1. Gastrointestinal cancers
Dr. Kocsis Judit

2. Gastrointestinal cancers and other disorders

3. ESOPHAGEAL CANCER

4. Esophageal cancer – etiology, symptoms
Predisposition:
GERD - Barrett metaplasia-dysplasia,
Gastric reflux (the backing up of stomach contents into the lower section of the esophagus) may irritate the esophagus and, over time, cause Barrett esophagus.
Tobacco use. Heavy alcohol use. Regular hot dishes.
Esophageal strictures;
(older; male; African-Americans)
Signs and symptoms:
Painful or difficult swallowing, progressive dysphagia;
Weight loss;
Pain behind the breastbone;
Hoarseness and cough;
Indigestion and heartburn;
Occult bleeding;
Esophageo-bronchial fistula;

5. Esophageal cancer - pathology
Localisation
Chest mid-third: 50% (SCC) >
Chest lower third: 35% (mainly adenocc.) >
Chest upper third: 15% (SCC) >
Cervical part of esophaguss
Anatomy: No serosal layer on the cervical and thoracic part of the esophagus!
Histology:
Squamosus cell carcinoma, SCC: 80%,
Adenocarcinoma: 20%.
stage I, cancer has formed and spread beyond the innermost layer of tissue to the next layer of tissue in the wall of the esophagus.
Stage II
Stage IIA: Cancer has spread to the layer of esophageal muscle or to the outer wall of the esophagus.
Stage IIB: Cancer may have spread to any of the first three layers of the esophagus and to nearby lymph nodes.
stage III, cancer has spread to the outer wall of the esophagus and may have spread to tissues or lymph nodes near the esophagus.
Stage IV
Stage IVA: Cancer has spread to nearby or distant lymph nodes.
Stage IVB: Cancer has spread to distant lymph nodes and/or organs in other parts of the body.

6. Esophageal cancer - Diagnosis
Endoscopy – histology;
Endoscopic US;
Barium swallow;
Chest x-ray, CT / PET-CT, abdominal US;
Bronchoscopy, Thoracoscopy
T3 N1 M0 (stage III) SCC of the midesophagus in a 66-year-old man. (a) CT scan obtained at the level of the midesophagus shows multiple enlarged periesophageal lymph nodes (arrowheads), findings that are suggestive of N1 disease. Note also the eccentric esophageal mass (arrow). RadioGraphics March-April 2009 vol. 29 no 6

7. Esophageal cancer – prognosis, treatment
Poor prognosis: after successful resection 5 y survival: %
Therapy:
T1-2: resection;
T1-4,N0-1: neoadjuvant radio- chemotherapy (cisplatin+5 FU), followed by resection;
M1 (or locally irresectable): palliative treatment (irradiation and/or chemotherapy) or palliative surgery (stent);
PEG /PEJ

8. GASTRIC CANCER

9. Mortality and Morbidity, ethnic differences
5-year survival for curative resections ranges from 30-50% for stage II disease and 10-25% in stage III.
High likelihood of systemic and local relapse.
Adjuvant therapy is offered .
Operative mortality is less than 3% for curative resections.
Higher in Asian countries.
Japanese detect patients at very early stage, patients appear to do quite well.
In Asian studies, patients with resected stage II and III disease have better outcomes than similar stages in the west.
Some believe this reflects a biologic difference between diseases in Asia and west.
Black race, low socioeconomic class.

10. Pathophysiology
Understand vascular supply, allows for understanding of routes of spread.
Derived from celiac artery.
Left gastric supplies upper right stomach.
Right gastric off common hepatic- lower portion.
Right gastroepiploic -lower portion of greater curve.
Understanding lymphatic drainage can clarify nodal involvement.
Complex drainage
Primarily along celiac axis.
Minor drainage along splenic hilum, suprapancreatic nodal groups, porta hepatis, and gastroduodenal areas

11. Anatomy
Five layers: Mucosa, submucosa, muscular layer, subserosal layer, serosal layer.
Peritoneum of greater sac covers anterior surface
A portion of lesser sac drapes posteriorly over stomach.
The GE junction has limited serosal covering
Stomach begins at GE junction, ends at duodenum.
3 parts- uppermost is cardia, largest part in middle is body, the last part is pylorus.
Cardia contains mucin producing cells.
Fundus or body mucoid cells, chief cells, parietal cells.
Pylorus has mucin producing cells.

