CANCER: PART 2
From the 30th Annual San Diego Postgraduate Assembly in Surgery, sponsored by the University of California, San Diego,
School of Medicine
| NONFUNCTIONING NEUROENDOCRINE TUMORS OF THE PANCREAS—Michael Bouvet, MD, Professor of
Surgery, University of California, San Diego, School of Medicine, and Moores UCSD Cancer Center, La Jolla, CA
|
| General: 2500 new cases of pancreatic endocrine tumors in United States each year (≈50% associated with functional
syndrome due to hormonal secretion); median age of 50 yr (most cases occur between 40 and 70 yr of age); no clear
gender predilection; most tumors benign and slow-growing; potential for metastasis; study—Mayo Clinic review of
pancreatic neuroendocrine tumors from 1960 to 1986 (N=322); ≈18% nonfunctioning tumors (many tumors now picked
up incidentally by computed tomography [CT] and require work-up)
|
| Pancreatic endocrine tumors: gastrinoma—survival rate ≈70%; ≈50% of tumors benign; cure rate 25% to 40%;
insulinoma—most tumors benign; 5-yr survival rate 95%; vasoactive intestinal peptide tumors (vipomas), glucagonoma,
and somatostatinoma—more rare; most have malignant potential; cure rate ≈20%; 5-yr survival rate 50%; nonfunctioning
islet cell tumors—median survival 7.1 yr if tumor removed; survival 5.2 yr with locally advanced, unresectable,
nonmetastatic disease; survival 2.1 yr for metastatic, unresectable disease
|
| Nonfunctioning pancreatic endocrine tumors: most secrete hormones (eg, neurotensin, pancreatic polypeptide,
chromogranin, and neuron-specific enolase), but considered nonfunctional because of absence of clinical syndrome
|
| Localization studies: CT (helpful, but visualization of tumor not always possible); magnetic resonance imaging
(MRI); angiography with portal venous sampling (not used often, but keep in mind); octreotide scanning (expensive;
images fuzzy at times); duodenal transillumination (during exploratory surgery); endoscopic ultrasonography (US; latest
technology); intraoperative US; CT—pancreatic ductal carcinoma on CT portal appears hypodense (does not take
up contrast as much on arterial phase) as opposed to pancreatic endocrine tumor; MRI—endocrine tumor looks dark on
T1-weighted image and bright on T2-weighted image; endoscopic US—probe at tip of endoscope; useful for imaging
common bile duct, pancreas, portal vein, and gallbladder; allows for biopsy
|
| Pathology: pancreatic ductal carcinomas arise from lining of pancreatic ducts; intense fibrosis and desmoplasia occur
around tumors; perineural invasion common; circumscription poor; neuroendocrine tumors well circumscribed
|
| Surgical treatment for neuroendocrine tumor: good exposure of entire pancreas important (Kocher maneuver);
subcostal incision; careful inspection of duodenum, regional lymph nodes, and liver; discrete removal of tumor—
enucleation (depending on location and size); partial to subtotal pancreatectomy more common than total pancreatectomy
(rarely done); debulking of malignant tumors and hepatic or lymphatic metastases potentially beneficial; for tumor
in tail or body of pancreas, perform distal pancreatectomy; for tumor in middle of pancreas, perform middle third or
central pancreatectomy (saves tail of pancreas; pancreaticojejunostomy to Roux-en-Y limb); for larger tumors in head
of pancreas, perform Whipple procedure
|
| Surgical pearls: removal of insulinoma—avoid intraoperative administration of glucose; follow glucose levels during
surgery (level rises upon removal of tumor); Musa’s patch—save as much falciform ligament as possible during laparotomy;
divide ligament near umbilicus; use as vascularized patch to reduce risk for pancreatic fistula
|
| Whipple procedure: exposure of infrapancreatic superior mesenteric vein— with tumor at head of pancreas, rotate
right colon and hepatic flexure to expose entire second and third portions of duodenum; ligate middle colic vein, if necessary;
extended Kocher maneuver—dissect all fiber and fatty tissue off inferior vena cava and aorta; ligate gonadal
vein, if necessary; portal dissection—remove gallbladder (usually); identify and divide gastroduodenal artery;
transections—stomach first, followed by jejunum (transect just beyond ligament of Treitz), then pancreas; ligate
branches of uncinate process as necessary; reconstruction—stepwise and counterclockwise; end-to-side pancreaticojejunostomy;
end-to-side choledochojejunostomy or hepaticojejunostomy; gastrojejunostomy; placement of drains
(speaker no longer uses gastrostomy or jejunostomy tubes)
|
| Minimally invasive procedures: laparoscopic distal pancreatectomy described for small tumors in distal body or tail
of pancreas; most small case series have leak rates of ≈25%; potential for bleeding may limit use; careful consideration
required when selecting patients for laparoscopic approach
|
| Multiple endocrine neoplasia (MEN) 1: autosomal dominant; genetic defect on chromosome 11 (MEN1 or “menin”
gene); glandular involvement (three Ps)—parathyroid involved in 100% of patients, resulting in hyperparathyroidism
