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InternalMed_Harrison. Tumors of the Liver and Biliary Tree patients with a single lesion ≤5 cm or three or fewer nodules, each ≤3 cm (Milan criteria), resulted in excellent taBLe 111-6 some ranDomizeD CLiniCaL triaLs invoLving transhepatiC artery ChemoemBoLization (taCe) for hepatoCeLLuLar CarCinoma 550 growing in the months until a donor liver becomes available. What remains unclear, however, is whether this translates into prolonged survival after transplant. Further, it is not known whether patients who have had their tumor(s) treated preoperatively follow the recurrence pattern predicted by their tumor status at the time of transplant (i.e., post–local ablative therapy), or if they follow the course set by their tumor parameters present before such treatment. The United Network for Organ Sharing (UNOS) point system for priority scoring of OLTX recipients now includes additional points for patients with HCC. The success of living related donor liver transplantation programs has also led to patients


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InternalMed_Harrison. point system for priority scoring of OLTX recipients now includes additional points for patients with HCC. The success of living related donor liver transplantation programs has also led to patients receiving transplantation earlier for HCC and often with greater than minimal tumors.


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InternalMed_Harrison. current directions Expanded criteria for larger HCCs beyond the Milan criteria (one lesion <5 cm or three lesions, each <3 cm), such as the University of California, San Francisco (UCSF) criteria (single lesion ≤6.5 cm or two lesions ≤4.5 cm with a total diameter ≤8 cm; 1and 5-year survival rates of 90 and 75%, respectively), are being increasingly accepted by various UNOS areas for OLTX with satisfactory longer-term survival comparable to Milan criteria results. Furthermore, downstaging of HCCs that are too large for the Milan criteria by medical therapy (TACE) is increasingly recognized as acceptable treatment before OLTX with equivalent outcomes to patients who originally were within Milan criteria. Within-criteria patients with AFP levels >1000 ng/mL have exceptionally high post-OLTX recurrence rates. Also, the use of “salvage” OLTX after recurrent HCC after resection has produced conflicting outcomes. Shortages of organs combined with advances in resection safety have led to


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InternalMed_Harrison. recurrence rates. Also, the use of “salvage” OLTX after recurrent HCC after resection has produced conflicting outcomes. Shortages of organs combined with advances in resection safety have led to increasing use of resection for patients with good liver function.


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InternalMed_Harrison. Adjuvant Therapy The role of adjuvant chemotherapy for patients after resection or OLTX remains unclear. Both adjuvant and neoadjuvant approaches have been studied, but no clear advantage in disease-free or overall survival has been found. However, a meta-analysis of several trials revealed a significant improvement in disease-free and overall survival. Although analysis of postoperative adjuvant systemic chemotherapy trials demonstrated no disease-free or overall survival advantage, single studies of TACE and neoadjuvant 131I-Ethiodol showed enhanced survival after resection. Antiviral therapy, instead of anticancer therapy, has been successful in decreasing postresection tumor recurrences in the postresection adjuvant setting. Nucleoside analogues in HBV-based HCC and peg-interferon plus ribavirin for HCV-based HCC have both been effective in reducing recurrence rates.


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InternalMed_Harrison. current directions A large adjuvant trial examining resection and transplantation, with or without sorafenib (see below) is in progress. The success of viral therapies in decreasing HCC recurrence after resection is part of a broader focus on the tumor microenvironment (stroma, blood vessels, inflammatory cells, and cytokines) as mediators of HCC progression and as targets for new therapies.


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InternalMed_Harrison. Fewer surgical options exist for stage III tumors involving major vascular structures. In patients without cirrhosis, a major hepatectomy is feasible, although prognosis is poor. Patients with Child A cirrhosis may be resected, but a lobectomy is associated with significant morbidity and mortality rates, and long-term prognosis is poor. Nevertheless, a small percentage of patients will achieve long-term survival, justifying an attempt at resection when feasible. Because of the advanced nature of these tumors, even successful resection can be followed by rapid recurrence. These patients are not considered candidates for transplantation because of the high tumor recurrence rates, unless their tumors can first be downstaged with neoadjuvant therapy. Decreasing the size of the primary tumor allows for less surgery, and the delay in surgery allows for extrahepatic disease to manifest on imaging studies and avoid unhelpful OLTX. The prognosis is poor for stage IV tumors, and no surgical


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InternalMed_Harrison. allows for less surgery, and the delay in surgery allows for extrahepatic disease to manifest on imaging studies and avoid unhelpful OLTX. The prognosis is poor for stage IV tumors, and no surgical treatment is recommended.


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InternalMed_Harrison. Systemic Chemotherapy A large number of controlled and uncontrolled clinical studies have been performed with most of the major classes of cancer chemotherapy. No single agent or combination of agents given systemically reproducibly leads to even a 25% response rate or has any effect on survival.


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InternalMed_Harrison. Regional Chemotherapy In contrast to the dismal results of systemic chemotherapy, a variety of agents given via the hepatic artery have activity for HCC confined to the liver (Table 111-6). Two randomized controlled trials have shown a survival advantage for TACE in a selected subset of patients. One used doxorubicin, and the other used cisplatin. Despite the fact that increased hepatic extraction of chemotherapy has been shown for very few drugs, some drugs such as cisplatin, doxorubicin, mitomycin C, and possibly neocarzinostatin, produce substantial objective responses when administered regionally. Few data are available on continuous hepatic arterial infusion for HCC, although pilot studies with cisplatin have shown encouraging responses. Because the reports have not usually stratified responses or survival based on TNM staging, it is difficult to know long-term prognosis in relation to tumor extent. Most of the studies on regional hepatic arterial chemotherapy also use an


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InternalMed_Harrison. responses or survival based on TNM staging, it is difficult to know long-term prognosis in relation to tumor extent. Most of the studies on regional hepatic arterial chemotherapy also use an embolizing agent such as Ethiodol, gelatin sponge particles (Gelfoam), starch (Spherex), or microspheres. Two products are composed of microspheres of defined size ranges—Embospheres (Biospheres) and Contour SE—using particles of 40–120, 100–300, 300–500, and 500–1000 μm in size. The optimal diameter of the particles for TACE has yet to be defined. Consistently higher objective response rates are reported for arterial administration of drugs together with some form of hepatic artery occlusion compared with any form of systemic chemotherapy to date. The widespread use of some form of embolization in addition to chemotherapy has added to its toxicities. These include a frequent but transient fever, abdominal pain, and anorexia (all in >60% of patients). In addition, >20% of patients have increased


InternalMed_Harrison

InternalMed_Harrison. to chemotherapy has added to its toxicities. These include a frequent but transient fever, abdominal pain, and anorexia (all in >60% of patients). In addition, >20% of patients have increased ascites or transient elevation of transaminases. Cystic artery spasm and cholecystitis are also not uncommon. However, higher responses have also been obtained. The hepatic toxicities associated with embolization may be ameliorated by the use of degradable starch microspheres, with 50–60% response rates. Two randomized studies of TACE versus placebo showed a survival advantage for treatment (Table 111-6). In addition, it is not clear that formal oncologic CT response criteria are adequate for HCC. A loss of vascularity on CT without size change may be an index of loss of viability and thus of response to TACE. A major problem that TACE trials have had in showing a survival advantage is that many HCC patients die of their underlying cirrhosis, not the tumor. Nevertheless, two randomized controlled


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InternalMed_Harrison. to TACE. A major problem that TACE trials have had in showing a survival advantage is that many HCC patients die of their underlying cirrhosis, not the tumor. Nevertheless, two randomized controlled trials, one using doxorubicin and the other using cisplatin, showed a survival advantage for TACE versus placebo (Table 111-6). However, improving quality of life is a legitimate goal of regional therapy. Drug-eluting beads using doxorubicin (DEB-TACE) have been claimed to produce equivalent survival with less toxicity, but this strategy has not been tested in a randomized trial.


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InternalMed_Harrison. Kinase Inhibitors A survival advantage has been observed for the oral multikinase inhibitor, sorafenib (Nexavar), versus placebo in two randomized trials. It targets both the Raf mitogenic pathway and the vascular endothelial growth factor receptor (VEGFR) endothelial vasculogenesis pathway. However, tumor responses were negligible, and the survival in the treatment arm in Asians was less than the placebo arm in the Western trial (Table 111-7). Sorafenib has considerable toxicity, with 30–40% of patients requiring “drug holidays,” dose reductions, or cessation of therapy. The most common toxicities include fatigue, hypertension, diarrhea, mucositis, and skin changes, such as the painful hand-foot syndrome, hair loss, and itching, each in 20–40% of patients. Several “look-alike” new agents that also target angiogenesis have either proved to be inferior or more toxic. These include sunitinib, brivanib, linifanib, everolimus, and bevacizumab (Table 111-8). The idea of angiogenesis alone


InternalMed_Harrison

InternalMed_Harrison. that also target angiogenesis have either proved to be inferior or more toxic. These include sunitinib, brivanib, linifanib, everolimus, and bevacizumab (Table 111-8). The idea of angiogenesis alone as a major HCC therapeutic target may need revision.


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InternalMed_Harrison. New Therapies Although prolonged survival has been reported in phase II trials using newer agents, such as bevacizumab plus Sorafenib vs placebo Raf, VEGFR, PDGFR 10.7 vs 7.9 Sorafenib vs placebo (Asians) Raf, VEGFR, PDGFR 6.5 vs 4.2 Abbreviations: PDGFR, platelet-derived growth factor receptor; Raf, rapidly accelerated fibrosarcoma; VEGFR vascular endothelial growth factor receptor.


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InternalMed_Harrison. erlotinib, the data from a phase III trial were disappointing. Several forms of radiation therapy have been used in the treatment of HCC, including external-beam radiation and conformal radiation therapy. Radiation hepatitis remains a dose-limiting problem. The pure beta emitter 90Yttrium attached to either glass (TheraSphere) or resin (SIR-Spheres) microspheres injected into a major branch hepatic artery has been assessed in phase II trials of HCC and has encouraging tumor control and survival effects with minimal toxicities. Randomized phase III trials comparing it to TACE have yet to be completed. The main attractiveness of 90Yttrium therapy is its safety in the presence of major branch portal vein thrombosis, where TACE is dangerous or contraindicated. Furthermore, external-beam radiation has been reported to be safe and useful in the control of major branch portal or hepatic vein invasion (thrombosis) by tumors. The studies have all been small. Vitamin K has been assessed in


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InternalMed_Harrison. has been reported to be safe and useful in the control of major branch portal or hepatic vein invasion (thrombosis) by tumors. The studies have all been small. Vitamin K has been assessed in clinical trials at high dosage for its HCC-inhibitory actions. This idea is based on the characteristic biochemical defect in HCC of elevated plasma levels of immature prothrombin (DCP or PIVKA-2), due to a defect in the activity of prothrombin carboxylase, a vitamin K–dependent enzyme. Two vitamin K randomized controlled trials from Japan show decreased tumor occurrence, but a major phase III trial aimed at limiting postresection recurrence was not successful.


