In general, initial symptoms of small bowel tumors are rather vague and a diagnostic delay of 8 \200\22312 months is common. Tumor markers are useful for carcinoids, particularly chr omogranin A and 5- HIAA. Markers such as CEA, CA-19-9, CA-50 are too non-speci \201c for d iagnosing small bowel tumors. Any patient who has a primary small bowel malignancy should b e monitored for the development of a second malignant tumor, frequently in the colon. OHO-20(349-374) 11/18/02 8:27 AM Page 359 SMALL INTESTINE AND CARCINOID tumors 359 Adenocarcinoma (cid:2) Commonest in proximal small bowel (80%) (cid:2) presents with abdominal pain and ja undice (obstruction) (cid:2) Anemia \200\224occult bleeding (cid:2) Diagnosis \200\224bariu m studies Endoscopy Carcinoid tumors 90% arise in the ileum and appendix and although they are often silent, ab dominal pain is a common symptom. Small bowel obstruct- ion can result from intense desmopl astic reaction around the primary tumor. The syndrome of chronic mesenteric ischaemia has b een described, related to elastic vascular sclerosis. Less than 20% present with the carcin oid syndrome which includes: (cid:2) Flushing (cid:2) Diarrhea (cid:2) Bronchial constricti on (cid:2) Right-sided valvular heart disease A majority of these patients are found to hav e liver metastases and have elevated urinary 5-HIAA levels and plasma chromogranin A and ta chykinins (neurokinin A and substance-P). Approximately 30% of small bowel carcinoids are m ultiple. Pre-operative diagnostic tests are both biochemical and radiological. Urinary 5-HI AA and chromogranin A are assayed, the latter is particularly useful in earlier stage disea se. The primary tumors and metastases can be seen by somatostatin receptor scintigraphy (Octreo scan); 80% of these tumors express somatostatin receptor subtype 2 that binds this somatost atin ana- logue. This investigation should be supplemented with CT or MRI scan for detectio n of lymph node and liver metastases. Sometimes a small bowel contrast enema can be informa tive in patients with inter- mittent obstructive symptoms. Lymphoma Primary small bowel lymphoma constitutes about 1% of all gastro- intestinal malign ancies. There are \201ve clinical distinct subtypes of primary small intestinal lymphoma: (cid:2) Adult Western type (cid:2) Pediatric type Immunoproliferative small intestinal disease (cid:2) (cid:2) Mediterranean type, enteropathy-associated T-cell lymphoma (cid:2) Hodgkin \200\231 s lymphoma Most small bowel lymphomas show intermediate or high histological grade. The dia gnosis of small intestinal lymphoma is often made only OHO-20(349-374) 11/18/02 8:27 AM Page 360 UPPER GASTROINTESTINAL CANCER 360 at laparotomy. Radiological \201ndings that might suggest this diagnosis include diffuse segment-thickened distal small bowel on a follow- through barium examination. CT can someti mes better demonstrate this \201nding. However, the radiological appearances are easily c onfused with other segmental diseases of the distal small intestine such as Crohn \200\231s disease. Sarcoma These tumors are exceedingly rare and most are of smooth muscle origin (leiomyoma/s arcoma). Recently, tumors derived from the autonomic nervous system have also been describe d. The clinical pre- sentation is either bleeding or obstruction. Treatment Surgery Surgical resection is the most important therapy for all small bowel tumors. All be nign tumors, such as leiomyomas, small bowel ade- nomas, angiomas, and lipomas, can be cure d by adequate segmental resections with clear serosal margins. The same holds true for the malignant tumors, although surgery should include lymph node resection. Pancreaticoduodenectomy may be required in patients with tumors arising in the proximal and second portion of the duoden- um. Carcinoid tumors con \201ned to the distal ileum requir e resection that sometimes includes part of the caecum. In patients with Peutz \200\223Jegh ers \200\231 syndrome and multiple polyps only limited resection should be performed and mo st of the tumors can be removed by endoscopic polypectomy. Resection of involved bowel is recommended for lymphomas, except the Mediterranean type, th at often involves the entire small bowel and responds to systemic therapy. Chemotherapy Chemotherapy for most malignant small bowel tumors is based around 5- \202uor ouracil (5FU). 