12. Gastric cancer - etiology, symptoms
Predisposition:
Previous gastric surgery, scar
H. pylori infection (MALT lymphoma);
Gastric ulceration;
Atrophic gastritis type I. (pernicious anemia), or other long-term inflammation;
Smoked foods, poor diet, lack of physical activity, or obesity;
Signs and symptoms
Anemia, Occult bleeding, vomiting blood, Iron- deficiency;
Loss of apetite, early sateity, (húsundor),
nausea, vomiting;
Weight loss;
Dyspepsia;
Discomfort or pain in the stomach area;
Difficulty of swallowing.
Certain diets are implicated.
Rich in pickled vegetables, salted fish, excessive dietary salt, smoked meats.
A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.
Helicobater
Implicated as precursor of gastric cancer.
H. Pylori associated with atrophic gastritis, and patients with a history of prolonged gastritis have a 6-fold increase in risk.
Particularly true of tumors of antrum, body, and fundus of stomach, but not in cardia.
Previous surgery
Implicated as risk factor, the rational being that previous gastric surgery alters normal pH of stomach.
Retrospective studies show that a small percentage of patients who have a gastric polyp removed have evidence of invasive carcinoma in the polyp.
Polyps may therefore be premalignant. 12

13. Gastric cancer - pathology
Macroscopic appearence (Borrmann classification):
Type I: polypoid or fungating
Type II: ulcerating lesions with elevated borders
Type III: ulceration with invasion of wall
Type IV: diffuse infiltration
Type V: cannot be classified
Histology:
Adenocarcinoma 95%
Lymphomas 2-5% - MALT
Adenocathomas 1%
Squamous cell 1%
Neuroendocrine tumors, carcinoid: 1%
GIST
Distant metastasis: distant lgl.: left supraclavicular (Wirchov) lgl., Hematogen metastasis: liver,bone. Direct spread: carcinosis peritonei, ovary (Kruckenberg tu. 6-8%)
Histology
Adenocarcinoma is classified according to the most unfavorable microscopic element present: tubular, papillary, mucinous, signet-ring cells.
Also identified by gross appearance: ulcerative, polypoid, scirrous, superficial spreading, multicentric, or Barrett ectopic.
Variety of other schemes: Borrmann, Lauren.
Lauren system
Epidemic or endemic
The intestinal, expansive epidemic type gastric cancer is associated with atrophic gastritis, retained glandular structure, little invasiveness, sharp margins. It would be a Borrmann I or II.
The epidemic or Borrmann I or II carries better prognosis, shows no family history.
The diffuse, infiltrative, endemic, is poorly differentiated, with dangerously deceptive margins, invades large areas of stomach. Younger patients, genetic factors, blood groups, and family history.
Diffuse type demonstrating individual red,
mucin-containing malignant cells in the lamina
propria of an intact mucosa. (Mucicarmine stain.)
Intestinal –type gastric carcinoma 13

14. Gastric cancer - diagnosis
Endoscopy – histology;
Endoscopic US;
Chest x-ray, CT / PET-CT, abdominal US;
Laparoscopy
Barium swallow;
Laboratory
Assists in determining optimal therapy.
CBC identifies anemia, with may be caused by bleeding, liver dysfunction, or poor nutrition.
30% have anemia.
Electrolyte panels and LFTs are also essential to better characterize patients clinical state.
Advanced gastric cancer (Borrmann type III) in 50-year-old woman. A, Virtual gastroscopy image shows typical ulcerated carcinoma in stomach body. B, Surgical specimen shows a similar lesion. C–E, Transverse dynamic contrast- enhanced CT images obtained in, C, arterial phase, D, portal venous phase, and, E, delayed phase show transmural, gradually enhancing tumor (arrow) with smooth outer border of gastric wall; these findings suggest pathologic stage T2. F, Photomicrograph shows subserosal invasion of gastric cancer (pT2). (Hematoxylin-eosin stain; original magnification, ×5.) - Radiology February 2007 vol. 242 no 14

15. Prognostic Features
Depth of invasion through gastric wall, presence or absence of regional lymph node involvement
The greater number of positive nodes, the greater the likelihood of local or systemic failure postoperatively
Spread Patterns
Directly, via lymphatics, or hematogenously
Direct extension into omentum, pancreas, diaphragm, transverse colon, and duodenum.
If lesion extends beyond wall to a free peritoneal surface, peritoneal involvement is frequent.
Spread Patterns
The visible gross lesion frequently underestimates true extent.
Abundant lymphatic channels in submucosal and subserosal layers allow for easy spread.
The submucosal plexus is prominent in esophagus, the subserosal plexus prominent in duodenum, which allows for proximal and distal spread.
Liver mets common, from hematogenous spread. 15