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InternalMed_Harrison. current directions A number of new kinase inhibitors are being evaluated for HCC (Tables 111-9 and 111-10). These include the biologicals, such as Raf kinase and vascular endothelial growth factor (VEGF) inhibitors, and agents that target various steps of the cell growth pathway. Current hopes focus particularly on the Met pathway inhibitors such as tivantinib and several IGF receptor antagonists. 90Yttrium looks promising and without chemotherapy toxicities. It is particularly attractive because, unlike TACE, it seems safe in the presence of portal vein thrombosis, a pathognomonic feature of HCC aggressiveness. The bottleneck of liver donors for OLTX is at last widening with increasing use of living donors, and criteria for OLTX for larger HCCs are slowly expanding. Patient participation in clinical trials assessing new therapies is encouraged (www.clinicaltrials.gov).


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InternalMed_Harrison. The main effort now is the evaluation of combinations of the compounds listed in Tables 111-7 to 111-9 that target different pathways, as well as the combination of any of these targeted therapies, but especially sorafenib, with TACE or 90Yttrium radioembolization. Combining TACE with sorafenib appears to be safe in phase II studies with promising survival data, but randomized studies are still in progress. The same is true for intra-arterial 90Yttrium plus sorafenib as therapy for HCC and as bridge to transplant therapy. Ubiquitin-proteasome Bortezomib Abbreviations: EGF, epidermal growth factor; FGF1, fibroblast growth factor 1; IGF-I, insulin-like growth factor I; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor.


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InternalMed_Harrison. Tumor growth or spread is considered a poor prognostic sign and evidence of treatment failure. By contrast, patients receiving chemotherapy are judged to have a response if there is shrinkage of tumor size. Lack of response/size decrease has been thought of as treatment failure. Three considerations in HCC management have completely changed the views concerning nonshrinkage after therapy. First, the correlation between response to chemotherapy and survival is poor in various tumors; in some tumors, such as ovarian cancer and small-cell lung cancer, substantial tumor shrinkage on chemotherapy is followed by rapid


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InternalMed_Harrison. EGF receptor antagonists: erlotinib, gefitinib, lapatinib, cetuximab, brivanib Multikinase antagonists: sorafenib, sunitinib VEGF antagonist: bevacizumab VEGFR antagonist: ABT-869 (linifanib) mTOR antagonists: sirolimus, temsirolimus, everolimus Proteasome inhibitors: bortezomib Vitamin K 131I–Ethiodol (lipiodol) 131I–Ferritin 90Yttrium microspheres (TheraSphere, SIR-Spheres) 166Holmium, 188Rhenium Three-dimensional conformal radiation Proton beam high-dose radiotherapy Gamma knife, CyberKnife New targets: inhibitors of cyclin dependent kinases (Cdk), TRAIL induction caspases, and stem cells Abbreviations: EGF, epidermal growth factor; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.


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InternalMed_Harrison. Tumors of the Liver and Biliary Tree 552 tumor regrowth. Second, the Sorafenib HCC Assessment Randomized Protocol (SHARP) phase III trial of sorafenib versus placebo for unresectable HCC showed that survival could be significantly enhanced in the treatment arm with only 2% of the patients having tumor response but 70% of patients having disease stabilization. This observation has led to a reconsideration of the usefulness of response and the significance of disease stability. Third, HCC is a typically highly vascular tumor, and the vascularity is considered to be a measure of tumor viability. As a result, the Response Evaluation Criteria in Solid Tumors (RECIST) have been modified to mRECIST, which requires measurement of vascular/ viable tumor on the CT or MRI scan. A partial response is defined as a 30% decrease in the sum of diameters of viable (arterially enhancing) target tumors. The need for semiquantitation of tumor vascularity on scans has led to the introduction of


InternalMed_Harrison

InternalMed_Harrison. is defined as a 30% decrease in the sum of diameters of viable (arterially enhancing) target tumors. The need for semiquantitation of tumor vascularity on scans has led to the introduction of diffusion-weighted MRI imaging. Tissue-specific imaging agents such as gadoxetic acid (Primovist or Eovist) and the move to functional and genetic imaging mark a shift in approaches. Furthermore, plasma AFP response may be a biologic marker of radiologic response.


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InternalMed_Harrison. Long-term survival is associated with resection or ablation or transplantation, all of which can yield >70% 5-year survival. Liver transplant is the only therapy that can treat the tumor and the underlying liver disease simultaneously and may be the most important advance in HCC therapy in 50 years. Unfortunately, it benefits only patients with limited size tumors without macrovascular portal vein invasion. Untreated patients with multinodular asymptomatic tumors without vascular invasion or extrahepatic spread have a median survival of approximately 16 months. Chemoembolization (TACE) improves their median survival to 19–20 months and is considered standard therapy for these patients, who represent the majority of HCC patients, although 90Yttrium therapy may provide similar results with less toxicity. Patients with advanced-stage disease, vascular invasion, or metastases have a median survival of around 6 months. Among this group, outcomes may vary according to their underlying liver


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InternalMed_Harrison. toxicity. Patients with advanced-stage disease, vascular invasion, or metastases have a median survival of around 6 months. Among this group, outcomes may vary according to their underlying liver disease. It is this group at which kinase inhibitors are directed.


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InternalMed_Harrison. The Most Common Modes of Patient Presentation 1. A patient with known history of hepatitis, jaundice, or cirrhosis, with an abnormality on ultrasound or CT scan, or rising AFP or DCP (PIVKA-2) 2. A patient with an abnormal liver function test as part of a routine examination 3. 4. Symptoms of HCC including cachexia, abdominal pain, or fever 1. Clinical jaundice, asthenia, itching (scratches), tremors, or disorientation 2. Hepatomegaly, splenomegaly, ascites, peripheral edema, skin signs of liver failure 1. Blood tests: full blood count (splenomegaly), liver function tests, ammonia levels, electrolytes, AFP and DCP (PIVKA-2), Ca2+ and Mg2+; hepatitis B, C, and D serology (and quantitative HBV DNA or HCV RNA, if either is positive); neurotensin (specific for fibrolamellar HCC) 2.


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InternalMed_Harrison. Triphasic dynamic helical (spiral) CT scan of liver (if inadequate, then follow with an MRI); chest CT scan; upper and lower gastrointestinal endoscopy (for varices, bleeding, ulcers); and brain scan (only if symptoms suggest) 3. Core biopsy: of the tumor and separate biopsy of the underlying liver 1. HCC <2 cm: RFA, PEI, or resection 2. HCC >2 cm, no vascular invasion: liver resection, RFA, or OLTX 3. Multiple unilobar tumors or tumor with vascular invasion: TACE or sorafenib 4. Bilobar tumors, no vascular invasion: TACE with OLTX for patients with tumor response 5. Extrahepatic HCC or elevated bilirubin: sorafenib or bevacizumab plus erlotinib (combination agent trials are in progress)


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InternalMed_Harrison. This rarer variant of HCC has a quite different biology than adult-type HCC. None of the known HCC causative factors seem important here. It is typically a disease of younger adults, often teenagers and predominantly females. It is AFP-negative, but patients typically have elevated blood neurotensin levels, normal liver function tests, and no cirrhosis. Radiology is similar for HCC, except that characteristic adult-type portal vein invasion is less common. Although it is often multifocal in the liver, and therefore not resectable, metastases are common, especially to lungs and locoregional lymph nodes, but survival is often much better than with adult-type HCC. Resectable tumors are associated with 5-year survival ≥50%. Patients often present with a huge liver or unexplained weight loss, fever, or elevated liver function tests on routine evaluations. These huge masses suggest quite slow growth for many tumors. Surgical resection is the best management option, even for metastases, as


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InternalMed_Harrison. fever, or elevated liver function tests on routine evaluations. These huge masses suggest quite slow growth for many tumors. Surgical resection is the best management option, even for metastases, as these tumors respond much less well to chemotherapy than adult-type HCC. Although several series of OLTX for FL-HCC have been reported, the patients seem to die from tumor recurrences, with a 2-to 5-year lag compared with OLTX for adult-type HCC. Anecdotal responses to gemcitabine plus cisplatin-TACE are reported.


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InternalMed_Harrison. Epithelioid Hemangioendothelioma (EHE) This rare vascular tumor of adults is also usually multifocal and can also be associated with prolonged survival, even in the presence of metastases, which are commonly in the lung. There is usually no underlying cirrhosis. Histologically, these tumors are usually of borderline malignancy and express factor VIII, confirming their endothelial origin. OLTX may produce prolonged survival.


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InternalMed_Harrison. Cholangiocarcinoma (CCC) CCC typically refers to mucin-producing adenocarcinomas (different from HCC) that arise from the biliary tract and have features of cholangiocyte differentiation. They are grouped by their anatomic site of origin, as intrahepatic (IHC), perihilar (central, ∼65% of CCCs), and peripheral (or distal, ∼30% of CCCs). IHC is the second most common primary liver tumor. Depending on the site of origin, they have different features and require different treatments. They arise on the basis of cirrhosis less frequently than HCC, but may complicate primary biliary cirrhosis. However, cirrhosis and both primary biliary cirrhosis and HCV predispose to IHC. Nodular tumors arising at the bifurcation of the common bile duct are called Klatskin tumors and are often associated with a collapsed gallbladder, a finding that mandates visualization of the entire biliary tree. The approach to management of central and peripheral CCC is quite different. Incidence is increasing.


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InternalMed_Harrison. with a collapsed gallbladder, a finding that mandates visualization of the entire biliary tree. The approach to management of central and peripheral CCC is quite different. Incidence is increasing. Although most CCCs have no obvious cause (etiology unknown), a number of predisposing factors have been identified. Predisposing diseases include primary sclerosing cholangitis (10–20% of primary sclerosing cholangitis [PSC] patients), an autoimmune disease, and liver fluke in Asians, especially Opisthorchis viverrini and Clonorchis sinensis. CCC seems also to be associated with any cause of chronic biliary inflammation and injury, with alcoholic liver disease, choledocholithiasis, choledochal cysts (10%), and Caroli’s disease (a rare inherited form of bile duct ectasia). CCC most typically presents as painless jaundice, often with pruritus or weight loss. Diagnosis is made by biopsy, percutaneously for peripheral liver lesions, or more commonly via endoscopic retrograde


InternalMed_Harrison

InternalMed_Harrison. most typically presents as painless jaundice, often with pruritus or weight loss. Diagnosis is made by biopsy, percutaneously for peripheral liver lesions, or more commonly via endoscopic retrograde cholangiopancreatography (ERCP) under direct vision for central lesions. The tumors often stain positively for cytokeratins 7, 8, and 19 and negatively for cytokeratin 20. However, histology alone cannot usually distinguish CCC from metastases from colon or pancreas primary tumors. Serologic tumor markers appear to be nonspecific, but CEA, CA 19-9, and CA-125 are often elevated in CCC patients and are useful for following response to therapy. Radiologic evaluation typically starts with ultrasound, which is very useful in visualizing dilated bile ducts, and then proceeds with either MRI or magnetic resonance cholangiopancreatography (MRCP) or helical CT scans. Invasive cholangiopancreatography (ERCP) is then needed to define the biliary tree and obtain a biopsy or is needed therapeutically


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InternalMed_Harrison. resonance cholangiopancreatography (MRCP) or helical CT scans. Invasive cholangiopancreatography (ERCP) is then needed to define the biliary tree and obtain a biopsy or is needed therapeutically to decompress an obstructed biliary tree with internal stent placement. If that fails, then percutaneous biliary drainage will be needed, with the biliary drainage flowing into an external bag. Central tumors often invade the porta hepatis, and locoregional lymph node involvement by tumor is frequent. Incidence has been increasing in recent decades; few patients survive 5 years. The usual treatment is surgical, but combination systemic chemotherapy may be effective. After complete surgical resection for IHC, 5-year survival is 25–30%. Combination radiation therapy with liver transplant has produced a 5-year recurrence-free survival rate of 65%.