5FU can be applied either alone or in combination with leucovorin and/or (ci d:2)-interferon. Sarcomas are treated, as at other sites, with doxorubicin-based regimens. Similarly, lymphomas are commonly treated with regimens such as CHOP. Carcinoid tumors, although malignant, should not be treated with cytotoxics in most cases. Streptozotocin and 5-FU or doxorubicin give modest (10 \200\22320%) response rates of short duration. Most patients with low-grade carcinoid tumors can be treated with (cid:2)-interf eron alone or in combination with somatostatin analogs. Five-year survival in patients with malignant adenocarcinoma of the small intestine is only 20 \200\22330%. For carcinoid tumors with local disease, \201ve-year survival is 75 \200 \22395%; with regional lymph node OHO-20(349-374) 11/18/02 8:27 AM Page 361 SMALL INTESTINE AND CARCINOID tumors 361 involvement, 40 \200\22360%; and with liver metastases and the carcinoid syndrome, 20 \200 \22330%. \200\230Aggressive \200\231 surgery combined with biotherapy ((cid:2)-interferon plus somatostatin analog) has recently afforded a \201ve-year survival rate of 60% in pat ients with liver metastases and the carcinoid syndrome. For lymphomas of the small bowel th e majority of deaths occur within two years of diagnosis, with \201ve-year survival of 20 \200\22330%. Combination therapy with resection and chemotherapy has been reported to give \201ve-year survival of 60%. The survival rate for patients with small bowel sarcoma is about 20%. Radiotherapy Radiotherapy is of limited value in most small bowel malignant tumors, not lea st because of the dif \201culty of localizing disease in a mobile organ and because of the low tolerance of the small bowel for ionizing radiation. However, tumor-targeted radiother apy can be applied to carcinoid tumors, using either Indium111-DTPA- octreotide or MIBG. Re sponse rates of 30 \200\22350% have been reported, but these are still considered investiga tional treatments. Cytokine therapy (cid:2)-interferon can be used both for adenocarcinomas and carcinoids of the small bowel, either alone or in combination with 5-FU. Bio- chemical response rates of 40 \200\22350% are reported in malignant carci- noids, although only 10 \200\22315% show me asurable reduction in tumor bulk, (cid:2)-interferon can be combined with somatostatin anal ogs in carcinoid tumor patients. Somatostatin analog treatment Somatostatin analogs are particularly useful for ameliorating clini- cal symptoms such as diarrhea and \202ushing related to carcinoid tumors. They al so demonstrate some anti-tumor effects with about 10% of patients showing signi \201cant t umor reduction and 30 \200\22340%, stabilization of the disease. High-dose therapy (>3 mg/d ay) has been shown to induce apoptosis in carcinoid tumors. Their parenteral administration is simpli \201ed with the recently mar- keted long-acting formulations (10 \200\22330 mg intramuscular injection monthly). Future treatment Novel approaches will be based on tumor biology, taking into con- siderati on the proliferation capacity, expression of adhesion mole- cules, and angiogenic factors. The carcinoid tumor determination of somatostatin receptor subtypes will be of importance a s subtype- speci \201c analogs are developed. New tumor-targeted radioactive treatments ar e also in development. OHO-20(349-374) 11/18/02 8:27 AM Page 362 UPPER GASTROINTESTINAL CANCER 362 Cancer of the liver Epidemiology Primary liver cancer or hepatocellular carcinoma (HCC) is uncom- mon in the We stern world but is prevalent in areas where hepatitis B is endemic. In the UK, HCC is most commonly associated with cirrhosis secondary to alcohol-induced liver injury or haemochroma tosis. The majority of cases present under the age of 50 years and males are affected more frequently than females. In the UK, chronic hepatitis B does account for a small proportion of cases but hepatitis C infection is becoming an increasing cause. Tumors may also be fou nd incidentally at the time of post-mortem examination in patients with cirrhosis. Symptoms Symptoms are often a late feature of the disease and can be divided into those ari sing from the mechanical effects of tumor growth, para-neoplastic symptoms, and deteriorati on of liver function. Right upper-quadrant abdominal pain is the most common symptom of HCC . Symptoms associated with advanced disease include: (cid:2) Weight loss (cid:2) Anorexia ( cid:2) Abdominal distension (cid:2) Fever Intra-peritoneal hemorrhage (cid:2) In cirrhotic patients, HCC may present as a rapid deterioration in hepatic function. Jaundi ce is uncommon unless liver function is severely impaired or the tumor has impinged upon a major intra- hepatic bile duct. Clinical examination may reveal stigmata of chronic liver d isease, and hepatomegaly is usual; 30 \200\22360% have ascites. Para-neoplastic effects include: (cid:2) Hypoglycaemia (cid:2) Erythrocytosis (cid:2) Hypercalcaemia (cid:2) Hypercholestero laemia Diagnosis The diagnosis of HCC is usually made on the basis of the history asso- ciated wit h radiological \201ndings of a mass lesion within the liver. The differential diagnosis i ncludes: OHO-20(349-374) 11/18/02 8:27 AM Page 363 CANCER OF THE LIVER 363 (cid:2) Secondary metastatic cancer (cid:2) Focal nodular hyperplasia (cid:2) Haemangioma ( cid:2) Macronodular cirrhosis Biopsy should be deferred in any patient in whom the potentia l for surgical resection exists because of the risk