16. Gastric cancer - surgery
Laparoscopy
Inspect peritoneal surfaces, liver surface.
Identification of advanced disease avoids non-therapeutic laparotomy in 25%.
Patients with small volume metastases in peritoneum or liver have a life expectancy of 3-9 months, thus rarely benefit from palliative resection.
“D” Nomenclature
number rather than location of LN is prognostic.
Describes extent of resection and lymphadenectomy.
D1- removes all nodes within 3cm of tumor.
D2- D1 plus hepatic, splenic, celiac, and left gastric nodes.
D3- D2 plus omentectomy, splenectomy, distal pancreatectomy, clearance of porta hepatis nodes.
Current standards include a D1 dissection only.
SURGERY
In general most surgeons perform total gastrectomy ( if required for negative margins), esophagogastrectomy for tumors of the cardia and GE junction, and a subtotal gastrectomy for tumors of the distal stomach.
Similar 5 year rates for subtotal vs. total in tumors of distal stomach.
Extensive lymphatics require 5cm margin.
LN dissection
AJCC: number rather than location of LN is prognostic.
Extent of dissection controversial.
Nodal involvement indicates poor prognosis, and more aggressive approaches to remove them are taking favor.
Ongoing trials regarding this in Europe.
Critics argue that the apparent benefit associated with extended LND reflects stage migration (each LN is reviewed more carefully). 16

17. Adjuvant Therapy
Rationale is to provide additional loco-regional control.
Radiotherapy- studies show improved survival, lower rates of local recurrence when compared to surgery alone.
In unresectable patients, higher 4 year survival with mutimodal tx, in comparison to chemo alone.

18. Chemotherapy
Numerous randomized clinical trials comparing combination chemotherapy in the adjuvant setting to surgery alone did not demonstrate a consistent survival benefit.
The most widely used regimen is 5-FU, doxorubicin, and mitomycin-c. The addition of leukovorin did not increase response rates.

19. Advanced Unresectable Disease
Surgery is for palliation, pain, allowing oral intake
Radiation provides relief from bleeding, obstruction and pain in 50-75%. Median duration of palliation is 4-18 months

20. PANCREATIC CANCER

21. Pancreatic cancer – etiology, symptoms
Clinical presentation:
Abdominal pain
Jaundice, obstructive
Right-side dominant
Curvoisier sign
Weight loss, anorexia
New-onset DM
Acute pancreatitis
Especially no risk factors, stones or alcohols
Physical signs
Jaundice: skin and sclera
Hepatomegaly
Palpable gall bladder
Lymphadenopathy
Left supraclavicle: Virchow’s node
Periumbilical: Sister Mary Joseph’s node
Peri-rectal region: Blumer’s shelf

22. Pathology adenocarcinoma Exocrine
Solid
Infiltrating ductal adenocarcioma: most
Variant of ductal adenocarcinoma - Signet-ring cell, medullary, adenosquamous, anaplastic
Acinar cell carcinoma
Pancreatoblastoma
Cystic
Mucinous cystic neoplasm
Intraductal papillary mucinous neoplasm
Serous cystic neoplasm
Solid pseudopapillary neoplasm
Endocrine - These are less common than non-endocrine tumours and generally benign and sometimes multiple. They includes:
 Insulinoma
 Glucogonomas
 Others: Gastrinomas ; Somatostatatinomas; VIPomas
Infiltrating ductal adenocarcinoma
Cytokeratin(CK): 7(+), 19(+), 20(-)
CEA
CA19-9
Mucins
Islet cell ca

23. Risk factors of pancreatic cancer
Advanced age
Low socioeconomic status
Cigarette
Diabetes mellitus
Chronic pancreatitis
High-fat and cholesterol diet
Carcinogens exposure
PCBs, DDT, NNK, benzidine

24. Diagnosis Image studies Histopathologic diagnosis
CT or MRI: image of choice, equivalent
ERCP: direct imaging of p-duct, replaced by CT/MRI
EUS: more accurate for tumor itself
EUS-FNA
PET: to be investigated
Histopathologic diagnosis
Direct operation: curative or palliative
Percutaneous
More complication: hemorrhage, pancreatitis, fistula, abscess, tract seeding
The outlines of the pancreatic duct are
extremely irregular at the juction between
body and head. Additionally there are
segmental stenosis
Tumorous formation arising from the body of pancreas, the tail of pancreas has
dilated duct and is atrophic. Multiple small nodules on the mesentery.
Massive ascites.