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InternalMed_Harrison. Hilar CCC is resectable in ∼30% of patients and usually involves bile duct resection and lymphadenectomy for prognostication. Typical survival is approximately 24 months, with recurrences being mainly in the operative bed but with ∼30% in the lungs and liver. Distal CCC, which involves the main ducts, is normally treated by resection of the extrahepatic bile ducts, often with pancreaticoduodenectomy. Survival is similar. Due to the high rates of locoregional recurrences or positive surgical margins, many patients receive postoperative adjuvant radiotherapy. Its effect on survival has not been assessed. Intraluminal brachyradiotherapy has also shown some promise. However, photodynamic therapy enhanced survival in one study. In this technique, sodium porfimer is injected intravenously and then subjected to intraluminal red light laser photoactivation. OLTX has been assessed for treatment of unresectable CCC. Five-year survival was ∼20%, so enthusiasm waned. However, neoadjuvant


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InternalMed_Harrison. and then subjected to intraluminal red light laser photoactivation. OLTX has been assessed for treatment of unresectable CCC. Five-year survival was ∼20%, so enthusiasm waned. However, neoadjuvant radiotherapy with sensitizing chemotherapy has shown better survival rates for CCC treated by OLTX and is currently used by UNOS for perihilar CCC <3 cm with neither intrahepatic or extrahepatic metastases. A 12-center data collection study of 287 patients with perihilar CCC confirmed the benefit of this approach in a subset of patients, with a 53% 5-year survival rate but with 10% patient dropout before transplantation. The patients had neoadjuvant external radiation with radiosensitizing therapy. Patients with tumors >3 cm had significantly shorter survival. Multiple chemotherapeutic agents have been assessed for activity and survival in unresectable CCC. Most have been inactive. However, both systemic and hepatic arterial gemcitabine have shown promising results. The combination of


InternalMed_Harrison

InternalMed_Harrison. have been assessed for activity and survival in unresectable CCC. Most have been inactive. However, both systemic and hepatic arterial gemcitabine have shown promising results. The combination of cisplatin plus gemcitabine has produced a survival advantage compared with gemcitabine alone in a 410-patient randomized controlled phase III trial for patients with locally advanced or metastatic CCC and is now considered standard therapy for unresectable CCC. Median overall survival in the combination arm was 11.7 months versus 8.1 months for gemcitabine alone. Significant responses were seen mainly in patients with IHC and gallbladder cancer. However, neither surgery for lymph node–positive disease nor regional chemotherapy in nonsurgical patients has shown any survival advantage thus far. Several case series have shown safety and some responses for hepatic arterial chemotherapy with gemcitabine, drug-eluting beads, and 90Yttrium microspheres, but no convincing clinical trials are


InternalMed_Harrison

InternalMed_Harrison. far. Several case series have shown safety and some responses for hepatic arterial chemotherapy with gemcitabine, drug-eluting beads, and 90Yttrium microspheres, but no convincing clinical trials are available. Clinical trials are under way with targeted therapies. Bevacizumab plus erlotinib gave a 10% partial response rate with median overall survival of 9.9 months. A sorafenib trial yielded an overall survival of 4.4 months, but 50% of the patients had received previous chemotherapy. Patients with unresectable tumors should be treated in clinical trials.


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InternalMed_Harrison. Gallbladder (GB) cancer has an even worse prognosis than CCC, with a typical survival of ∼6 months or less. Women are affected much more commonly than men (4:1), unlike HCC or CCC, and GB cancer occurs more frequently than CCC. Most patients have a history of antecedent 553 gallstones, but very few patients with gallstones develop GB cancer (∼0.2%). GB cancer presents similarly to CCC and is often diagnosed unexpectedly during gallstone or cholecystitis surgery. Presentation is typically that of chronic cholecystitis, chronic right upper quadrant pain, and weight loss. Useful but nonspecific serum markers include CEA and CA 19-9. CT scans or MRCP typically reveal a GB mass. The mainstay of treatment is surgical, either simple or radical cholecystectomy for stage I or II disease, respectively. Survival rates are near 100% at 5 years for stage I, and range from 60–90% at 5 years for stage II. More advanced GB cancer has worse survival, and many patients are unresectable. Adjuvant


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InternalMed_Harrison. Survival rates are near 100% at 5 years for stage I, and range from 60–90% at 5 years for stage II. More advanced GB cancer has worse survival, and many patients are unresectable. Adjuvant radiotherapy, used in the presence of local lymph node disease, has not been shown to enhance survival. Chemotherapy is not useful in advanced or metastatic GB cancer.


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InternalMed_Harrison. This tumor arises within 2 cm of the distal end of the common bile duct and is mainly (90%) an adenocarcinoma. Locoregional lymph nodes are commonly involved (50%), and the liver is the most frequent site for metastases. The most common clinical presentation is jaundice, and many patients also have pruritus, weight loss, and epigastric pain. Initial evaluation is performed with an abdominal ultrasound to assess vascular involvement, biliary dilation, and liver lesions. This is followed by a CT scan or MRI and especially MRCP. The most effective therapy is resection by pylorus-sparing pancreaticoduodenectomy, an aggressive procedure resulting in better survival rates than with local resection. Survival rates are ∼25% at 5 years in operable patients with involved lymph nodes and ∼50% in patients without involved nodes. Unlike CCC, approximately 80% of patients are thought to be resectable at diagnosis. Adjuvant chemotherapy or radiotherapy has not been shown to enhance survival. For


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InternalMed_Harrison. patients without involved nodes. Unlike CCC, approximately 80% of patients are thought to be resectable at diagnosis. Adjuvant chemotherapy or radiotherapy has not been shown to enhance survival. For metastatic tumors, chemotherapy is currently experimental.


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InternalMed_Harrison. These are predominantly from colon, pancreas, and breast primary tumors but can originate from any organ primary. Ocular melanomas are prone to liver metastasis. Tumor spread to the liver normally carries a poor prognosis for that tumor type. Colorectal and breast hepatic metastases were previously treated with continuous hepatic arterial infusion chemotherapy. However, more effective systemic drugs for each of these two cancers, especially the addition of oxaliplatin to colorectal cancer regimens, have reduced the use of hepatic artery infusion therapy. In a large randomized study of systemic versus infusional plus systemic chemotherapy for resected colorectal metastases to the liver, the patients receiving infusional therapy had no survival advantage, mainly due to extrahepatic tumor spread. 90Yttrium resin beads are approved in the United States for treatment of colorectal hepatic metastases. The role of this modality, either alone or in combination with chemotherapy, is being


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InternalMed_Harrison. spread. 90Yttrium resin beads are approved in the United States for treatment of colorectal hepatic metastases. The role of this modality, either alone or in combination with chemotherapy, is being evaluated in many centers. Palliation may be obtained from chemoembolization, PEI, or RFA.


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InternalMed_Harrison. Three common benign tumors occur and all are found predominantly in women. They are hemangiomas, adenomas, and focal nodular hyperplasia (FNH). FNH is typically benign, and usually no treatment is needed. Hemangiomas are the most common and are entirely benign. Treatment is unnecessary unless their expansion causes symptoms. Adenomas are associated with contraceptive hormone use. They can cause pain and can bleed or rupture, causing acute problems. Their main interest for the physician is a low potential for malignant change and a 30% risk of bleeding. For this reason, considerable effort has gone into differentiating these three entities radiologically. On discovery of a liver mass, patients are usually advised to stop taking sex steroids, because adenoma regression may then occasionally occur. Adenomas can often be large masses ranging from 8–15 cm. Due to their size and definite, but low, malignant potential and potential for bleeding, adenomas are typically resected. The most


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InternalMed_Harrison. occur. Adenomas can often be large masses ranging from 8–15 cm. Due to their size and definite, but low, malignant potential and potential for bleeding, adenomas are typically resected. The most useful diagnostic differentiating tool is a triphasic CT scan performed with HCC fast bolus protocol for arterial-phase imaging, together with subsequent delayed venous-phase imaging. Adenomas usually do not appear on


InternalMed_Harrison

InternalMed_Harrison. Tumors of the Liver and Biliary Tree 554 the basis of cirrhosis, although both adenomas and HCCs are intensely vascular on the CT arterial phase and both can exhibit hemorrhage (40% of adenomas). However, adenomas have smooth, well-defined edges, and enhance homogeneously, especially in the portal venous phase on delayed images, when HCCs no longer enhance. FNHs exhibit a characteristic central scar that is hypovascular on the arterial-phase and hypervascular on the delayed-phase CT images. MRI is even more sensitive in depicting the characteristic central scar of FNH. Elizabeth Smyth, David Cunningham


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InternalMed_Harrison. Elizabeth Smyth, David Cunningham Pancreatic cancer is the fourth leading cause of cancer death in the United States and is associated with a poor prognosis. Endocrine tumors affecting the pancreas are discussed in Chap. 113. Infiltrating ductal adenocarcinomas, the subject of this Chapter, account for the vast majority of cases and arise most frequently in the head of pancreas. At the time of diagnosis, 85–90% of patients have inoperable or metastatic disease, which is reflected in the 5-year survival rate of only 6% for all stages combined. An improved 5-year survival of up to 24% may be achieved when the tumor is detected at an early stage and when complete surgical resection is accomplished.


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InternalMed_Harrison. Pancreatic cancer represents 3% of all newly diagnosed malignancies in the United States. The most common age group at diagnosis is 65–84 years for both sexes. Pancreatic cancer was estimated to have been diagnosed in approximately 45,220 patients and accounted for approximately 38,460 deaths in 2013. Although survival rates have almost doubled over the past 35 years for this disease, overall survival remains low.


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InternalMed_Harrison. An estimated 278,684 cases of pancreatic cancer occur annu ally worldwide (the thirteenth most common cancer globally), with up to 60% of these cases diagnosed in more developed countries. It remains the eighth most common cause of cancer death in men and the ninth most common in women. The incidence is highest in the United States and western Europe and lowest in parts of Africa and South Central Asia. However, increasing rates of obesity, diabetes, and tobacco use in addition to access to diagnostic radiology in the developing world are likely to increase incidence rates in these countries. In this situation, consideration of the cost implications of adoption of current treatment paradigms in resource-constrained environments will be necessary. Primary prevention such as limiting tobacco use and avoiding obesity may be more cost effective than improvements in treatment of preexisting disease.


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InternalMed_Harrison. Cigarette smoking may be the cause of up to 20–25% of all pancreatic cancers and is the most common environmental risk factor for this disease. A longstanding history of type 1 or type 2 diabetes also appears to be a risk factor; however, diabetes may also occur in association with pancreatic cancer, possibly confounding this interpretation. Other risk factors may include obesity, chronic pancreatitis, and ABO blood group status. Alcohol does not appear to be a risk factor unless excess consumption gives rise to chronic pancreatitis.