(typically affects all four glands); pancreatic endocrine tumors occur in ≈70% of patients; pituitary adenomas
occur in ≈30% of patients; other tumors—carcinoid; adrenal; ovarian; thyroid; lipomas; clinical symptoms—begin in
third decade of life; serum calcium and parathyroid hormone (PTH) levels reveal hyperparathyroidism; relevant
history—ulcer disease; menstrual changes; galactorrhea; loss of libido; hyperinsulinism
|
 | Screening: pituitary tumors—head CT; serum prolactin levels; pancreatic tumors—gastrin, insulin, glucose, and pancreatic
polypeptide levels; abdominal CT if hormone levels elevated
|
| Management of hyperparathyroidism: options include total parathyroidectomy with autograft or 3.5-gland parathyroidectomy;
some surgeons recommend removing thymus in case ectopic parathyroid gland present; autograft—
identify “most normal” parathyroid gland; bisect gland and implant into forearm (nondominant brachioradialis muscle)
|
| Pancreatic tumors: islet-cell tumors (usually multiple); most secrete pancreatic polypeptide; bimodal distribution (gastrinomas,
nonfunctioning polypeptide-secreting tumors [Ppomas], and somatostatinomas usually found on right side
of superior mesenteric artery; insulinomas [variable distribution], glucagonomas, and vipomas usually found on left
side); gastrinoma—associated with peptic ulcer disease; insulinomas—associated with Whipple’s triad (hypoglycemia);
symptoms relieved by administration of glucose; vipomas—patients typically have watery diarrhea (often
secretory) and hypokalemia; glucagonoma—uncommon; patients present with weight loss, necrolytic dermatis, and
rash (cardinal feature); somatostatinoma—mild symptoms, including malabsorption, diarrhea, and gallstones;
Ppomas—nonfunctioning; no symptoms
|
| Unresectable tumors: chemotherapy—commonly used agents include streptozocin, chlorozotocin, 5-fluorouracil (5-
FU), doxorubicin, and dacarbazine (DTIC); objective response rates of ≈63%, with mean duration of 17 mo
|
| Liver metastasis: treatment options include chemoembolization (hepatic artery embolization), radiofrequency ablation,
and resection (if already taking out primary tumor)
|
| NONRESECTION IMAGE-GUIDED TECHNIQUES FOR HEPATOCELLULAR CARCINOMA: TACE VS YTTRIUM
90 VS ALCOHOL INJECTION VS RFA—Steven C. Rose, MD, Professor of Radiology, Chief, Interventional
Oncology Section, University of California, San Diego, School of Medicine, San Diego, CA
|
| General: hepatocellular carcinoma (HCC) among most common solid malignancies worldwide; nonhomogeneous distribution;
high incidence in sub-Saharan Africa (related to aflatoxin) and East and Southeast Asia (hepatitis B virus); intermediate
incidence in peri-Mediterranean regions (hepatitis C virus [HCV]); incidence rising in United States (due to
epidemic of HCV); most patients with HCC have underlying cirrhosis; patients with large tumors, presenting with nonspecific
symptoms have poor survival (3 to 6 mo); fewer data on survival rates associated with small tumors
|
| Therapeutic options: systemic chemotherapy—ineffective against HCC (no proven survival benefit; low response
rates), but best therapy for metastatic disease; radiation therapy—external beam radiation destroys liver and adjacent organs
before tumor; surgical resection—gold standard for long-term survival, but few patients qualify; transplantation—
best chance for cure in patients with cirrhosis and HCC (75%-80% 5-yr survival); delays common; goal to keep patient
alive and reduce tumor burden while waiting for liver; percutaneous image-guided techniques—regional therapy and focal
ablation
|
Regional Therapy
| Background: hepatocytes receive majority of nutrients from portal vein (PV); tumors depend on hepatic artery (HA)
for 90% to 100% of nutrients
|
| Transcatheter arterial chemoembolization (TACE): keystone of regional therapy approach; slurry of chemotherapeutic
agents (eg, doxorubicin [Adriamycin], cisplatin, and mitomycin-C); agents mixed with iodinated poppy
seed oil (eg, Ethiodol) and small particles to help trap agent in proximity to tumor (prolongs dwell time); concentrated
dose delivered to tumor, sparing as much nontumorous liver as possible; mechanisms of action—delivery through hepatic
artery increases concentration of agent at tumor (by 10- to 100-fold), compared to intravenous administration; prolonged
dwell time; infarction (caused by small particles); ischemia disables cell membrane pumps on tumor cells,
prolonging effectiveness of chemotherapy; HCC cells phagocytize Ethiodol droplets containing chemotherapeutic
agent; liver extracts ≥50% of chemotherapeutic agent in first pass through liver, reducing toxic effects on nontargeted
parts of body (eg, hair follicles; bone marrow; mucosal membranes); candidates—HCC; metastatic disease (especially
hypervascular metastases [neuroendocrine, colorectal, melanoma; some sarcomas]); disease contained or mostly contained
to liver; patients not candidates for operative resection; relative contraindications—liver failure (eg, total bilirubin