of tumor seeding out- with the liver. H owever, if coagulation is satisfactory, \201ne-needle aspi- ration is safe. Pathology Macroscopically, HCC may appear as a large solitary tumor or as a multicentric tu mor with satellite lesions evident around a central tumor. True multifocal tumors can also occur. The tumors may appear as yellowish-white nodules and may be punctuated with areas of hemorrhage or necrosis. Microscopically differentiated tumors contain large cells identi- \201able as being hepat ocytic in origin, with clear cytoplasm, and often have a similar appearance to renal cell c arcinoma. Undifferentiated or anaplastic tumors have a variable appearance with multiple mi toses and differing cell shape and size depending on type. Investigations (cid:2) CT scan (cid:2) Laparoscopy (cid:2) Laparoscopic ultrasound (cid:2) Angiography (ci d:2) Lipiodol and CT scanning \200\224picks up multifocal tumors (cid:2) CXR + CT chest to exclude metastases (cid:2) (cid:2) fetoprotein \200\224useful for diagnosis and monitoring recurrence (cid:2) Liver function tests \200\224to assess functional reserve Therapeutic options Surgical resection Surgery offers the only hope of cure of HCC. However, resection is not p ossible in many patients. The most common reasons for irresecti- bility are bilobar or mult ifocal disease and liver failure associated with cirrhosis. Non-cirrhotic patients can tole rate extensive hepatic resec- tion through compensatory hypertrophy of the unaffected liver , but in cirrhotic patients even limited segmental resection can induce liver failure. Mult icentric tumors are most common in patients with cirrhosis and resection of the primary tum or may leave other, OHO-20(349-374) 11/18/02 8:27 AM Page 364 UPPER GASTROINTESTINAL CANCER 364 undetected deposits; higher recurrence rates following resection are observed in cirrhotic compared with non-cirrhotic patients. Liver transplantation is appropriate for some cirrhotic patients with HCC <3 cm and is pref erred to resection in the treatment of HCC arising from hepatitis C because of the high lik elihood of further tumor development in these patients. Systemic chemotherapy For irresectable tumors systemic chemotherapy has been used. A variet y of cytotoxic drugs including doxorubicin, mitozantrone, methotrexate and cisplatinum have been used as single agents or in combination with 5- \202uorouracil. Response rates are h owever poor. Tumor devascularization techniques Surgical ligation of the hepatic artery and insertion of a hepatic artery catheter have been used to deprive the tumor of oxygenated blood and to p rovide a route for the direct administration of cytotoxic chemotherapy. Such techniques hav e been superceded by the use of chemo-embolization via radiologically placed catheters in t he hepatic artery. This technique is less invasive and, using chemotherapy such as adriamyc in combined with lipiodol uptake by the tumor, is demonstrable on CT scan. Repeat embolizat ion is performed at 2 \200\2233 month intervals and tumor regression with associ- ated rege neration of normal liver may render some tumors resectable. Chemo-embolization or hepatic artery ligation can be complicated by acute hepatic decompens ation and liver failure, although this is uncommon with appropriate patient selection. Interstitial therapy Instillation of absolute alcohol has been used during operation to ave rt hemorrhage following spontaneous rupture of a tumor, and alcohol can be injected percuta neously in patients under ultrasound guidance if resection is not being considered. Cryothe rapy and laser ablation of tumors have been proposed but are not generally estab- lished th erapies. Palliation Pain due to stretching of the liver capsule may respond to tumor regression foll owing chemo-embolization or systemic chemotherapy. In recalcitrant cases, dexamethasone may provide symptomatic relief and reduce opiate analgesic requirements. Associated features o f liver disease including peripheral oedema, ascites, and encephalopathy may require treatm ent. OHO-20(349-374) 11/18/02 8:27 AM Page 365 CANCER OF THE LIVER 365 Prognosis Accurate prognosis is dif \201cult to estimate due to the rarity of HCC in the U K, but overall survival is poor, with <10% of patients alive at three years. Surgical resec tion provides \201ve-year survival rates of up to 50% for non-cirrhotic patients with cle ar resection margins. OHO-20(349-374) 11/18/02 8:27 AM Page 366 UPPER GASTROINTESTINAL CANCER 366 Cancer of the biliary tract Introduction Microscopically, tumors of the biliary tract are adenocarcinomas of the papill ary, nodular, or sclerosing type. Papillary tumors develop more commonly in the gall bladde r or in the distal bile duct; scleros- ing and nodular tumors, in the proximal bile duct. A denocarcinomas without speci \201c features are the most common. Papillary tumors represen t 10% of cases and have a better