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InternalMed_Harrison. Pancreatic cancer is associated with a number of well-defined molecular hallmarks. The four genes most commonly mutated or inactivated in pancreatic cancer are KRAS (predominantly codon 12, in 60–75% of pancreatic cancers), the tumor-suppressor genes p16 (deleted in 95% of tumors), p53 (inactivated or mutated in 50–70% of tumors), and SMAD4 (deleted in 55% of tumors). The pancreatic cancer precursor lesion pancreatic intraepithelial neoplasia (PanIN) acquires these genetic abnormalities in a progressive manner associated with increasing dysplasia; initial KRAS mutations are followed by p16 loss and finally p53 and SMAD4 alterations. SMAD4 gene inactivation is associated with a pattern of widespread metastatic disease in advanced-stage patients and poorer survival in patients with surgically resected pancreatic adenocarcinoma.


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InternalMed_Harrison. Up to 16% of pancreatic cancers may be inherited. Germline mutations in the following genes are associated with a significantly increased risk of pancreatic cancer and other cancers: (1) STK11 gene (Peutz-Jeghers syndrome), which carries a 132-fold increased lifetime risk of pancreatic cancer above the general population; (2) BRCA2 (increased risk of breast, ovarian, and pancreatic cancer); (3) p16/CDKN2A (familial atypical multiple mole melanoma), which carries an increased risk of melanoma and pancreatic cancer; (4) PALB2, which confers an increased risk of breast and pancreatic cancer; (5) hMLH1 and MSH2 (Lynch syndrome), which carries an increased risk of colon and pancreatic cancer; and (6) ATM (ataxia-telangiectasia), which carries an increased risk of breast cancer, lymphoma, and pancreatic cancer. Familial pancreatitis and an increased risk of pancreatic cancer are associated with mutations of the PRSS1 (serine protease 1) gene. However, for most familial pancreatic syndromes,


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InternalMed_Harrison. cancer. Familial pancreatitis and an increased risk of pancreatic cancer are associated with mutations of the PRSS1 (serine protease 1) gene. However, for most familial pancreatic syndromes, the underlying genetic cause remains unexplained. The absolute number of affected first-degree relatives is also correlated with increased cancer risk, and patients with at least two first-degree relatives with pancreatic cancer should be considered to have familial pancreatic cancer until proven otherwise.


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InternalMed_Harrison. The desmoplastic stroma surrounding pancreatic adenocarcinoma functions as a mechanical barrier to chemotherapy and secretes compounds essential for tumor progression and metastasis. Key mediators of these functions include the activated pancreatic stellate cell and the glycoprotein SPARC (secreted protein acidic and rich in cysteine), which is expressed in 80% of pancreatic ductal adenocarcinomas. Targeting this extracellular environment has become increasingly important in the treatment of advanced disease.


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InternalMed_Harrison. Screening is not routinely recommended because the incidence of pancreatic cancer in the general population is low (lifetime risk 1.3%), putative tumor markers such as carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have insufficient sensitivity, and computed tomography (CT) has inadequate resolution to detect pancreatic dysplasia. Endoscopic ultrasound (EUS) is a more promising screening tool, and preclinical efforts are focused on identifying biomarkers that may detect pancreatic cancer at an early stage. Consensus practice recommendations based largely on expert opinion have chosen a threshold of greater than fivefold increased risk for developing pancreatic cancer to select individuals who may benefit from screening. This includes people with two or more first-degree relatives with pancreatic cancer, patients with Peutz-Jeghers syndrome, and BRCA 2, p16, and hereditary nonpolyposis colorectal cancer (HNPCC) mutation carriers with one or more affected


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InternalMed_Harrison. first-degree relatives with pancreatic cancer, patients with Peutz-Jeghers syndrome, and BRCA 2, p16, and hereditary nonpolyposis colorectal cancer (HNPCC) mutation carriers with one or more affected first-degree relatives.


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InternalMed_Harrison. PanIN represents a spectrum of small (<5 mm) neoplastic but noninvasive precursor lesions of the pancreatic ductal epithelium demonstrating mild, moderate, or severe dysplasia (PanIN 1–3, respectively); however, not all PanIN lesions will progress to frank invasive malignancy. Cystic pancreatic tumors such as intraductal mucinous papillary neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) are increasingly detected radiologically and are frequently asymptomatic. Main duct IPMNs are more likely to occur in older persons and have higher malignant potential than branched duct IPMNs (invasive cancer in 45% vs 18% of resected lesions, respectively). In contrast, MCNs are solitary lesions of the distal pancreas that do not communicate with the duct system. MCNs have an almost exclusive female distribution (95%). The rate of invasive cancer in resected MCNs is lower (<18%) with increased rates associated with larger tumors or the presence of nodules.


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InternalMed_Harrison. CLINICAL FEATURES Clinical Presentation Obstructive jaundice occurs frequently when the cancer is located in the head of the pancreas. This may be accompanied by symptoms of abdominal discomfort, pruritus, lethargy, and weight loss. Less common presenting features include epigastric pain, backache, new-onset diabetes mellitus, and acute pancreatitis caused by pressure effects on the pancreatic duct. Nausea and vomiting, resulting from gastroduodenal obstruction, may also be a symptom of this disease. Physical Signs Patients can present with jaundice and cachexia, and scratch marks may be present. Of patients with operable tumors, 25% have a palpable gallbladder (Courvoisier’s sign). Physical signs related to the development of distant metastases include hepatomegaly, ascites, left supraclavicular lymphadenopathy (Virchow’s node), and periumbilical nodules (Sister Mary Joseph’s nodes).


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InternalMed_Harrison. DIAGNOSIS Diagnostic Imaging Patients who present with clinical features suggestive of pancreatic cancer undergo imaging to confirm the presence of a tumor and to establish whether the mass is likely to be inflammatory or malignant in nature. Other imaging objectives include the local and distant staging of the tumor, which will determine resectability and provide prognostic information. Dual-phase, contrast-enhanced spiral CT is the imaging modality of choice (Fig. 112-1). It provides accurate visualization of surrounding viscera, vessels, and lymph nodes, thus determining tumor resectability. Intestinal infiltration and liver and lung metastases are also reliably depicted on CT. There is no advantage of magnetic resonance imaging (MRI) over CT in predicting tumor resectability, but selected cases may benefit from MRI to characterize the nature of small indeterminate liver lesions and to evaluate the cause of biliary dilatation when no obvious mass is seen on CT. Endoscopic


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InternalMed_Harrison. but selected cases may benefit from MRI to characterize the nature of small indeterminate liver lesions and to evaluate the cause of biliary dilatation when no obvious mass is seen on CT. Endoscopic retrograde cholangiopancreatography (ERCP) is useful for revealing small pancreatic lesions, identifying stricture or obstruction in pancreatic or common bile ducts, and facilitating stent placement; however, it is associated with a risk of pancreatitis (Fig. 112-2). Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive method for accurately depicting the level and degree of bile and pancreatic duct dilatation. EUS is highly sensitive in detecting lesions less than 3 cm in size (more sensitive than CT for lesions <2 cm) and is useful as a local staging tool for assessing vascular invasion and lymph node involvement. Fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered before surgery or radical chemoradiotherapy (CRT), because it is superior to


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InternalMed_Harrison. invasion and lymph node involvement. Fluorodeoxyglucose positron emission tomography (FDG-PET) should be considered before surgery or radical chemoradiotherapy (CRT), because it is superior to conventional imaging in detecting distant metastases.


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InternalMed_Harrison. Tissue Diagnosis and Cytology Preoperative confirmation of malignancy is not always necessary in patients with radiologic appearances consistent with operable pancreatic cancer. However, EUS-guided fine-needle aspiration is the technique of choice when there is any doubt, and also for use in patients who require neoadjuvant treatment. It has an accuracy of approximately 90% and has a smaller risk of intraperitoneal dissemination compared with the percutaneous route. FIGURE 112-1 Coronal computed tomography showing pancre-atic cancer and dilated intrahepatic and pancreatic ducts (arrows). showing contrast in dilated pancreatic duct (arrows). Percutaneous biopsy of the pancreatic primary or liver metastases is only acceptable in patients with inoperable or metastatic disease. ERCP is a useful method for obtaining ductal brushings, but the sensitivity of ERCP for diagnosis ranges from 35 to 70%.


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InternalMed_Harrison. Serum Markers Tumor-associated CA19-9 is elevated in approximately 70–80% of patients with pancreatic carcinoma but is not recommended as a routine diagnostic or screening test because its sensitivity and specificity are inadequate for accurate diagnosis. Preoperative CA19-9 levels correlate with tumor stage, and postresection CA19-9 level has prognostic value. It is an indicator of asymptomatic recurrence in patients with completely resected tumors and is used as a biomarker of response in patients with advanced disease undergoing chemotherapy. A number of studies have established a high pretreatment CA19-9 level as an independent prognostic factor.


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InternalMed_Harrison. The American Joint Committee on Cancer (AJCC) tumor-nodemetastasis (TNM) staging of pancreatic cancer takes into account the location and size of the tumor, the involvement of lymph nodes, and distant metastasis. This information is then combined to assign a stage (Fig. 112-3). From a practical standpoint, patients are grouped according to whether the cancer is resectable, locally advanced (unresectable, but without distant spread), or metastatic.


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InternalMed_Harrison. Approximately 10% of patients present with localized nonmetastatic disease that is potentially suitable for surgical resection. Approximately 30% of patients have R1 resection (microscopic residual disease) following surgery. Those who undergo R0 resection (no microscopic or macroscopic residual tumor) and who receive adjuvant treatment have the best chance of cure, with an estimated median survival of 20–23 months and a 5-year survival of approximately 20%. Outcomes are more favorable in patients with small (<3 cm), well-differentiated tumors and lymph node–negative disease.