>2.5 mg/dL); poorly controlled hepatic encephalopathy; extensive extrahepatic disease; biliary obstruction or
absence of intact sphincter; tumor burden >50% of liver; increased risk—no portal vein inflow (eg, transjugular intrahepatic
portosystemic shunt [TIPS]; portocaval shunt; portal vein thrombosis); important to spare nontumorous parts of
liver and avoid particle embolization; reasonable expectations—reduction in tumor size; relief of tumor-related symptoms;
survival benefit (life expectancy may double); cure not realistic; why not curative—residual portal venous connections
(eg, small tumors; satellite, peripheral tumors); other arterial supply; new primary tumor (HCC) or metastasis
|
| Selective internal radiation therapy (SIRT): yttrium-90 (Y90 ) radioembolization; microspheres embedded with
Y90 (beta emitter); average penetration of 2.5 mm (in soft tissue); maximum penetration of ≈1 cm; hepatic artery delivery;
preferential uptake by tumor (due to neovascularity); role—treatment of metastases (neuroendocrine; colorectal);
reduced toxicity; risks—potential role in HCC, but associated arteriovenous (AV) shunting may introduce Y90 to lung;
risk for radiation-induced liver disease (select for patients with total bilirubin <2 mg/dL)
|
Focal Ablative Therapy
| Liquid agents: percutaneous injection with ethanol; outpatient procedure; needle placement and injection of ethanol
monitored by US; well tolerated by most patients; mechanism—protein denaturation, dehydration of cytoplasm, and intravascular
thrombosis cause coagulation necrosis, ultimately resulting in fibrosis (weeks to months); benefits—
minimal risks; repeatable; inexpensive; limitations—liquid agent has unpredictable distribution (eg, nonhomogeneous
distribution within tumor); high rate of local recurrence; good option in patients with HCC (agent contained in
pseudocapsule and does not leak into liver), but not in those with metastasis
|
| Thermal agents: more predictable zone of tissue necrosis than liquid agents; specific with regard to geometry but not
tissue (kills everything within given radius); hepatic cryotherapy—early thermal technique; open procedure with large
probes inserted under US guidance; relatively high morbidity; possibility of hepatic fractures with hemorrhage; high
rate of local recurrence; radiofrequency ablation (RFA)—smaller probes allow percutaneous approach; focal electric
field with rapid alternating current generates frictional heat (diffuses to predictable distance), resulting in coagulation
necrosis; candidates include patients with liver-only or liver-dominant disease, small tumors, and small number of physically
approachable tumors; cell type not important; maximum diameter of necrotic zone, <5 cm (must encompass tumor
plus 1 cm margin), so tumors must measure ≤2 cm; overlapping spheres or cylinders may be used to treat larger
tumors, but time consuming and has risk of leaving islands of viable tumor
|
| Synergistic treatment with TACE and RFA: arterial occlusion with embolic agent reduces heat sink, allowing
larger diameter of necrosis and more thorough heating; embolization also reduces risk for hemorrhage; Ethiodol (visible
on CT) provides target for guiding probe
|
| Routes of probe delivery: percutaneous—minimizes scarring in right upper quadrant (beneficial for patients receiving
liver transplants); challenging to maneuver around structures; US images often not clear (sound attenuated through
fatty tissue; tumor difficult to distinguish from echogenic liver); difficult to identify bleeding (coagulate tract on way
out, use color flow [Doppler US] to look for signs of bleeding, and recheck hematocrit 3-4 hr after surgery); open—best
for staging disease and inspecting peritoneum; intraoperative US visualizes small lesions (10%-20% chance of identifying
additional tumors missed by CT and MRI); US-guided manipulation of probe improves targeting; Pringle maneuver
(clamping off portal vein inflow) reduces heat sink effect; good approach for patients with limited metastatic disease;
potential to combine with resection; laparoscopic—protection of nontargeted structures possible; laparoscopic US
probe also may be used; disadvantages include small field of view and potential for disorientation; good option in patients
with surface tumors next to nontargeted structures
|
| Safety and efficacy of RFA: mortality <1%; major morbidity (bleeding, liver failure, biliary injury), ≈10%; track
seeding, ≈1%; complete focal tumor ablation occurs in 70% to 80% of cases (increases to 90%-100% when combined
with TACE); no long-term data; high likelihood of tumor in other locations; expanding applications of RFA—lung;
kidney; bone
|
| Conclusions: many promising, minimally invasive image-guided techniques; good outcome depends on careful patient
selection and meticulous technique
|
Suggested Reading
Bahra M et al: Surgical strategies and predictors of outcome for malignant neuroendocrine tumors of the pancreas.
