GI and Liver Malignancies

GI & Liver Malignancies Bushra Ibnauf Sulieman, MD MS Consultant, Gastroenterology & Hepatology Department of Medicine King Faisal Specialist Hospital & Research Center - Jeddah

Question
A 45 year old man was referred by his PCP because of new onset of dysphagia of 4 weeks duration. The patient has had a history of smoking, 5-pack years, in high school and a history of heartburn self medicated with OTC antiacids. An UGI study showed a mass lesion in the distal esophagus. Which of the following statements is INCORRECT?
The lesion is most likely produced by a metastatic cancer
The patient probably has had Barrett’s esophagus
Biopsy specimens from the gastroesophageal junction of this patient would show adenocarcinoma
Squamous cell cancer is unlikely in this location
Most patients with this cancer would likely be male

Question
A 45 year old man was referred by his PCP because of new onset of dysphagia of 4 weeks duration. The patient has had a history of smoking , 5-pack years, in high school and a history of heartburn self medicated with OTC antiacids. An UGI study showed a mass lesion in the distal esophagus.
Which of the following statements is INCORRECT?
The lesion is most likely produced by a metastatic cancer
The patient probably has had Barrett’s esophagus
Biopsy specimens from the gastroesophageal junction of this patient would show adenocarcinoma
Squamous cell cancer is unlikely in this location
Most patients with this cancer would likely be male

Pathogenesis of Adenocarcinoma GERD Reflux Esophagitis Intestinal metaplasia (Barrett’s esophagus) Dysplasia Adenocarcinoma

Barrett’s HGD

Barrett’s Esophagus
Intestinal metaplasia of the esophagus : Replacement of the stratified squamous mucosa by specialized columnar cells

Epidemiology of Esophageal Cancer in the US
Squamous Adeno
New cases per year ~ 6000 ~ 6000
Male-to-female ratio 3:1 7:1
Black-to-white ratio 6:1 1:4
Major risk factors smoking Barrett’s
Alcohol esophagus
Socioeconomic class lower high
Geography SE Asia western /
Africa industrial
Iran

Esophageal AdenoCa: Risk Factors
Barrett’s mucosa: most significant (40 fold)
GERD
AC is largely a disease of Caucasians and males
Obesity has been associated with AC but not SCC
Smoking probably increases the risk of AC
Development of HGD in Barrett’s
Alcohol is probably not an important risk factor
Cameron A, et al. Gastroenterology 1995; 109: 1541. Lagergren et al. NEJM 1999; 340:825.

Esophageal SCCA: Risk Factors
Diet:
N-nitroso compounds
Alcohol
Hot tea
Tobacco
HPV 16
Lye induced strictures
Chronic esophagitis
Associated diseases:
Head & neck cancer
Achalasia
Plummer-Vinson syndrome
Tylosis
Celiac disease
Gastrectomy
Radiation therapy
Axelard A, et al. In Sleizenger & Fordtran’s Gastro & Liver Dis, 6 th Ed.

Clinical Presentation & Symptoms
Dysphagia:
Most common
Initially intermittent
Solids then liquids
History of GERD (AdenoCa):
Esophagitis / Barrett’s in 50% on presentation
Food intolerance, anorexia and wt. Loss
Odynophagia and back pain:
Mediastinal involvement
Hoarseness
Esophago-pulmonary fistula
Liver / diaphragm / airway mets

Esophageal Cancer: Diagnosis
Endoscopy:
Location: Distal vs. proximal
Associated Barrett’s
Appearance: Flat vs. polypoid
Endoscopic biopsy: Most valuable
Sensitivity of 6-8 bxies: 98%
Sensitivity of cytology and bx: 100%
Radiology:
Esophagogram: Filling defect
CAT scan: Thickening