25. Treatment – surgical resection
Pancreatic head and neck
Pancreaticoduodenectomy +/- distal gastrectomy: Whipple’s operation
Mortality: 2-3%
Sepsis, hemorrhage , CV event
Morbidity: 40-50%
Leakage, abscess, delayed gastric emptying, hemorrhage
Pancreatic tail
No obstructive jaundice in early state
Tend to be larger, usually metastasis at dx
Distal pancreatectomy
Palliative surgery
Obstructive jaundice
Duodenal obstruction
Hepaticojejunostomy
Choledochoduodenostomy
Cholecystojejunostomy
Pain relief
Neurolysis

26. Treatment for recurrence
Disease nature
Locally recurrence and distant mets
Neoadjuvant/adjuvant treatment
Chemoradiation
5FU, MMC, Cisplatin, Paclitaxel, Gemcitabine
Relative radioresistant
Mostly single arm
No definite evidence of survival benefit

27. Treatment for unresectable disease
Palliative surgery
RT or CCRT
Radio-resistance
5FU, Gemcitabine
Really benefit?
Palliative chemotherapy

28. Systemic chemotherapy
Problems
Highly resistant to chemotherapy
Usually poor performance
Pain, N/V, cachexia, weakness
Impaired liver function
Usually lack of measurable lesions
Variation in phase II studies

29. Chemotherapy – historical
5-FU is cornerstone
Combination with
Adramycin, mitomycin: FAM
Cyc, MTX, Vincristine, Mitomycin
Epirubicin, cisplatin, carboplatin, Ara-C
 High response rate in phase II : 40%
 Not confirmed in phase III
Combination not better than 5FU alone

30. Gemcitabine Well-tolerated agent Phase III study, Gemzar vs. 5-FU
Response rate: 5.4% vs. 0%
Survival: 5.65m vs. 4.41m (p=0.0025)
Clinical benefit: 23.8% vs. 4.8
Pain, performance status, weight gain
Toxicity similar with 5-FU
Gemcitabine superior to 5-FU

31. Gemcitabine-based combination

32. ASCO annual meeting 2005, abstr no. 1
Take care of interpretation!! (a negative example) Gemzar+Tarceva vs. Gemzar
Difference:
0,46 month =
= 14 days!
(but significant!)
Difference:
0,2 month =
= 6 days!
(but significant!)
ASCO annual meeting 2005, abstr no. 1

33. BILIARY TRACT CANCER

34. Biliary tract cancer – etiology, symptoms
Chronic inflammation
Primary sclerosing cholangitis : autoimmune
Choledochal cyst : congenital
Parasite
Stone : maybe
Repeat inflammation, stricture
Young age-onset
Carcinogens
Clinical manifestation
Painless jaundice
Early in hilum/distal type
Late in intrahepatic type
Abnormal ALP/GGT
Weight loss, nausea/vomit
Palpable liver
Intrahepatic type
Biliary tract infection
Due to obstruction
Epidemiology
Old age: median 65 year-old
Slightly more in men
Uncommon cancer
Uncertain nature course and treatment
Tumor markers
Elevated serum CEA and CA19-9 34

35. Pathology - Classification
Cholangiocarcinoma
All tumors arise from bile duct epithelium
Mostly adenocarcinoma
Intrahepatic (6%)
Hilum (67%): Klaskin’s tumor
Distal extrahepatic (27%)
Gall bladder
Histology
Adenocarcinoma: 95%, most
CK20(-), CK7(+)
Squamous cell, small cell, sarcoma, lymphoma
Pathological differential diagnosis
CholangioCa, pancreatic Ca, lung adenoCa
CK20(+), CK7(-)
Colon cancer
Growth pattern
Nodular type
Intrahepatic
Differential diagnosis of hepatic tumor
HCC, cholangioCa, metastatic tumor
Sclerosing type
Hilum and distal
Growth along the bile duct, difficult to diagnosis

36. Diagnostic evaluation
CT scan, ultrasound
For painless jaundice, to exclude stone
ERCP (Endoscopic Retrograde CholangioPancreatography)
Biliary tree evaluation
Intervention: stenting, brushing cytology
MRI/MRCP
Non-invasive entire biliary tree evaluate

37. Treatment Surgery: mainstay Prognosis: not clear, due to rarity
Biliary tree evaluation for resectability
Intrahepatic: hepatic resection
Extrahepatic: may require pancreaticoduodenectomy, morbidity
Prognosis: not clear, due to rarity

38. Multimodality treatment
Pre-op neoadjuvant tx
RT, C/T, CRT  no benefit
Post-op adjuvant tx
A trial suggest adjuvant C/T may benefit GB ca
Adjuvant CCRT for locally advance dz?