J Gastroenterol Hepatol 22:930, 2007; Blum M et al: MR-guided percutaneous ethanol ablation of hepatocellular
carcinomas before liver transplantation. Minim Invasive Ther Allied Technol 16:230, 2007; Cho YB et al: Hepatic resection
compared to percutaneous ethanol injection for small hepatocellular carcinoma using propensity score matching.
J Gastroenterol Hepatol 22:1643, 2007; Forner A et al: Transarterial chemoembolization for patients with
hepatocellular carcinoma. Hepatol Res 37(Suppl 2):s230, 2007; Gates VL et al: Radioembolization with yttrium-90
microspheres: review of an emerging treatment for liver tumors. Future Oncol 3:73, 2007; Kalafat H et al: Intraoperative
Doppler ultrasound: a reliable diagnostic method in insulinoma. Hepatogastroenterology 54:1256, 2007; Kouvaraki
MA, et al: Management of pancreatic endocrine tumors in multiple endocrine neoplasia type 1. World J
Surg 30:643, 2006; Kulik LM et al: Emerging Approaches in Hepatocellular Carcinoma. J Clin Gastroenterol
41:839, 2007; Kulik LM et al: Yttrium-90 microspheres (Therasphere) treatment of unresectable hepatocellular
carcinoma: downstaging to resection, RFA and bridge to transplantation. J Surg Oncol 94:572, 2006; Rockall AG,
Reznek RH: Imaging of neuroendocrine tumors (CT/MR/US). Best Pract Res Clin Endocrinol Metab 21:43, 2007;
Singh N et al: Laparoscopic enucleation of a nonfunctioning neuroendocrine tumor at the head of the pancreas.
JSLS 10:259, 2006; Zhang YJ et al: Hepatocellular carcinoma treated with radiofrequency ablation with or without
ethanol injection: a prospective randomized trial. Radiology 244:599, 2007.
Cultural and Linguistic Resources
In compliance with California Assembly Bill 1195, Audio-Digest Foundation offers selected cultural and linguistic
resources on its website. Please visit this site: www.audio-digest.org/CLCresources.
Educational Objectives
| The goal of this program is to improve the management of nonfunctioning neuroendocrine tumors of the pancreas and
hepatocellular carcinoma (HCC). After hearing and assimilating this program, the clinician will be better able to:
|
| Identify the different neuroendocrine tumors of the pancreas and list modalities for their localization.
|
| Summarize the treatment options for neuroendocrine tumors.
|
| Describe the therapeutic options for patients with HCC.
|
| Discuss transcatheter arterial chemoembolization and selective internal radiation therapy as regional therapy
for patients with HCC.
|
| Compare alcohol injections and radiofrequency ablation as focal ablative therapy for patients with HCC.
|
Faculty Disclosure
In adherence with ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not
a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Rose is a minor
stockholder and proctor for SIRTEX Medical and a minor stockholder in Boston Scientific Corporation.
Acknowledgements
Drs. Bouvet and Rose were recorded at the 30th Annual San Diego Postgraduate Assembly in Surgery, held February 26
to March 2, 2007, in San Diego, CA, and sponsored by the University of California, San Diego, School of Medicine,
Department of Surgery. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in
the production of this program.
|