Esophageal Cancer: Diagnosis

Question
You performed an EGD, with biopsy of the mass. The results confirm your suspicions. You now wish to begin to stage the mass.
Which of the following would be the first procedure of choice?
PET scan
CT of the chest and abdomen
EUS, with FNA of lymph nodes, if present
Video assissted thoracosocpy, with biopsy

Staging Classification: TNM
T : Primary tumor
Tis: Carcinoma in situ / high grade dysplasia
T1: Mucosa and submucosa
T2: Muscularis propria
T3: Transmural / periesophageal
N : Regional lymph nodes
N0: No adenopathy
N1: Regional nodal metastasis
M : Distant metastasis
M0 vs. M1

Esophageal Cancer Staging
Stage 0: Tis, N0, M0
Stage I: T1, N0, M0
Stage II:
IIA: T2/3, N0, M0
IIB: T1/2, N1 , M0
Stage III:
T3, N1 , M0
T4 , N1, M0
Stage IV: Any T, any N, M1

Esophageal Cancer: Survival
STAGE 5-Year Survival
Stage 0: 75%
Stage I: 50%
S tage IIA: 40%
Stage IIB: 20%
Stage III: 15%
Stage IV: < 5%

Staging Tools
Endoscopic Ultrasound (EUS)
Best modality for locoregional staging
Limited role in distant metastasis
CAT scan:
T staging: no role
Nodal staging: very low sensitivity
Detection of metastasis
PET scan:
Whole body survey
Helpful in diagnosing metastatic disease
Limited role in T / local staging
Flamen P, et al. J Clin Oncol 2000; 18: 3202.

EUS: Esophageal Cancer
T & N staging
Metastasis:
Celiac lymph nodes
Liver lesions
Change in management decisions
Prognostic information

7.5 / 12 MHz. 7.5 MHz. UC-30P UM-130 Mechanical Radial Scanning Curved Linear Array Scanning

EUS: Gastrointestinal Wall Mucosa Submucosa Muscularis propria Serosa Lumen Scope

T2N0 T3N0 T4N0

Treatment: Early Disease
Stages: T is , I and IIA
Surgery:
Mainstay of treatment
Surgery alone
Best outcome:
T is & HGD: cure rate of 100%
Stages I & IIA: cure rate ~ 80%
Steup W, et al. J Thorac Cardiovasc Surg 1996; 5:S17-26.

Treatment: Locally advanced Disease
Stages IIB and III
Difficult and controvercial
Surgery alone: 10% cure!
Neoadjuvant chemo or XRT: No difference
Neoadjuvant chemo and radiation:
Greatest chance for prolonged survival
Cisplatin and 5-Fluorouracil
Patient and Dr.’s decision!!!
Lightdale C. Am J Gastro 1999; 94: 20.

Treatment: Metastatic Disease
Palliative
Chemotherapy +/- XRT:
Potential prolongation of life?
Fit and willing patient
Lightdale C. Am J Gastro 1999; 94: 20.

Endoscopic Therapy
Limited role
Endoscopic Mucosal resection
Coagulation therapy (Barrett’s HGD):
Photodynamic therapy
Bipolar / heat coagulation
Laser

Palliative Treatment
XRT
Chemotherapy
Endoscopic dilation
Endoscopic stenting
Photodynamic therapy
Endoscopic laser therapy
Access for nutritional support

Screening & Prevention
Aggressive treatment of GERD
Medical
Surgical
Screening of target population :
Barrett’s metaplasia
High incidence areas
Tools:
Endoscopy
Balloon cytology
Endoscopic ultrasound
Biomarkers

Question
A 72 year old man presents with 10 kg weight loss, early
satiety and melena. He has a great fear of gastric
cancer because his father died of it at age 59. EGD was
Done and revealed a large ulcer with raised edges. You recommend:
Imatinib to shrink the tumor
Radiotherapy and Chemotherapy
Eradication of H Pylori to reverse
the condition
Surgical resection
Laser therapy