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InternalMed_Harrison. Patients should have surgery in dedicated pancreatic centers that have lower postoperative morbidity and mortality rates. The standard surgical procedure for patients with tumors of the pancreatic head or uncinate process is a pylorus-preserving pancreaticoduodenectomy (modified Whipple’s procedure). The procedure of choice for tumors of the pancreatic body and tail is a distal pancreatectomy, which routinely includes splenectomy. Postoperative treatment improves long-term outcomes in this group of patients. Adjuvant chemotherapy comprising six cycles of gemcitabine is common practice worldwide based on data from three randomized controlled trials (Table 112-1). The Charité FIGURE 112-3 Staging of pancreatic cancer, and survival according to stage. AJCC, American Joint Committee on Cancer. (Illustration by Stephen Millward.) Survival Study Comparator Arm No. of Patients PFS/DFS (months) Median Survival (months)


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InternalMed_Harrison. Survival Study Comparator Arm No. of Patients PFS/DFS (months) Median Survival (months) ESPAC-1, Neoptolemos et al: N Engl J Chemotherapy (folinic acid 289 PFS 15.3 vs 9.4. (p = .02) 20.1 vs 15.5 (HR 0.71; 95% CI Med 350:1200, 2004 + bolus 5-FU) vs no 0.55–0.92; p = .009) chemotherapy CONKO 001, Oettle et al: JAMA Gemcitabine vs observation 368 Median DFS 13.4 vs 6.9 22.1 vs 20.2 (p = .06) 297:267, 2007 (p <.001) ESPAC-3, Neoptolemos et al: JAMA 5-FU/LV vs gemcitabine 1088 23 vs 23.6 (HR 0.94; 95% CI 0.81–1.08, 304:1073, 2010 p = .39) Abbreviations: CI, confidence interval; CONKO, Charité Onkologie; DFS, disease-free survival; ESPAC, European Study Group for Pancreatic Cancer; 5-FU, 5-fluorouracil; HR, hazard ratio; LV, leucovorin; PFS, progression-free survival. Survival Study Comparator Arm No. of Patients PFS (months) Median Survival (months) Moore et al: J Clin Oncol 26:1960, Gemcitabine vs gemcitabine 569 2007 + erlotinib


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InternalMed_Harrison. Survival Study Comparator Arm No. of Patients PFS (months) Median Survival (months) Moore et al: J Clin Oncol 26:1960, Gemcitabine vs gemcitabine 569 2007 + erlotinib Cunningham et al: J Clin Oncol Gemcitabine vs gemcitabine 533 27:5513, 2009 + capecitabine (GEM-CAP) Von Hoff et al: N Engl J Med Gemcitabine vs gemcitabine 861 369:1691, 2013 + nab-paclitaxel Conroy et al: N Engl J Med Gemcitabine vs FOLFIRINOX 342 364:1817, 2011


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InternalMed_Harrison. Conroy et al: N Engl J Med Gemcitabine vs FOLFIRINOX 342 364:1817, 2011 Onkologie trial (CONKO 001) found that the use of gemcitabine after complete resection significantly delayed the development of recurrent disease compared with surgery alone. The European Study Group for Pancreatic Cancer 3 (ESPAC-3) trial, which investigated the benefit of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine, revealed no survival difference between the two drugs. However, the toxicity profile of adjuvant gemcitabine was superior to 5-FU/FA by virtue of its lower incidence of stomatitis and diarrhea. Adjuvant radiotherapy is not commonly used in Europe based on the negative results of the ESPAC-1 study. Adjuvant 5-FU-based CRT with gemcitabine before and after radiotherapy as used in the Radiation Therapy Oncology Group (RTOG) 97-04 trial is preferred in the United States. This approach may be most beneficial in patients with bulky tumors involving the pancreatic head.


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InternalMed_Harrison. Approximately 30% of patients present with locally advanced, unresectable, but nonmetastatic pancreatic carcinoma. The median survival with gemcitabine is 9 months. Patients who respond to chemotherapy or who achieve stable disease after 3–6 months of gemcitabine have frequently been offered consolidation radiotherapy. However, a large, phase III, randomized controlled trial, LAP-07, did not demonstrate any improvement in survival for patients treated with CRT after 4 months of disease control on either gemcitabine or a gemcitabine/erlotinib combination. Approximately 60% of patients with pancreatic cancer present with metastatic disease. Patients with poor performance status do not usually benefit from chemotherapy. Gemcitabine was the standard


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InternalMed_Harrison. Approximately 60% of patients with pancreatic cancer present with metastatic disease. Patients with poor performance status do not usually benefit from chemotherapy. Gemcitabine was the standard Gastrointestinal (GI) neuroendocrine tumors (NETs) are tumors derived from the diffuse neuroendocrine system of the GI tract; that system is composed of amineand acid-producing cells with different hormonal profiles, depending on the site of origin. The tumors historically are divided into GI-NETs (in the GI tract) (also frequently called carcinoid tumors) and pancreatic neuroendocrine tumors (pNETs), although newer pathologic classifications have proposed that they all be classified as GI-NETs. The term GI-NET has been proposed to replace the term carcinoid; however, the term carcinoid is widely used, and many are not familiar with this change.


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InternalMed_Harrison. 3.55 vs 3.75 (HR 0.77; 95% CI 5.91 vs 6.24 (HR 0.82; 95% CI 0.69– 0.64–0.92; p = .004) 0.99; p = .038) 3.8 vs 5.3 (HR 0.78; 95% CI 6.2 vs 7.1 (HR 0.86; 95% CI 0.72–1.02; 0.66–0.93; p = .004) p = .08) 3.7 vs 5.5 (HR 0.69; 95% CI 6.7 vs 8.5 (HR 0.72; 95% CI 0.62–0.83; 0.58–0.82; p <.001) p <.001) 3.3 vs 6.4 (HR 0.47; 95% CI 6.8 vs 11.1 (HR 0.57; 95% CI 0.45–0.73; 0.37–0.59; p <.001) p <.001) treatment with a median survival of 6 months and a 1-year survival rate of only 20%. The addition of nab-paclitaxel (an albumin bound nanoparticle formulation of paclitaxel) to gemcitabine results in significantly improved 1-year survival compared to gemcitabine alone (35% vs 22%, p <.001). Capecitabine, an oral fluoropyrimidine, has also been combined with gemcitabine (GEM-CAP) in a phase III trial that showed an improvement in response rate and progression-free survival over single-agent gemcitabine, but no overall survival benefit. However, pooling of two other randomized controlled trials with


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InternalMed_Harrison. showed an improvement in response rate and progression-free survival over single-agent gemcitabine, but no overall survival benefit. However, pooling of two other randomized controlled trials with this trial in a meta-analysis resulted in a survival advantage with GEM-CAP. Addition of erlotinib, a small-molecule epidermal growth factor receptor inhibitor, produced a statistically significant but clinically marginal benefit when added to gemcitabine in the advanced disease setting. A phase III trial limited to good performance status patients with metastatic pancreatic cancer showed improved survival with the combination of 5-FU/FA, irinotecan, and oxaliplatin (FOLFIRINOX) compared with gemcitabine, but with increased toxicity (Table 112-2).


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InternalMed_Harrison. The early detection and future treatment of pancreatic cancer relies on an improved understanding of molecular pathways involved in the development of this disease. This will ultimately lead to the discovery of novel agents and the identification of patient groups who are likely to benefit most from targeted therapy. Dr. Irene Chong is acknowledged for her work on this chapter in the 18th edition.


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InternalMed_Harrison. Dr. Irene Chong is acknowledged for her work on this chapter in the 18th edition. Accordingly, this chapter will use the term GI-NETs (carcinoids). These tumors originally were classified as APUDomas (for amine precursor uptake and decarboxylation), as were pheochromocytomas, melanomas, and medullary thyroid carcinomas, because they share certain cytochemical features as well as various pathologic, biologic, and molecular features (Table 113-1). It was originally proposed that APUDomas had a similar embryonic origin from neural crest cells, but it is now known the peptide-secreting cells are not of neuroectodermal origin. Nevertheless, the concept of APUDomas is useful because these tumors have important similarities as well as some differences (Table 113-1). In this section, the areas of similarity between pNETs and GI-NETs (carcinoids) will be discussed together, and areas in which there are important differences will be discussed separately.


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InternalMed_Harrison. NETs generally are composed of monotonous sheets of small round cells with uniform nuclei, and mitoses are uncommon. They can be identified tentatively on routine histology; however, these tumors are now recognized principally by their histologic staining patterns due to shared cellular proteins. Historically, silver staining was used, and Endocrine Tumors of the Gastrointestinal Tract and Pancreas endocrine tumors of the gastrointestinal tract and pancreas Robert T. Jensen GENERAL FEATURES OF GASTROINTESTINAL 113 generaL CharaCteristiCs of gastrointestinaL neuroenDoCrine tumors (gi-nets [CarCinoiDs], panCreatiC neuroenDoCrine tumors [pnets]) A. Share general neuroendocrine cell markers (identification used for diagnosis) 1. Chromogranins (A, B, C) are acidic monomeric soluble proteins found in the large secretory granules. Chromogranin A is the most widely used. 2.


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InternalMed_Harrison. Chromogranins (A, B, C) are acidic monomeric soluble proteins found in the large secretory granules. Chromogranin A is the most widely used. 2. Neuron-specific enolase (NSE) is the γ-γ dimer of the enzyme enolase and is a cytosolic marker of neuroendocrine differentiation. 3. Synaptophysin is an integral membrane glycoprotein of 38,000 molecular weight found in small vesicles of neurons and neuroendocrine tumors. B. Pathologic similarities 1. All are APUDomas showing amine precursor uptake and decarboxylation. 2. Ultrastructurally, they have dense-core secretory granules (>80 nm). 3. Histologically, they generally appear similar with few mitoses and uniform nuclei. 4. Frequently synthesize multiple peptides/amines, which can be detected immunocytochemically but may not be secreted. 5. Presence or absence of clinical syndrome or type cannot be predicted by immunocytochemical studies. 6.


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InternalMed_Harrison. 5. Presence or absence of clinical syndrome or type cannot be predicted by immunocytochemical studies. 6. Histologic classifications (grading, TNM classification) have prognostic significance. Only invasion or metastases establish malignancy. C. Similarities of biologic behavior 1. Generally slow growing, but some are aggressive. 2. Most are well-differentiated tumors having low proliferative indices. 3. Secrete biologically active peptides/amines, which can cause clinical symptoms. 4. Generally have high densities of somatostatin receptors, which are used for both localization and treatment. 5. Most (>70%) secrete chromogranin A, which is frequently used as a tumor marker. D. Similarities/differences in molecular abnormalities 1. Similarities a. Uncommon—mutations in common oncogenes (ras, jun, fos, etc). b. Uncommon—mutations in common tumor-suppressor genes (p53, retinoblastoma). c.


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InternalMed_Harrison. Uncommon—mutations in common oncogenes (ras, jun, fos, etc). b. Uncommon—mutations in common tumor-suppressor genes (p53, retinoblastoma). c. Alterations at MEN 1 locus (11q13) (frequently foregut, less commonly mid/hindgut NETs) and p16INK4a (9p21) occur in a proportion (10–45%). d. Methylation of various genes occurs in 40–87% (ras-associated domain family I, p14, p16, O6-methylguanine methyltransferases, retinoic acid receptor β). 2. Differences a. pNETs—loss of 1p (21%), 3p (8–47%), 3q (8–41%), 11q (21–62%), 6q (18–68%), Y (45%). Gains at 17q (10–55%), 7q (16–68%), 4q (33%), 18 (up to 45%). b. GI-NETs (carcinoids)—loss of 18q (38–88%), >18p (33–43%), >9p, 16q21 (21–23%). Gains at 17q, 19p (57%), 4q (33%), 14q (20%), 5 (up to 36%). c. pNETs: ATRX/DAXX mutations in 43%, MEN 1 mutations in 44%, mTor mutations (14%); uncommon in midgut GI-NETs (0–2%).


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InternalMed_Harrison. c. pNETs: ATRX/DAXX mutations in 43%, MEN 1 mutations in 44%, mTor mutations (14%); uncommon in midgut GI-NETs (0–2%). Abbreviations: ATRX, alpha-thalassemia X-lined mental retardation protein; DAXX, death domain associated protein; MEN 1, multiple endocrine neoplasia type 1; TNM, tumor, node, metastasis. tumors were classified as showing an argentaffin reaction if they took up and reduced silver or as being argyrophilic if they did not reduce it. Currently, immunocytochemical localization of chromogranins (A, B, C), neuron-specific enolase, and synaptophysin, which are all neuroendocrine cell markers, is used (Table 113-1). Chromogranin A is the most widely used.