prognosis, contrary to mucus-secreting tumors (5%) with a worse outcome. Tumors of the bile ducts In the Western world, the annual incidence is approximately 1.5/10 0 000. The most important predisposing factor is sclerosing cholangitis, with tumors develo ping in 9 \200\22320% of the patients (often heralded by a recent worsening of symptoms or an increase in the tumor markers CEA or CA19 \200\2239). Other predisposing diseases are ch ronic infection with Clonorchis sinensis, intra- hepatic stones, and bile stasis (such as i n congenital choledochal cysts). Anatomical classi \201cation and mode of spread Tumors of the bile duct can develop within the head of the pancreas (lower third tumors), in the hepatoduodenal ligament (middle thir d tumors), or at the level of the hepatic hilum, de \201ned by the portal bifurcation, whe re the ducts converge into the right and left hepatic duct and into the main hepatic duct. Hilar cholangio- carcinomas (Klatskin \200\231s tumors) account for more than half in most series. Cholangiocarcinomas, especially of the sclerosing and nodular type, in \201ltrate along th e walls of the ducts and the perineural tissue before obstructing the lumen. Metastases to the lymph nodes are seen in 13 \200\22330% of patients undergoing surgery. Direct duodenal invasion and peritoneal carcinomatosis occur late. Clinical presentation (cid:2) Painless jaundice (occasionally intermittent) (cid:2) Palpable gall bladder (Courvo isier \200\231s sign) (cid:2) Weight loss (cid:2) Fatigue Itch (cid:2) OHO-20(349-374) 11/18/02 8:27 AM Page 367 CANCER OF THE BILIARY TRACT 367 Diagnosis (cid:2) Blood tests \200\224obstructive jaundice \200\224if cholangitis (transminases \227 5) \200\224tumor markers CA19 \200\2239, ACE elevated \200\224coagulation abnormalit y (Vitamin K de \201ciency) (cid:2) Ultrasound \200\224level of obstruction \200\224excludes stones \200\224may see nodes or hepatic secondaries \200\224doppler to assess vessels \200\224endoscopic ultrasound good for tumor of lower one third (cid:2) CT scan \200\224excludes cancer of head of pancreas \200\224assesses liver (cid:2) Angiography \200\224useful \200\230road map \200\231 for surgeon (cid:2) MRI chola ngiography \200\224good biliary tree map (cid:2) ERCP (cid:2) Percutaneous cholangiography Treatment Cholangiocarcinomas should be resected if there are no distant metastases and no irreparable involvement of the hepatic artery and portal vein. Lower third tumors can be tr eated by a standard pancreatico-duodenectomy and middle third tumors by resection of the bi le duct. It is advisable to perform a full lymph-node dissection, including the retro-pancr eatic and para-aortic stations, as cure has been reported even with hilar nodal metastases. The results of surgery are good, with microscopically curative resec- tions possible in ove r 75% of the patients, and \201ve-year survival of approximately 50% in the best series. In cases of unresectable tumors, cholestatic jaundice requires surgi- cal, endoscopic, or p ercutaneous palliation. Cholangiocarcinomas often grow slowly, and in young patients surgic al bypass is preferred. A gastroenterostomy can also be performed to prevent duodenal obstr uction. Endoscopic stenting is less invasive but the failure rate is high and the prosthese s often need to be replaced (polyethylene tubes) or unblocked (Wallstent). The percutaneous transhepatic route is gen- erally superior because of better access to negotiate the obstr uction. The results of trials comparing the different modalities are incon- clusive. Percutaneous t ranshepatic stenting is de \201nitely preferred in cases of recurrence after surgery. Alth ough cholangiocarcinomas are not generally considered chemosensitive or radiosensitive, res ponses to chemotherapy with cisplatin and 5- \202uorouracil and folinic acid have been obs erved, occasionally allowing resection of apparently unresectable tumors. Newer agents such as gemcitabine and irinote- can are under investigation. OHO-20(349-374) 11/18/02 8:27 AM Page 368 UPPER GASTROINTESTINAL CANCER 368 Tumors of the gall bladder In Western countries, the annual incidence is 1 \200\2231.5/100 000, with women affected twice as often as men because of their increased predisposition to gallstones, the most important aetiological factor. The risk of gall bladder cancer is 1%, 20 years after diagnosis of cholelithiasis. Endemic peaks are observed in some populations of Chile and in some native American tribes with a very high prevalence of gallstones. Gal l bladder polyps may degenerate and, if larger than 10 mm, should be removed by laparoscopi c cholecystec- tomy. Mode of spread and clinical presentation The tumor in \201ltrates the muscular wall of the gall bladder and the neighboring liver tissue in segments 4 and 5, and spreads to regional lymph nodes and to the liver. Distant metastases occur late. Two modes of presentation are