Gastric Cancer
Lung (1.4 million deaths)
Stomach (740 000 deaths)
Liver (700 000 deaths)
Colorectal (610 000 deaths)
Breast (460 000 deaths).
WHO 2008

Gastric Cancer
Environmental : preserved meats, nitrates
Genetics: First degree relatives 2-3x
H Pylori Infection more related to distal stomach cancers
Pernicious anemia
? Partial gastrectomy for benign disease
Gastric polyps
95% adenocarcinoma
5% lymphoma, sarcoma, carcinoiud
Linitis plastica 10% of adenoacarcinomas

Gastric Cancer - Diagnosis

Gastric Cancer- Staging & Prognosis TNM

Other Gastric Tumors

Case
55 y.o. male w/ chronic active HBV, decompensated Child B cirrhosis
Abdominal pain and jaundice
AFP 400’s
MRI- 3 enhancing liver nodules 1.5cm, 1cm and 9mm (segments III, V, VIII)
Diagnosis/Treatment?

Hepatocellular Carcinoma
One million new cases yearly worldwide; 15,000 new cases in the US
One million deaths yearly worldwide
Peak age
Industrialized nations: 6-7 th decade
Fibrolamellar subtype (3-10%): <40 yr
High incidence areas: 30-40 yr
Children: <5yr
Median survival 2-10 months; 5 year survival <3%
Gastroenterology. 2002; 122:1609-1619

Clinical Features
Asymptomatic 23%
Abdominal pain 32%
Malaise 9%
Fever 8%
Ascites 8%
Jaundice 6%
Anorexia 6%
Weight Loss 4%
Hemorrhage 2%
Encephalopathy 2%
(461 Patients)
Gastroenterology. 2002; 122:1609-1619 Paraneoplastic Syndromes Sexual precocity Gynecomastia Feminization Carcinoid Syndrome Hypertrophic arthropathy Hypercholesterolemia Hypoglycemia Hypercalcemia Erythrocytosis Vitiligo Thrombophlebitis

Etiology
Cirrhosis (60-90%)
Alcohol
Hemochromatosis
Cardiac
Biliary atresia
Hepatitis B/C (~15%)
Carcinogens
Aflatoxin
Siderosis
Androgens
Thorotrast
Inborn errors of metabolism
Alph-1-antitrypsin
Galactosemia
Type I glycogen storage disease (von Gierke)
Wilson disease
Tyrosinosis

Risk of HCC in Cirrhosis High >15% HCV HBV +iron Moderate Alcohol Low <5% Wilson PBC Autoimmune

Diagnosis
AFP
AFP > 20 ng/mL in > 70% w/ HCC
AFP 10-500 ng/mL in necroinflammatory conditions -> Viral hepatitis
Sensitivity (39-64%), Specificity (76-91%)
Liver Biopsy
Not needed in everyone (AFP 500, cirrhosis)
Needle track spread of HCC (1%)

Trabecular pattern, increased N:C ratio Abnormal nuclei Microtrabecular pattern, irregular hepatocytes Gastroenterology. 2002; 122:1609-1619

Acinar structures, bile Mixed acinar, trabecular structures Mitros F. Atlas of Liver Pathology. Virtual Hospital

Central vein and portal triad involvement of HCC Bizzare hepatocyte giant cell Mitros F. Atlas of Liver Pathology. Virtual Hospital

Histology FNH Adenoma Regenerative Nodule Well-differentiated HCC can be confused with FNH, adenoma, and macroregenrative nodules

Imaging in HCC
Multiple forms
Rapid enhancement
Enhancing rim capsule
Heterogenous (fat, hemorrhage, fibrosis)
PV thrombosis
Ultrasound (86-99% sens, 90-93% spec)
Mixed echogenicity (60%): tumor necrosis
Hypechoic (30%): solid tumor
Hyperechoic (10%): fatty change
Radiographics. 2002; 22: 1023-1039