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InternalMed_Harrison. Ultrastructurally, these tumors possess electron-dense neurosecretory granules and frequently contain small clear vesicles that correspond to synaptic vesicles of neurons. NETs synthesize numerous peptides, growth factors, and bioactive amines that may be ectopically secreted, giving rise to a specific clinical syndrome (Table 113-2). The diagnosis of the specific syndrome requires the clinical features of the disease (Table 113-2) and cannot be made from the immunocytochemistry results alone. The presence or absence of a specific clinical syndrome also cannot be predicted from the immunocytochemistry alone (Table 113-1). Furthermore, pathologists cannot distinguish between benign and malignant NETs unless metastasis or invasion is present.


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InternalMed_Harrison. GI-NETs (carcinoids) frequently are classified according to their anatomic area of origin (i.e., foregut, midgut, hindgut) because tumors with similar areas of origin share functional manifestations, histochemistry, and secretory products (Table 113-3). Foregut tumors generally have a low serotonin (5-HT) content; are argentaffin-negative but argyrophilic; occasionally secrete adrenocorticotropic hormone (ACTH) or 5-hydroxytryptophan (5-HTP), causing an atypical carcinoid syndrome (Fig. 113-1); are often multihormonal; and may metastasize to bone. They uncommonly produce a clinical syndrome due to the secreted products. Midgut carcinoids are argentaffin-positive, have a high serotonin content, most frequently cause the typical carcinoid syndrome when they metastasize (Table 113-3, Fig. 113-1), release serotonin and tachykinins (substance P, neuropeptide K, substance K), rarely secrete 5-HTP or ACTH, and less commonly metastasize to bone. Hindgut carcinoids (rectum, transverse and


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InternalMed_Harrison. 113-1), release serotonin and tachykinins (substance P, neuropeptide K, substance K), rarely secrete 5-HTP or ACTH, and less commonly metastasize to bone. Hindgut carcinoids (rectum, transverse and descending colon) are argentaffin-negative, are often argyrophilic, rarely contain serotonin or cause the carcinoid syndrome (Fig. 113-1, Table 113-3), rarely secrete 5-HTP or ACTH, contain numerous peptides, and may metastasize to bone.


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InternalMed_Harrison. pNETs can be classified into nine well-established specific functional syndromes (Table 113-2), six additional very rare specific functional syndromes (less than five cases described), five possible specific functional syndromes (pNETs secreting calcitonin, neurotensin, pancreatic polypeptide, ghrelin) (Table 113-2), and nonfunctional pNETs. Other functional hormonal syndromes due to nonpancreatic tumors (usually intraabdominal in location) have been described only rarely and are not included in (Table 113-2). These include secretion by intestinal and ovarian tumors of peptide tyrosine tyrosine (PYY), which results in altered motility and constipation, and ovarian tumors secreting renin or aldosterone causing alterations in blood pressure or somatostatin causing diabetes or reactive hypoglycemia. Each of the functional syndromes listed in Table 113-2 is associated with symptoms due to the specific hormone released. In contrast, nonfunctional pNETs release no products that cause a


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InternalMed_Harrison. Each of the functional syndromes listed in Table 113-2 is associated with symptoms due to the specific hormone released. In contrast, nonfunctional pNETs release no products that cause a specific clinical syndrome. “Nonfunctional” is a misnomer in the strict sense because those tumors frequently ectopically secrete a number of peptides (pancreatic polypeptide [PP], chromogranin A, ghrelin, neurotensin, α subunits of human chorionic gonadotropin, and neuron-specific enolase); however, they cause no specific clinical syndrome. The symptoms caused by nonfunctional pNETs are entirely due to the tumor per se. pNETs frequently ectopically secrete PP (60–85%), neurotensin (30–67%), calcitonin (30–42%), and to a lesser degree, ghrelin (5–65%). Whereas a few studies have proposed their secretion can cause a specific functional syndrome, most studies support the conclusion that their ectopic secretion is not associated with a specific clinical syndrome, and thus they are listed in Table 113-2


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InternalMed_Harrison. can cause a specific functional syndrome, most studies support the conclusion that their ectopic secretion is not associated with a specific clinical syndrome, and thus they are listed in Table 113-2 as possible clinical syndromes.


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InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas Abbreviations: ACTH, adrenocorticotropic hormone; GRFoma, growth hormone–releasing factor secreting pancreatic endocrine tumor; IGF-II, insulin-like growth factor II; MEN, multiple endocrine neoplasia; pNET, pancreatic neuroendocrine tumor; PPoma, tumor secreting pancreatic polypeptide; PTHrP, parathyroid hormone–related peptide; VIPoma, tumor secreting vasoactive intestinal peptide; WDHA, watery diarrhea, hypokalemia, and achlorhydria syndrome. aPancreatic polypeptide–secreting tumors (PPomas) are listed in two places because most authorities classify these as not associated with a specific hormonal syndrome (nonfunctional); however, rare cases of watery diarrhea proposed to be due to PPomas have been reported. Because a large proportion of nonfunctional pNETs (60–90%) secrete PP, these tumors are often referred to as PPomas (Table 113-2).


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InternalMed_Harrison. GI-NETs (carcinoids) can occur in almost any GI tissue (Table 113-3); however, at present, most (70%) have their origin in one of three sites: bronchus, jejunoileum, or colon/rectum. In the past, GI-NET (carcinoids) most frequently were reported in the appendix (i.e., 40%); however, the bronchus/lung, rectum, and small intestine are now the most common sites. Overall, the GI tract is the most common site for these tumors, accounting for 64%, with the respiratory tract a distant second at 28%. Both race and sex can affect the frequency as well as the distribution of GI-NETs (carcinoids). African Americans have a higher incidence of carcinoids. Race is particularly important for rectal carcinoids, which are found in 41% of Asians/Pacific Islanders with NETs compared to 32% of American Indians/Alaskan natives, 26% of African Americans, and 12% of white Americans. Females have a lower incidence of small intestinal and pancreatic carcinoids.


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InternalMed_Harrison. The term pancreatic neuroendocrine or endocrine tumor, although widely used and therefore retained here, is also a misnomer, strictly speaking, because these tumors can occur either almost entirely in the pancreas (insulinomas, glucagonomas, nonfunctional pNETs, pNETs causing hypercalcemia) or at both pancreatic and extrapancreatic sites (gastrinomas, VIPomas [vasoactive intestinal peptide], somatostatinomas, GRFomas [growth hormone–releasing factor]). pNETs are also called islet cell tumors; however, the use of this term is discouraged because it is not established that they originate from the islets, and many can occur at extrapancreatic sites.


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InternalMed_Harrison. Whereas the classification of GI neuroendocrine tumors into fore-gut, midgut, or hindgut is widely used and generally useful because the NETs within these areas have many similarities, they also have marked differences, particularly in biologic behavior, and it has not proved useful for prognostic purposes. More general classifications have been developed that allow NETs with similar features in different locations to be compared, have proven prognostic value, and are widely used. New classification systems have been developed for both GI-NETs (carcinoids) and pNETs by the World Health Organization (WHO), European Neuroendocrine Tumor Society (ENETS), and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC). Although there are some differences between these different classification systems, each uses similar information, and it is now recommended that the basic data underlying the classification be included in all standard pathology reports. These


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InternalMed_Harrison. these different classification systems, each uses similar information, and it is now recommended that the basic data underlying the classification be included in all standard pathology reports. These classification systems divide NETs from all sites into those that are well differentiated (low grade [G1] or intermediate grade [G2]) and those that are poorly differentiated (high grade [G3] divided into either small-cell carcinoma or large-cell neuroendocrine carcinoma). In these classification systems, both pNETs and GI-NETs (carcinoids) are classified as neuroendocrine tumors, and the old term of carcinoid is equivalent to well-differentiated neuroendocrine tumors of the GI tract. These classification systems are based on not only the differentiation of the NET, but also a grading system assessing proliferative indices (Ki-67 and the mitotic count). NETs are considered low grade (ENETS G1) if the Ki-67 is <3% and the mitotic count is <2 mitoses/high-power field (HPF), intermediate


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InternalMed_Harrison. assessing proliferative indices (Ki-67 and the mitotic count). NETs are considered low grade (ENETS G1) if the Ki-67 is <3% and the mitotic count is <2 mitoses/high-power field (HPF), intermediate grade (ENETS G2) if the Ki-67 is 3–20% and the mitotic count is 2–20 mitoses/HPF, and high grade (ENETS G3) if the Ki-67 is >20% and the mitotic count is >20 mitoses/HPF. In addition to the grading system, a TNM classification has been proposed that is based on the level of tumor invasion, tumor size, and tumor extent (see Table 113-4 for an example with pNETs and appendiceal GI-NETs [carcinoids]). Because of the proven prognostic value of these classification and grading systems, as well as the fact that NETs with different classifications/grades respond differently to treatments, the systems are now essential for the management of all NETs.


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InternalMed_Harrison. In addition to these classification/grading systems, a number of other factors have been identified that provide important prognostic information that can guide treatment (Table 113-5). The exact incidence of GI-NETs (carcinoids) or pNETs varies according to whether only symptomatic tumors or all tumors are considered. The incidence of clinically significant carcinoids is 7–13 cases/million population per year, whereas any malignant carcinoids taBLe 113-3 gi-net (CarCinoiD) LoCation, frequenCy of metastases, anD assoCiation With the CarCinoiD synDrome Esophagus <0.1 — — Stomach 4.6 10 9.5 Duodenum 2.0 — 3.4 Pancreas 0.7 71.9 20 Gallbladder 0.3 17.8 5 Bronchus, lung, trachea 27.9 5.7 13 Jejunum 1.8 {58.4 Ileum 14.9 9 Meckel’s diverticulum 0.5 — 13 Appendix 4.8 38.8 <1 Colon 8.6 51 5 Liver 0.4 32. — Ovary 1.0 2 32 50 Testis <0.1 — 50 Rectum 13.6 3.9 — Abbreviation: GI-NET, gastrointestinal neuroendocrine tumor.


