resection remains the gold standard for suspected adrenocortical carcinoma.

Long-Term Follow-up for Small Nonfunctional Incidentalomas Few studies have documented the long-term evolution of the adrenal incidentaloma. One by Barzon and colleagues followed 75 patients for a median of 4 years. The estimated 5-year risk of enlargement was 18%, and the 5-year risk of hyperfunction was 9.5%. No patients in that series developed adrenocortical cancer, illustrating that the majority of adrenal incidentalomas that do enlarge prove to be benign. Two patients developed Cushing’s syndrome, 3 developed subclinical Cushing’s syndrome, and 1 developed pheochromocytoma.91 Hormonal secretion can develop in up to 20% of patients in follow-up,77 and current recommendations are that patients should undergo annual screening for pheochromocytoma and cortisol secretion for 4 years after an incidentaloma is first detected. In a patient with a tumor smaller than 4 cm and no radiographic suggestion of malignancy, annual CT scan should be performed for 2 to 3 years. If there is no change, then it is generally safe to assume that the lesion will remain benign.88 However, repeat CT is recommended at 3, 6, and 12 months if the radiographic characteristics raise suspicion of possible malignancy, as the growth rate for adrenocortical cancer is expected to be greater than 2 cm/year.78 Lesions that enlarge more than 1 cm in follow-up should be 368

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removed, again emphasizing that biopsy is rarely helpful in the decision analysis.

Summary Having entered an age in which cross-sectional imaging has become routine in the evaluation of abdominal pain, there has been a significant increase in the detection of adrenal incidentalomas. As general surgeons it is imperative that we have a solid understanding of the nature of these lesions, both the functional and malignant potential that they possess, so that we can astutely advise both patients and referring physicians of the proper evaluation and course of action. It is imperative to rule out the possibility of pheochromocytoma before any type of tumor manipulation, be it a biopsy or surgical removal, but it is only a small minority of such lesions that warrant a biopsy. Adrenalectomy is generally performed in patients with hyperfunctioning tumors and for potentially malignant disease. Rational management of patients with incidentally discovered adrenal tumors is predicated on identification of hormonally active tumors and lesions that are potentially malignant. Although a laparoscopic adrenalectomy can be performed for most incidentalomas requiring resection, the authors believe that an open approach is indicated for known malignant primary adrenal tumors or those tumors exhibiting features suggestive of malignancy.

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