Radiographics. 2002; 22: 1023-1039 Axial T2, fat-sat, fast spin echo Axial T1, in-phase, gradient echo Axial T1, arterial phase

Axial portal phase dynamic enhanced Coronal contrast enhanced Radiographics. 2002; 22: 1023-1039

Early arterial Portal venous Delayed FNH Adenoma Pre-contrast Early contrast No contrast Early contrast Portal venous Delayed Hemangioma

Management
Resection
Tumor ablation
Radiofrequency ablation
Chemoembolization
Percutaneous alcohol injection
Cryoablation
Microwave ablation
Laser ablation
Liver transplant
Chemotherapy

Factors Influencing Treatment
Tumor size, number and distribution
Artery or venous proximity or invasion
Extrahepatic metastatic disease
Liver function/reserve
Comorbid conditions
Local expertise and resources

Surgical Resection
Indications
Ability to remove all the tumor
Well compensated Child A or B cirrhosis
Non-cirrhotic with HCC
Contraindications
Extrahepatic metastasis
Excessive comorbid conditions
Disadvantages
No improvement in liver function
HCC risk remains
Only 5-30% are candidates
Gastroenterology. 2002; 122:1609-1619 CW Pinson, AASLD 1999, post-grad course

CW Pinson, AASLD 1999, post-grad course

Chemoembolization
Technique
Requires hepatic arteriogram
Chemo agents: doxorubicin, cisplatin, others
Occlusive agent: gelfoam, lipiodol
Extensive tumor necrosis achieved in ~80%
Radiographics. 2002; 20:9-27 Gastroenterology. 2002; 122:1609-1619

Chemoembolization
Applications
Tumor downsizing for resection
Palliative therapy
Neoadjuvant therapy for transplant
Contraindications:
Diffuse tumor involvement,
Encephalopathy
Borderline liver function
Absent hepatopedal blood flow, portal vein thrombosis

Complications of TACE (197 procedures) Fever 74% Abdominal pain 45% Nausea/emesis 59% Bleeding or hematoma 7% GI bleeding 3% Positive blood culture 2% Development of ascites 1% Hepatic encephalopathy 1% Variceal bleeding 1% Acalculous cholecystitis .5% Liver abscess .5% Splenic abscess .5% Cancer. 2002; 94:1747-52

POST- TACE PRE- TACE CW Pinson, AASLD 1999, post-grad course

61 RCT 1 º treatment of HCC 26 RCT adequate control arm 14 RCT Sample size adequate 7 RCT TAE/TACE 7 RCT tamoxifen Hepatology. 2003; 37:429-442

Prospective RCTs of TAE/TACE # % Child A % response 1/2 yr survival Lin et al. (1988) ? TAE 21 13(70%) 42 25 TAE + IV 5-FU 21 10(48%) 20 20 IV 5-FU 21 2(10%) 13 13 Pelletier et al. (1990) ? TACE 21 7(33) 24 NA Conservative tx 21 0 33 NA Group d’etude (1995) 100 TACE 50 7(16) 62 38 Conservative tx 46 2(5) 43 26 Bruix et al. (1998) 82 TAE + coils 40 22(55) 70 49 Conservative tx 40 0 72 50 Pelletier et al. (1998 ) 76 TACE + tamoxifen 37 9(24) 51 24 Tamoxifen 36 2(5) 55 26 Lo et al. (2002) ? TACE 40 11(27) 57 31 Conservative tx 39 1(3) 31 11 Llovet et al. (2002) 70 TAE 37 16(43) 75 50 TACE 40 14(35) 82 63 Conservative tx 35 0 63 27 Hepatology. 2003; 37:429-442

Hepatology. 2003; 37:429-442
TAE improves 2-yr survival – 41% vs 27% (OR 0.53: 95% confidence interval 0.32-0.89)
TACE w/ cisplatin or doxorubicin better than TAE alone
Objective response in 35% (16-61%)
No survival benefit with tamoxifen