common. During cholecystectomy for gallstones (approximately 1% of cholecystectomies) either a small, non-penetrating mass is found on examination of th e resected speci- men or an obvious mass is seen penetrating the gall bladder wall. Alterna tively, patients present with obstructive jaundice, abdominal pain, and a mass in the right upper quadrant \200\224either the tumor itself or lymph node metastases. Diagnosis (cid:2) Liver function tests may be abnormal (cid:2) CEA, CA19 \200\2239 may be increased ( cid:2) Ultrasound \200\224may reveal tumor \200\224invasion of ducts \200\224nodes \200\224liver secondaries (cid:2) CT scan (cid:2) Angiogram \200\224vessel invasion Treatment Incidental tumors diagnosed after a laparoscopic cholecystectomy need no further action unless the gall bladder was ruptured, in which case the trocar sites should be excis ed because abdominal wall metas- tases may occur. Tumors of more advanced stages should be treated with radical surgery (resection of segments 4 and 5, bile duct, and lymphadenectomy ). Post-operative chemotherapy with cisplatin is of no proven bene \201t. Radiotherapy is used in cases of incomplete resec- tion. For unresectable tumors, surgical or radiological biliary drainage is performed according to the same principles as for the pal- liative trea tment of cholangiocarcinoma. OHO-20(349-374) 11/18/02 8:27 AM Page 369 CANCER OF THE BILIARY TRACT 369 Outcome The \201ve-year survival rate for Stage I tumors is 90% and for Stage II tumors i s 80%. The results of surgery for more advanced disease have improved in centers performing very extensive resections, where a \201ve-year survival rate of 40% for Stage III tumors has been obtained. OHO-20(349-374) 11/18/02 8:27 AM Page 370 UPPER GASTROINTESTINAL CANCER 370 Pancreatic cancer Etiology The cause of this disease is largely unknown. Smoking accounts for about 30% of th e risk. Diets high in saturated fats may be important, but not the previously controversial factors such as alcohol and caf- feine intake. Sporadic chronic pancreatitis is associated with a 5% life- time risk. In hereditary pancreatitis there is an elevated 40 \200\22370-f old risk of pancreatic cancer. There is also increased risk in various famil- ial cancer sy ndromes, for example: (cid:2) Peutz \200\223Jeghers \200\231 syndrome (cid:2) von Hippel \200\223Lindau disease (cid:2) Lynch II families (cid:2) Familial atypical multiple-mole me lanoma (FAMMM) (cid:2) Breast and breast \200\223ovarian cancer families (cid:2) Familial p ancreatic cancer Epidemiology There is relatively high incidence in North America, northern Europe, and Aust ralasia. The age-standardized incidence is 8 \200\22311 per 100 000 women, and 10 \200\2231 2.5 per 100 000 men. The male:female incidence ratio of 2:1 decreases with age. 40% of case s present before the age of 75 years. The mean age of presentation is 67 years for men and 63 years for women. Pancreatic cancer is the seventh commonest cause of cancer death in the UK (7000 deaths per annum). Pathology The majority of exocrine tumors are ductal adenocarcinomas (90%) and 1 \200\2232% are acinar; the remainder are of diverse histology. 75% arise in the head of the organ, 15 % in the body, and 10% in the tail. Genetic abnormalities found in pancreatic cancer includ e the K-ras oncogene (90 \200\223100%) and mutations in p53 (60%), p16 (80%), and SMAD4 (50 %) tumor suppressor genes. Spread is mainly to retroperitoneal tissue, the liver, and the peritoneum, with distant met astases to the lung, liver, and the bone. The most signi \201cant prognostic indicators are tumor size, grade, stage, and resection margin status. Staging is according to TNM classi \201cation. OHO-20(349-374) 11/18/02 8:27 AM Page 371 PANCREATIC CANCER 371 Presentation Classical symptoms are painless jaundice, weight loss, and back pain (70 \200 \22390%). Anorexia is present in 60%. It may present with: (cid:2) Pruritus (cid:2) Diabete s mellitus (cid:2) Acute pancreatitis (cid:2) Ascites (cid:2) Cholangitis (cid:2) Deep-vein thrombosis Signs of pancreatic cancer are: Jaundice (85%) (cid:2) Cachexia (70%) (cid:2) Hepatomegaly (60%) (cid:2) Palpable gall blad der (Courvoisier \200\231s sign \200\22440%) Epigastric masses, ascites, and abdominal tend erness are common. (cid:2) Rare signs include: (cid:2) Trousseau \200\231s syndrome (migratory thrombophlebitis) (cid:2) Troisier \200\231 s sign (left supraclavicular lymph-node enlargement) (cid:2) Splenic-vein thrombosis (cid:2 ) Gastric fundal varices Investigations (cid:2) Tumor markers CA19 \200\2239, CA125 \200\224poor sensitivity (cid:2) Ultrasound \200\22475% accuracy (cid:2) Endoluminal ultrasound \200\22490% accuracy (cid:2) CT, MRI \200\224identify liver metastases >1 cm (cid:2) ERCP \200\224positive cytology in 60% (cid: 2) Laparoscopy \200\224unexpected peritoneal deposits (cid:2) Laparoscopic ultrasound (cid: 2) Fine-needle