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InternalMed_Harrison. Rectum 13.6 3.9 — Abbreviation: GI-NET, gastrointestinal neuroendocrine tumor. Source: Location is from the PAN-SEER data (1973–1999), and incidence of metastases is from the SEER data (1992–1999), reported by IM Modlin et al: Cancer 97:934, 2003. Incidence of carcinoid syndrome is from 4349 cases studied from 1950–1971, reported by JD Godwin: Cancer 36:560, 1975. FIGURE 113-1 Synthesis, secretion, and metabolism of serotonin (5-HT) in patients with typical and atypical carcinoid syndromes. 5-HIAA, 5-hydroxyindolacetic acid. Comparison of the Criteria for the tumor Category in the enets anD seventh eDition ajCC tnm CLassifiCations of panCreatiC anD appenDiCeaL nets I. Both GI-NETs (carcinoids) and pNETs


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InternalMed_Harrison. Comparison of the Criteria for the tumor Category in the enets anD seventh eDition ajCC tnm CLassifiCations of panCreatiC anD appenDiCeaL nets I. Both GI-NETs (carcinoids) and pNETs Symptomatic presentation (p <.05) Presence of liver metastases (p <.001) Extent of liver metastases (p <.001) Presence of lymph node metastases (p <.001) Development of bone or extrahepatic metastases (p <.01) Depth of invasion (p <.001) Rapid rate of tumor growth Elevated serum alkaline phosphatase levels (p = .003) Primary tumor site (p <.001) Primary tumor size (p <.005) High serum chromogranin A level (p <.01) Presence of one or more circulating tumor cells (p <.001) Various histologic features


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InternalMed_Harrison. Tumor differentiation (p <.001) High growth indices (high Ki-67 index, PCNA expression) High mitotic counts (p <.001) Necrosis present Presence of cytokeratin 19 (p <.02) Vascular or perineural invasion Vessel density (low microvessel density, increased lymphatic density) High CD10 metalloproteinase expression (in series with all grades of NETs) Flow cytometric features (i.e., aneuploidy) High VEGF expression (in low-grade or well-differentiated NETs only) WHO, ENETS, AJCC/UICC, and grading classification Presence of a pNET rather than GI-NET associated with poorer prognosis (p = .0001) Older age (p <.01) II. GI-NETs (Carcinoids) Location of primary: appendix < lung, rectum < small intestine < pancreas Presence of carcinoid syndrome Laboratory results (urinary 5-HIAA levels [p <.01], plasma neuropeptide


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InternalMed_Harrison. Location of primary: appendix < lung, rectum < small intestine < pancreas Presence of carcinoid syndrome Laboratory results (urinary 5-HIAA levels [p <.01], plasma neuropeptide K [p <.05], serum chromogranin A [p <.01]) Presence of a second malignancy Male sex (p <.001) Molecular findings (TGF-α expression [p <.05], chr 16q LOH or gain chr 4p [p <.05]) WHO, ENETS, AJCC/UICC, and grading classification Molecular findings (gain in chr 14, loss of 3p13 [ileal carcinoid], upregulation III. pNETs Location of primary: duodenal (gastrinoma) better than pancreatic Ha-ras oncogene or p53 overexpression Female gender MEN 1 syndrome absent Presence of nonfunctional tumor (some studies, not all) WHO, ENETS, AJCC/UICC, and grading classification Various histologic features: IHC positivity for c-KIT, low cyclin B1 expression (p <.01), loss of PTEN or of tuberous sclerosis-2 IHC, expression of


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InternalMed_Harrison. Molecular findings (increased HER2/neu expression [p = .032], chr 1q, 3p, 3q, or 6q LOH [p = .0004], EGF receptor overexpression [p = .034], gains in chr 7q, 17q, 17p, 20q; alterations in the VHL gene [deletion, methylation]; presence of FGFR4-G388R single-nucleotide polymorphism)


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InternalMed_Harrison. Abbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; AJCC, American Joint Committee on Cancer; chr, chromosome; EGF, epidermal growth factor; FGFR, fibroblast growth factor receptor; GI-NET, gastrointestinal neuroendocrine tumor; IHC, immunohistochemistry; Ki-67, proliferation-associated nuclear antigen recognized by Ki-67 monoclonal antibody; LOH, loss of heterozygosity; MEN, multiple endocrine neoplasia; NET, neuroendocrine tumors; PCNA, proliferating cell nuclear antigen; pNET, pancreatic neuroendocrine tumor; PTEN, phosphatase and tensin homologue deleted from chromosome 10; TGF-α, transforming growth factor α; TNM, tumor, node, metastasis; UICC, International Union Against Cancer; VEGF, vascular endothelial growth factor; WHO, World Health Organization. Confined to pancreas, <2 cm Confined to pancreas, >2 cm Peripancreatic spread, but without major vascular invasion (truncus coeliacus, superior mesenteric artery) T1 ≤1 cm; invasion of


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InternalMed_Harrison. Confined to pancreas, <2 cm Confined to pancreas, >2 cm Peripancreatic spread, but without major vascular invasion (truncus coeliacus, superior mesenteric artery) T1 ≤1 cm; invasion of T1a, ≤1 cm; T1b, >1–2 cm muscularis propria >2–4 cm or invasion of of subserosa/mesoappendix T3 >2 cm or >3 mm invasion of >4 cm or invasion of ileum subserosa/mesoappendix T4 Invasion of peritoneum/ Invasion of peritoneum/ other organs Abbreviations: AJCC, American Joint Committee on Cancer; ENETS, European Neuroendocrine Tumor Society; NET, neuroendocrine tumor; pNET, pancreatic neuroendocrine tumor; TNM, tumor, node, metastasis; UICC, International Union Against Cancer. Source: Modified from DS Klimstra: Semin Oncol 40:23, 2013 and G Kloppel et al: Virchow Arch 456:595, 2010.


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InternalMed_Harrison. at autopsy are reported in 21–84 cases/million population per year. The incidence of GI-NETs (carcinoids) is approximately 25–50 cases per million in the United States, which makes them less common than adenocarcinomas of the GI tract. However, their incidence has increased sixfold in the last 30 years. In an analysis of 35,825 GI-NETs (carcinoids) (2004) from the U.S. Surveillance, Epidemiology, and End Results (SEER) database, their incidence was 5.25/100,000 per year, and the 29-year prevalence was 35/100,000. Clinically significant pNETs have a prevalence of 10 cases/million population, with insulinomas, gastrinomas, and nonfunctional pNETs having an incidence of 0.5–2 cases/million population per year (Table 113-2). pNETs account for 1–10% of all tumors arising in the pancreas and 1.3% of tumors in the SEER database, which consists primarily of malignant tumors. VIPomas are 2–8 times less common, glucagonomas are 17–30 times less common, and somatostatinomas are the least common.


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InternalMed_Harrison. of tumors in the SEER database, which consists primarily of malignant tumors. VIPomas are 2–8 times less common, glucagonomas are 17–30 times less common, and somatostatinomas are the least common. In autopsy studies, 0.5–1.5% of all cases have a pNET; however, in less than 1 in 1000 cases was a functional tumor thought to occur.


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InternalMed_Harrison. Both GI-NETs (carcinoids) and pNETs commonly show malignant behavior (Tables 113-2 and 113-3). With pNETs, except for insulinomas in which <10% are malignant, 50–100% in different series are malignant. With GI-NETs (carcinoids), the percentage showing malignant behavior varies in different locations (Table 113-3). For the three most common sites of occurrence, the incidence of metastases varies greatly from the jejunoileum (58%), lung/bronchus (6%), and rectum (4%) (Table 113-3). With both GI-NETs (carcinoids) and pNETs, a number of factors (Table 113-5) are important prognostic factors in determining survival and the aggressiveness of the tumor. Patients with pNETs (excluding insulinomas) generally have a poorer prognosis than do patients with GI-NETs (carcinoids). The presence of liver metastases is the single most important prognostic factor in single and multivariate analyses for both GI-NETs (carcinoids) and pNETs. Particularly important in the development of liver metastases is


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InternalMed_Harrison. metastases is the single most important prognostic factor in single and multivariate analyses for both GI-NETs (carcinoids) and pNETs. Particularly important in the development of liver metastases is the size of the primary tumor. For example, with small intestinal carcinoids, which are the most common cause of the carcinoid syndrome due to metastatic disease in the liver (Table 113-2), metastases occur in 15–25% if the tumor is <1 cm in diameter, 58–80% if it is 1–2 cm in diameter, and >75% if it is >2 cm in diameter. Similar data exist for gastrinomas and other pNETs; the size of the primary tumor is an independent predictor of the development of liver metastases.


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InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas 562 The presence of lymph node metastases or extrahepatic metastases; the depth of invasion; the rapid rate of growth; various histologic features (differentiation, mitotic rates, growth indices, vessel density, vascular endothelial growth factor [VEGF], and CD10 metalloproteinase expression); necrosis; presence of cytokeratin; elevated serum alkaline phosphatase levels; older age; presence of circulating tumor cells; and flow cytometric results, such as the presence of aneuploidy, are all important prognostic factors for the development of metastatic disease (Table 113-5). For patients with GI-NETs (carcinoids), additional associations with a worse prognosis include the development of the carcinoid syndrome (especially the development of carcinoid heart disease), male sex, the presence of a symptomatic tumor or greater increases in a number of tumor markers (5-hydroxyindolacetic acid [5-HIAA], neuropeptide K, chromogranin


InternalMed_Harrison

InternalMed_Harrison. of carcinoid heart disease), male sex, the presence of a symptomatic tumor or greater increases in a number of tumor markers (5-hydroxyindolacetic acid [5-HIAA], neuropeptide K, chromogranin A), and the presence of various molecular features. With pNETs or gastrinomas, a worse prognosis is associated with female sex, overexpression of the Ha-ras oncogene or p53, the absence of multiple endocrine neoplasia type 1 (MEN 1), higher levels of various tumor markers (i.e., chromogranin A, gastrin), and presence of various histologic features (immunohistochemistry for c-KIT, low cyclin B1, loss of PTEN/TSC-2, expression of fibroblast growth factor-13) and various molecular features (Table 113-5). The TNM classification systems and the grading systems (G1–G3) have important prognostic value. A number of diseases due to various genetic disorders are associated with an increased incidence of NETs (Table 113-6). Each one is caused by a loss of a possible tumor-suppressor gene. The most important


InternalMed_Harrison

InternalMed_Harrison. of diseases due to various genetic disorders are associated with an increased incidence of NETs (Table 113-6). Each one is caused by a loss of a possible tumor-suppressor gene. The most important is MEN 1, which is an autosomal dominant disorder due to a defect in a 10-exon gene on 11q13, which encodes for a 610-amino-acid nuclear protein, menin (Chap. 408). Patients with MEN 1 develop hyperparathyroidism due to parathyroid hyperplasia in 95–100% of cases, pNETs in 80–100%, pituitary adenomas in 54–80%, adrenal adenomas in 27–36%, bronchial carcinoids in 8%, thymic carcinoids in 8%, gastric carcinoids in 13–30% of patients with Zollinger-Ellison syndrome, skin tumors (angiofibromas [88%], collagenomas [72%]), central nervous system (CNS) tumors (meningiomas [<8%]), and smooth-muscle tumors (leiomyomas, leiomyosarcomas [1–7%]). Among patients with MEN 1, 80–100% develop nonfunctional pNETs (most are microscopic with 0–13% large/symptomatic), and functional pNETs occur in 20–80% in


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InternalMed_Harrison. (leiomyomas, leiomyosarcomas [1–7%]). Among patients with MEN 1, 80–100% develop nonfunctional pNETs (most are microscopic with 0–13% large/symptomatic), and functional pNETs occur in 20–80% in different series, with a mean of 54% developing Zollinger-Ellison syndrome, 18% insulinomas, 3% glucagonomas, 3%


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InternalMed_Harrison. Location of Gene Mutation and Gene Syndrome Product NETs Seen/Frequency Multiple endocrine 11q13 (encodes neoplasia type 1 610-amino-acid protein, (MEN 1) menin) von Recklinghausen’s 17q11.2 (encodes disease (neurofibro-2485-amino-acid protein, matosis 1 [NF-1]) neurofibromin) Tuberous sclerosis 9q34 (TSCI) (encodes 1164-amino-acid protein, hamartin), 16p13 (TSC2) (encodes 1807-aminoacid protein, tuberin) 80–100% develop pNETS (microscopic), 20–80% (clinical): (nonfunctional > gastrinoma > insulinoma) GI-NETs (Carcinoids): gastric (13–30%), bronchial/ thymic (8%) 0–10% develop pNETs, primarily duodenal somatostatinomas (usually nonfunctional) Rarely insulinoma, gastrinoma Uncommonly develop pNETS (nonfunctional and functional [insulinoma, gastrinoma]) VIPomas, and <1% GRFomas or somatostatinomas. MEN 1 is present in 20–25% of all patients with Zollinger-Ellison syndrome, 4% of patients with insulinomas, and a low percentage (<5%) of patients with other pNETs.