Technique
Percutaneous, laparoscopic or open
U/S guided probe placement
Thermal induced coagulation necrosis
Indications
Small unresectable tumors
Tumor downstaging for transplant
Radiographics. 2002; 20:9-27 Radio-frequency Ablation

Radio-frequency Ablation
Well tolerated and safe
Side effects
13% complications (14/110)
Ascites, hydropneumothorax, pleural effusion, fever, abdominal pain, bleeding, transient jaundice
Needle track seading?
4/32 patients all with tumors < 1cm from capsule
Cooled electrode tip used
Ann Surg 2000 Sep;232(3):381-91

Radiology. 2000; 217(3):633-46
POST-RFA PRE-RFA

Liver Transplantation in HCC
Theoretic best treatment
Widest resection margins
Restores hepatic function
Removes remaining liver at high risk of de novo HCC formation
Early results were poor
3 year survival 21-47%
Recurrence rate 29-54%

Current indications
Child B/C cirrhosis
TNM, stage I/II
Contraindications
Extrahepatic spread
Advanced stage

Liver Transplant for Small HCC in Patients with Cirrhosis N Engl J Med. 1996; 334(11):693-699
Exclusions
Vascular invasion
Extrahepatic metastasis
48 Transplanted
Criteria for OLTx
One tumor <5cm
3 tumors <3cm
bx confirmed or AFP >300
21 Child B 12 Child A 15 Child C F/U 26 mo (9-54mo) 26 Chemoembolization Iodized oil + Doxarubicin 14; Iodized oil +Mitoxantrone 12 No TACE

Results
Overall mortality 17%
Explanted liver examined
Predetermined criteria met in 35 patients (73%)
TNM status, # of tumors, AFP level, pre-OLTx TACE not correlated with survival
N Engl J Med. 1996; 334(11):693-699 4-yr survival 75% 4-yr survival 83% 4-yr survival 85% 4-yr survival 92% Recurrence free survival > overall survival: cancer recurrence excluded at autopsy in some

OLT for HCC
Regalia et al. (2001), 122 pts
Single tumor <5, 3 tumors < 3cm
5 year survival 80%
Yao et al. (2001), 70 pts
25% had single tumor 5-6.5 cm or <3 tumors, all < 4.5cm w/ total diameter <8 cm
One and 5 year mortality 90% and 75%
No difference in survival in patients w/ larger tumors
Am J Surg . 2002; 183:309-316.

Model for End Stage Liver Disease MELD Score = (0.957 x Log e (creatinine mg/dL) + 0.378 x Log e (bilirubin mg/dL) + 1.120 x Log e (INR) + 0.643) X 10 Range 6-40
Superior to CTP in predicting mortality
Elective TIPS
Equivalent to CTP
Acute variceal hemorrhage
www.unos.org

(MELD) and Allocation of Donor Livers
3437 adult liver transplant candidates
Listed as 2A or 2B between 11/99-12/01
3-month mortality 412 (12%)
MELD score <9 -> 1.9% mortality
MELD score >40 -> 71.3% mortality
C-statistic (ROC) curve
AUC 0.83 MELD vs. 0.76 CTP, P <0.001

MELD Provisions for HCC
UNOS policy 3.6.1 (2/2002)
T1- MELD score = 15% 3 mo pre-transplant risk of death
T2- MELD score = 30%
Additional MELD points awarded Q 3mo (= to 10% increase mortality)
UNOS 2002, policy 3.6, www.unos.org

Hepatocellular Cancer Single tumor <5cm 3 tumors, each <3cm Consider liver transplant Resection Local ablation TACE Large tumor >5cm or More than 3 tumors Resection Local ablation techniques No treatment Longer waiting list Liver Transplant Short waiting list 3-6 months Am J Surg . 2002; 183:309-316.

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GI and Liver Malignancies

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