aspiration \200\224percutaneous Treatment options For all patients the aim is to relieve jaundice, duodenal obstruction, we ight loss, and pain. The majority of patients will present with advanced disease, and a thi rd present with disease so advanced only pain relief and symptomatic palliative care is pos sible. Oral pancreatic enzyme supplements may be required for pancreatic exocrine insuf \201cienc y. Non-surgical relief of jaundice is indicated for patients with unresectable disease and those un \201t for resection of OHO-20(349-374) 11/18/02 8:27 AM Page 372 UPPER GASTROINTESTINAL CANCER 372 localized disease. Prior to any procedure attention is required to ensure adequate urine ou tput and correction of coagulopathy, anemia, and hypoproteinaemia. Antibiotic prophylaxis i s mandatory. Endoscopic stents have relative low morbidity rates and metallic stents are pr eferred for patients with expected longer survival. Percutaneous transhepatic stenting has a higher complication rate. Surgical biliary bypass is indicated for younger patients with a low tumor burden; 10 \200\22315% of these will develop duodenal obstruction, so prophylac tic duodenal bypass may be indicated. Following these palliative maneuvers the median survival rate is dismal \200\224between 3 a nd 6 months; the overall \201ve-year survival rate is 0.5%. Surgery Resection is the only treatment that offers the possibility of cure, but its feasib ility will depend on individual criteria such as tumor size and invasion, medical \201tne ss of the patient, and the surgical expertise available. Resection is possible in 10 \200 \22315% of cases \200\224most commonly, Kausch \200\223Whipple \200\231s procedure with or without pylorus preservation. Post-operative complications include bronchopneumonia, pancre- atic \201stulae, sepsis, a bscess, and hemorrhage \200\224but the mortality rate is less than 10% in specialist center s. Although surgery is curative for the minority, resection can result in good palliation. The median survival time after surgery is 10 \200\22318 months, with a \201ve-year survival rate of 10 \200\22324%. The sites of tumor recurrence are: (cid:2) Loco-regional (60 \200 \22380%) (cid:2) Hepatic (40 \200\22380%) (cid:2) Peritoneal (27 \200\22362%) (cid:2) Dista nt (6 \200\22320%) The majority occur within two years following surgery. Chemotherapy There is no standard chemotherapy for pancreatic cancer. One ran- domized cont rolled study has shown that the nucleoside analog, gemcitabine, marginally improved surviva l compared to a simple 5- \202uorouracil (5FU) regimen \200\224median survival, 5.7 month s vs. 4.6 months. Adjuvant therapy using 5-FU, doxorubicin, and mito- mycin C doubled media n survival in a randomized controlled trial (11 months vs. 23 months) but did not improve l ong-term survival. Radiotherapy Patients with good performance status and localized resectable tumor may be co nsidered for radiotherapy, with or without chemo- therapy. Moertel showed that 5FU increase d median survival after OHO-20(349-374) 11/18/02 8:27 AM Page 373 PANCREATIC CANCER 373 radiotherapy (35 \200\22340 Gy) by 4 months (10.4 months vs 6.3 months). With 3D-CT plannin g of external-beam radiotherapy it is possible to deliver 50.4 Gy in 28 daily fractions to pancreatic tumors without exceeding tolerance for the adjacent stomach, bowel, or kidneys. Both external-beam radiotherapy (EBRT) and intra-operative radiotherapy (IORT) have been us ed in the adjuvant settings. The EORTC and ESPAC-1 randomized controlled trials have shown no bene \201t from adjuvant chemoradiotherapy. Future treatments The ESPAC trial has shown evidence of a benefit for adjuvant chemotherapy and justifies further randomized trials.1 The possible value of gemcitabine needs repeatin g in other randomized controlled trials. Other drugs under examination in advanced disease are: (cid:2) Thymidylate synthase inhibitors (e.g. tomudex) (cid:2) Topoisomerase I inhibitors ( topotecan, irinotecan) (cid:2) Taxanes (cid:2) Angiogenesis inhibitors Reference 1. Neoptolemos, J.P., Dunn, J.A., Stocken, D.D. et al. (2001) Adjuvant chemoradio therapy in resectable pancreatic cancer: a randomized controlled trial. Lancet 358, 1576 \200\22385. OHO-20(349-374) 11/18/02 8:27 AM Page 374 UPPER GASTROINTESTINAL CANCER 374 Controversies in management The proposed superiority of radical extended pancreaticoduoden- ectomy has been advocated t o increase patient survival. However, a small randomized trial comparing radical and standa rd pancreatico- duodenectomy showed no signi \201cant difference in survival between the t wo groups. The use of chemotherapy in advanced cancer and as adjuvant therapy still needs t o be con \201rmed in large randomized con- trolled trials. Further reading 1. Berlin, J.D., Rothenberg, M. (2001) Chemotherapy for resectable and advanced pancreatic cancer. Oncology 15, 1241 \200\223590. 