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InternalMed_Harrison. Three phacomatoses associated with NETs are von Hippel–Lindau disease (VHL), von Recklinghausen’s disease (neurofibromatosis type 1 [NF-1]), and tuberous sclerosis (Bourneville’s disease) (Table 113-6). VHL is an autosomal dominant disorder due to defects on chromosome 3p25, which encodes for a 213-amino-acid protein that interacts with the elongin family of proteins as a transcriptional regulator (Chaps. 118, 339, 407, and 408). In addition to cerebellar hemangioblastomas, renal cancer, and pheochromocytomas, 10–17% develop a pNET. Most are nonfunctional, although insulinomas and VIPomas have been reported. Patients with NF-1 (von Recklinghausen’s disease) have defects in a gene on chromosome 17q11.2 that encodes for a 2845-amino-acid protein, neurofibromin, which functions in normal cells as a suppressor of the ras signaling cascade (Chap. 118). Up to 10% of these patients develop an upper GI-NET (carcinoid), characteristically in the periampullary region (54%). Many are classified


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InternalMed_Harrison. as a suppressor of the ras signaling cascade (Chap. 118). Up to 10% of these patients develop an upper GI-NET (carcinoid), characteristically in the periampullary region (54%). Many are classified as somatostatinomas because they contain somatostatin immunocytochemically; however, they uncommonly secrete somatostatin and rarely produce a clinical somatostatinoma syndrome. NF-1 has rarely been associated with insulinomas and Zollinger-Ellison syndrome. NF-1 accounts for 48% of all duodenal somatostastinomas and 23% of all ampullary GI-NETs (carcinoids). Tuberous sclerosis is caused by mutations that alter either the 1164-amino-acid protein hamartin (TSC1) or the 1807-amino-acid protein tuberin (TSC2) (Chap. 118). Both hamartin and tuberin interact in a pathway related to phosphatidylinositol 3-kinases and mammalian target of rapamycin (mTOR) signaling cascades. A few cases including nonfunctional and functional pNETs (insulinomas and gastrinomas) have been reported in these patients


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InternalMed_Harrison. 3-kinases and mammalian target of rapamycin (mTOR) signaling cascades. A few cases including nonfunctional and functional pNETs (insulinomas and gastrinomas) have been reported in these patients (Table 113-6). Mahvash disease is associated with the development of α-cell hyperplasia, hyperglucagonemia, and the development of NF pNETs and is due to a homozygous P86S mutation of the human glucagon receptor.


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InternalMed_Harrison. Mutations in common oncogenes (ras, myc, fos, src, jun) or common tumor-suppressor genes (p53, retinoblastoma susceptibility gene) are not commonly found in either pNETs or GI-NETs (carcinoids) (Table 113-1). However, frequent (70%) gene amplifications in MDM2, MDM4, and WIPI inactivating the p53 pathway are noted in well-differentiated pNETs, and the retinoblastoma pathway is altered in the majority of pNETs. In addition to these genes, additional alterations that may be important in their pathogenesis include changes in the MEN1 gene, p16/MTS1 tumor-suppressor gene, and DPC4/ Smad4 gene; amplification of the HER-2/neu protooncogene; alterations in transcription factors (Hoxc6 [GI carcinoids]), growth factors, and their receptors; methylation of a number of genes that probably results in their inactivation; and deletions of unknown tumor-suppressor genes as well as gains in other unknown genes (Table 113-1). The clinical antitumor activity of everolimus, an mTOR inhibitor, and


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InternalMed_Harrison. in their inactivation; and deletions of unknown tumor-suppressor genes as well as gains in other unknown genes (Table 113-1). The clinical antitumor activity of everolimus, an mTOR inhibitor, and sunitinib, a tyrosine kinase inhibitor (PDGFR, VEGFR1, VEGFR2, c-KIT, FLT-3), support the importance of the mTOR-AKT pathway and tyrosine kinase receptors in mediating growth of malignant NETs (especially pNETs). The importance of the mTOR pathway in pNET growth is further supported by the finding that a single-nucleotide polymorphism (FGFR4-G388R, in fibroblast growth factor receptor 4) affects selectivity to the mTOR inhibitor and can result in significantly higher risk of advanced pNET stage and liver metastases (Table 113-5). Comparative genomic hybridization, genome-wide allelotyping studies, and genome-wide single-nucleotide polymorphism analyses have shown that chromosomal losses and gains are common in pNETs and GI-NETs (carcinoids), but they differ between these two NETs, and some


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InternalMed_Harrison. and genome-wide single-nucleotide polymorphism analyses have shown that chromosomal losses and gains are common in pNETs and GI-NETs (carcinoids), but they differ between these two NETs, and some have prognostic significance (Table 113-5). Mutations in the MEN1 gene are probably particularly important. Loss of heterozygosity at the MEN 1 locus on chromosome 11q13 is noted in 93% of sporadic pNETs (i.e., in patients without MEN 1) and in 26–75% of sporadic GI-NETs (carcinoids). Mutations in the MEN1 gene are reported in 31–34% of sporadic gastrinomas. Exomic sequencing of sporadic pNETs found that the most frequently altered gene was


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InternalMed_Harrison. Abbreviations: GI, gastrointestinal; PNETs, pancreatic neuroendocrine tumors. MEN1, occurring in 44% of patients, followed by mutations in 43% of patients in genes encoding for two subunits of a transcription/ chromatin remodeling complex consisting of DAXX (death-domainassociated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) and in 15% of patients in the mTOR pathway. The presence of a number of these molecular alterations in pNETs or GI-NETs (carcinoids) correlates with tumor growth, tumor size, and disease extent or invasiveness and may have prognostic significance (Table 113-5).


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InternalMed_Harrison. CHARACTERISTICS OF THE MOST COMMON GI-NETs (CARCINOIDS) Appendiceal NETs (Carcinoids) Appendiceal NETs (carcinoids) occur in 1 in every 200–300 appendectomies, usually in the appendiceal tip, have an incidence of 0.15/100,000 per year, comprise 2–5% of all GI-NETs (carcinoids), and comprise 32–80% of all appendiceal tumors. Most (i.e., >90%) are <1 cm in diameter without metastases in older studies, but more recently, 2–35% have had metastases (Table 113-3). In the SEER data of 1570 appendiceal carcinoids, 62% were localized, 27% had regional metastases, and 8% had distant metastases. The risk of metastases increases with size, with those <1 cm having a 0 to <10% risk of metastases and those >2 cm having a 25–44% risk. Besides tumor size, other important prognostic factors for metastases include basal location, invasion of mesoappendix, poor differentiation, advanced stage or WHO/ENETS classification, older age, and positive resection margins. The 5-year survival is 88–100% for


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InternalMed_Harrison. include basal location, invasion of mesoappendix, poor differentiation, advanced stage or WHO/ENETS classification, older age, and positive resection margins. The 5-year survival is 88–100% for patients with localized disease, 78–100% for patients with regional involvement, and 12–28% for patients with distal metastases. In patients with tumors <1 cm in diameter, the 5-year survival is 95–100%, whereas it is 29% if tumors are >2 cm in diameter. Most tumors are well-differentiated G1 tumors (87%) (Table 113-4), with the remainder primarily well-differentiated G2 tumors (13%); poorly differentiated G3 tumors are uncommon (<1%). Their percentage of the total number of carcinoids decreased from 43.9% (1950–1969) to 2.4% (1992–1999). Appendiceal goblet cell (GC) NETs (carcinoids)/ carcinomas are a rare subtype (<5%) that are mixed adeno-neuroendocrine carcinomas. They are malignant and are thought to comprise a distinct entity; they frequently present with advanced disease and are


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InternalMed_Harrison. are a rare subtype (<5%) that are mixed adeno-neuroendocrine carcinomas. They are malignant and are thought to comprise a distinct entity; they frequently present with advanced disease and are recommended to be treated as adenocarcinomas, not carcinoid tumors.


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InternalMed_Harrison. Small intestinal (SI) NETs (carcinoids) have a reported incidence of 0.67/100,000 in the United States, 0.32/100,000 in England, and 1.12/100,000 in Sweden and comprise >50% of all SI tumors. There is a male predominance (1.5:1), and race affects frequency, with a lower frequency in Asians and greater frequency in African Americans. The mean age of presentation is 52–63 years, with a wide range (1–93 years). Familial SI carcinoid families exist but are very uncommon. These are frequently multiple; 9–18% occur in the jeunum, 70–80% are present in the ileum, and 70% occur within 6 cm (2.4 in.) of the ileocecal valve. Forty percent are <1 cm in diameter, 32% are 1–2 cm, and 29% are >2 cm. They are characteristically well differentiated; however, they are generally invasive, with 1.2% being intramucosal in location, 27% penetrating the submucosa, and 20% invading the muscularis propria. Metastases occur in a mean of 47–58% (range 20–100%). Liver metastases occur in 38%, to lymph nodes in


InternalMed_Harrison

InternalMed_Harrison. in location, 27% penetrating the submucosa, and 20% invading the muscularis propria. Metastases occur in a mean of 47–58% (range 20–100%). Liver metastases occur in 38%, to lymph nodes in 37% and more distant in 20–25%. They characteristically cause a marked fibrotic reaction, which can lead to intestinal obstruction. Tumor size is an important variable in the frequency of metastases. However, even small NETs (carcinoids) of the small intestine (<1 cm) have metastases in 15–25% of cases, whereas the proportion increases to 58–100% for tumors 1–2 cm in diameter. Carcinoids also occur in the duodenum, with 31% having metastases. Duodenal tumors <1 cm virtually never metastasize, whereas 33% of those >2 cm had metastases. SI NETs (carcinoids) are the most common cause (60–87%) of the carcinoid syndrome and are discussed in a later section (Table 113-7). Important prognostic factors are listed in (Table 113-5), and particularly important are the


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InternalMed_Harrison. During Course At Presentation of Disease Mean 57 yrs 59.2 yrs tumor extent, proliferative index by grading, and stage (Table 113-4). The overall survival at 5 years is 55–75%; however, it varies markedly with disease extent, being 65–90% with localized disease, 66–72% with regional involvement, and 36–43% with distant disease.