2. Bonenkamp, J.J. et al. (1999) Evaluation of extended lymph node dissection in the random ized D \200\223D2 Dutch Gastric Cancer Trial. New England Journal of Medicine 340, 908 \200 \22314. 3. (1997) Improving outcomes in colorectal cancer: the research evidence. Wetherby UK: NHS Executive Department of Health. 4. Nerenstone, S.R., Ihde, D.C., Friedman, M.A. (1988) Clinical trials in primary hepatocellular carcinoma: current status and future directions. Cancer Treatment Re views 15, 1 \200\22331. OHO-21(375-388) 11/18/02 8:33 AM Page 375 Chapter 21 Endocrine cancers Thyroid cancer 376 Adrenal cancer 380 Neuroblastoma 384 Further reading 388 OHO-21(375-388) 11/18/02 8:33 AM Page 376 ENDOCRINE CANCERS 376 Thyroid cancer Thyroid cancer has a UK incidence of 1:100 000 and a median age at presentation of 47 years , and is three times more frequent in females (amongst whom there is a young adult rise in incidence). It usually presents as a painless lump in the neck. Classi \201cation is on a histolog- ical basis:1. differentiated (papillary or follicular); 2. anaplastic; 3. lymphom a; 4. medullary. Differentiated thyroid cancer Management is similar for all cases and commences with radica l thyroidectomy preserving parathyroid and recurrent laryngeal nerve function. Low risk pat ients (those with small intrathyroidal papillary or micro-angioinvasive/minimally invasive follicular tumors) are sometimes managed by thyroid lobectomy but most clinicians prefer th e radical approach for all patients. Radioiodine therapy (40 \200\22380 mCi = 1500 \200\223 3000 MBq) to ablate the thyroid remnant follows the operation. This rids the body of all io dine avid normal thyroid, obviat- ing the risk of future second tumors (papillary) and rend ering the subsequent screening program (both thyroglobulin and radioio- dine) more sensitiv e and speci \201c for detecting relapse. External beam radiotherapy is delivered to the ne ck where the tumor was locally invasive at operation (giving a dose of 5000 cGy in 5 weeks via a well executed, CT planned, three \201eld MV photon plan in a shelled patient, the v olume being parallel to a straight cervical spine). If the patient presents with metastatic disease, or at relapse after par- tial thyroidectom y, radical thyroidectomy and ablation is still required because optimal management is based on the ability of most differen- tiated cancers to concentrate radioiodine (I131) \200\224 albeit usually less avidly than the parent gland. A carefully conducted radioiodine pro- gr amme can prolong life substantially in many of these patients and achieve complete and dura ble response in a signi \201cant number \200\224 small bulk relapse and high iodine avidit y being better response predictors. Following radical thyroidectomy and radioiodine ablation of the stump, the patient has seri al clinical examinations with at least two whole body radioiodine whole body pro \201le sc ans in the next 11 \201\2042 years (each performed after 3 months off thyroxine, 8 days off liothyronine and the tracer dose being given when the TSH is known to be above 30 Uu/L or after 200 (cid:2)g of TRH iv \200\224hereafter referred to as \200\230optimal conditions f or radioiodine \200\231). Serum thyroglobulin is measured at each clinical consultation and this important serum marker is more sensi- tive for relapse under the optimal conditions j ust described, although OHO-21(375-388) 11/18/02 8:33 AM Page 377 THYROID CANCER 377 worthwhile when the patient is on thyroid replacement. If two iodine scans over the \201r st 1.5 years are negative, and the clinical examination and thyroglobulin are negative, the n iodine scanning is only used in suspected relapse (and even then many would go straight t o an iodine therapy dose with a whole body scan on the \200\230tail-end \200\231 of the do se, because of the possibility of a tracer dose scan missing low avidity, but therapeutical ly relevant, uptake). Papillary cancer tends to relapse \201rst in neck nodes (and then medi- astinal nodes) be fore the lungs and then bones. The treatment of neck nodal disease is surgical resection (p receded by an iodine pro \201le scan under optimal conditions) followed by radiodine thera py where appropriate. Pre-operative imaging to de \201ne the extent of the nodal disease s hould be with MRI and not CT, because of the iodine load with CT contrast agents. Metastatic disease further a \201eld is treated by serial doses of radio- iodine (150 mCi = 5500 MBq), using the whole body scans after each dose and the serial thyroglobulin estima tion to guide progress, as well as other imaging. Iodine therapy is continued at 4 \200\223 6 monthly inter- vals until maximal remission, so long as the FBC and creatinine are satisf actory; care is needed after a cumulative dose of 1 Ci. In patients who do not relapse, physical examination (with careful attention to the neck an d CXR) and blood checks to ensure TSH sup- pression and minimal serum thyroglobulin reading s (<2 (cid:2)g/L) con- stitute follow-up, the periodicity of which decreases with the passa ge of time; remember that this disease can relapse up to 15 years from diagnosis. Anaplastic carcinoma Again presenting as a lump in the neck, the treatment is altogether mo re palliative as these tumors are rarely a radical surgical proposi- tion and do not take u p iodine. Radiotherapy to the neck is the stan- dard treatment, with palliative chemotherap y a not very promising systemic alternative (as indeed it is not in differentiated cancers) . Lymphoma Lymphomas tend to occur in elderly women, frequently against a background of prolo nged autoimmune thyroid disease. They are high grade immunoblastic non-Hodgkin \200\231s tu mors and are treated with a combination of combination chemotherapy and wide \201eld radi o- therapy to the neck. Prognosis is guarded. Medullary carcinoma Medullary carcinoma of the thyroid arises from the parafollicular C cel ls (the cell of origin of calcitonin), and may be sporadic or famil- ial. If the latter, it may or may not be part of the MEN syndrome, and OHO-21(375-388) 11/18/02 8:33 AM Page 378 ENDOCRINE CANCERS 378 the diagnosing clinician should take a family history and screen for phaeochromocytoma. Sur gical clearance of apparently localized disease to the neck is the only curative hope and i s the \201rst therapeutic step. For recurrent disease (for which the serum calcitonin ser ves as a good marker), occasional avidity of uptake to meta-iodo-benzyl- guanadine (MIBG) m akes radioiodinated MIBG therapy a possibly useful therapeutic modality. Otherwise there is no useful therapy except for palliative radiotherapy where appropriate; we have had little to no success with palliative chemotherapy. OHO-21(375-388) 11/18/02 8:33 AM Page 379 THYROID CANCER 379 OHO-21(375-388) 11/18/02 8:33 AM Page 380 ENDOCRINE CANCERS 380 Adrenal cancer The adrenal gland is composed of a cortex and a medulla and the tumors that arise in these two regions are aetiologically and func- tionally different, re \202ecting their cells of origin. Etiology The etiology of adrenocortical carcinomas is generally unknown. There are rare rep orts of familial incidence. About 10% of adrenal medullary tumors are familial, although in future more may be iden- ti \201ed as hereditary. These are usually associated with multi ple endocrine neoplasia (MEN) syndrome II and, occasionally, von Hippel \200\223Lindau dise ase. The RET proto-oncogene was the \201rst to be associated with MEN IIA and familial me dullary thyroid cancer and, subsequently, MEN IIB. The ability to identify this oncogene is of con- siderable importance in prophylaxis of the disease (discussed later). In over 80% of cases exons 10 and 11 are affected, which is useful for screening purposes. Epidemiology Both medullary and cortical tumors are rare. The incidence is about 1.0 per 10 6 population for cortical tumors and lower for phaeo- chromocytomas, at 0.6 per 106 populat ion. Pathology Both benign and malignant tumors are seen in the adrenal gland and, in the heredi tary variants, hyperplasia and pre-malignant changes may be evident. The differentiation be tween benign and malignant tumors is usually only made by their clinical behavior \200\224 the presence of local invasion or metastases indicates a malignant tumor. Only about 10% of adrenal medullary tumors are malignant. The hereditary tumors often occur in younger age groups, are more like- ly to be bilateral, and tend to be more benign in th eir behavior. Adreno-medullary tumors are usually phaeochromocytomas, so- called because of their golden or tan-colored appearance. About 10% of phaeochromocytomas are extra-adrenal and arise anywhere in the sympathetic chain. Rarely, neuroblastomas may present in late ado les- cence or adulthood. Immunocytochemistry is important in establishing the diagnosis. Adrenocortical carcinomas a re usually adenocarcinomas and malig- nancy is con \201rmed by the presence of metastatic spread. These OHO-21(375-388) 11/18/02 8:33 AM Page 381 ADRENAL CANCER 381 tumors extend locally to nodes and the liver but have a high fre- quency of distant spread when malignant. Presentation Adreno-medullary tumors (phaeochromocytomas) tend to present at a younger age when associated with the MEN syndrome, whereas sporadic tumors tend to occur in older patie nts. Classical symptoms include paroxysmal headaches, palpitations, tremors, and sweating a ttacks. A few may be diagnosed incidentally and a rare, but occasional case may be diagnose d after a maternal death in an unrecognized MEN family. Intermittent, severe hypertension i s a rare but classical presentation. Patients often have a long history and these tumors can be dif \201cult to diagnose. Many doctors will never see a patient with this condition, but a low threshold for investigation is appropriate.