39. Locally advanced disease
CCRT, can be considered
5FU/LV
Good performance
Liver toxicity, GI toxicity
Palliative chemotherapy

40. Palliative chemotherapy
Pooled analysis, extra- and intra-hepatic
5FU/LV remained mainstay
Infusion, bolus
RR: 20%-30%
Survival 6-7m
Combination:
Traditional: cisplatin, mitomycin
Newer agents: gemcitabine, capecitabine, taxane
MoAb: cetuximab

41. Palliative procedure Biliary stenting, PTCD
Complication of biliary stenting
Communicate bile duct and intestine
Bile is sterile
Resultant repeat infection (BTI)

42. LIVER CANCER

43. Classification Benign Malignant Primary liver cancers 2. Metastases
Hemangioma
Focal nodular hyperplasia
Adenoma
Liver cysts
Primary liver cancers
Hepatocellular carcinoma
Fibrolamellar carcinoma
Hepatoblastoma
2. Metastases

44. Benign Liver Lesions Hemangioma Focal nodular hyperplasia Adenoma
The commonest liver tumor
5% of autopsies
Usually single small, well demarcated capsule
Usually asymptomatic
Focal nodular hyperplasia
Benign nodule formation of normal liver tissue
Central stellate scar
More common in young and middle age women
No relation with sex hormones
Usually asymptomatic or may cause minimal pain
Adenoma
Benign neoplasm composed of normal hepatocytes no portal tract, central veins, or bile ducts
More common in women
Associated with contraceptive hormones
Usually asymptomatic but may have RUQ pain
Mat presents with rupture, hemorrhage, or malignant transformation (very rare)
Cysts
May be single or multiple
May be part of polycystic kidney disease
Patients often asymptomatic
No specific management required
Hydated cyst
Hemangioma
Diagnosis
US: echogenic spot, well demarcated
CT: venous enhancement from periphery to center
MRI: high intensity area
No need for FNA
Treatment
No need for treatment
FNH
Diagnosis:
US: Nodule with varying echogenicity
CT: Hypervascular mass with central scar
MRI: iso or hypo intense
FNA: Normal hepatocytes and Kupffer cells with central core.
Treatment:
No treatment necessary
Pregnancy and hormones OK
Adenoma: DX
US: filling defect
CT: Diffuse arterial enhancement
MRI: hypo or hyper intense lesion
FNA : may be needed Tx
Stop hormones
Observe every 6m for 2 y
If no regression then surgical excision 44

45. Malignant Liver Lesions

46. Malignant Liver Tumors
Hepatocellular carcinoma (HCC)
Fibro-lamellar carcinoma of the liver
Hepatoblastoma
Intrahepatic cholangiocarcinoma
Others

47. HCC: Risk Factors & Clinical Features
The most important risk factor is cirrhosis from any cause:
Hepatitis B (integrates in DNA)
Hepatitis C
Alcohol
Aflatoxin
Other
Clinical features
Wt loss and RUQ pain (most common)
Asymptomatic
Worsening of pre-existing chronic liver dis
Acute liver failure
O/E:
Signs of cirrhosis
Hard enlarged RUQ mass
Liver bruit (rare)
Systemic features
Hypercalcemia
Hypoglycemia
Hyperlipidemia
Hyperthyroidism
Labs of liver cirrhosis:
AFP (Alfa feto protein)
Is an HCC tumor marker
Values more than 100ng/ml are highly suggestive of HCC
Elevation seen in more than 70% of pt
Incidence
The most common primary liver cancer
The most common tumor in Saudi men
Increasing in US and all the world 47

48. HCC: Metastases Rest of the liver Portal vein Lymph nodes Lung Bone
Brain

49. HCC: Diagnosis Clinical presentation Elevated AFP US
Triphasic CT scan: very early arterial perfusion
MRI
Biopsy
Venous phase Arterial phase

50. HCC: Prognosis Tumor size Extrahepatic spread Underlying liver disease
Pt performance status
Laboratory:
Albumin
Trombocyte
Bilirubine

51. Barcelona Liver Cancer Classification
Liver Transplantation, Vol 10, No 2, Suppl 1 (February), 2004: pp S115–S120

52. HCC: Liver Transplantation
Best available treatment
Removes tumor and liver
Only if single tumor less than 5cm or less than 3 tumors less than 3 cm each
Recurrence rate is low
Not widely available

53. HCC: Resection
Feasible for small tumors with preserved liver function (no jaundice or portal HTN)
Recurrence rate is high
Single curative therapy (beside transplantation)

54. HCC: Local Ablation For non resectable pt
For pt with advanced liver cirrhosis
Alcohol injection
Radiofrequency ablation
Temporary measure only

55. HCC: Chemoembolization
Inject chemotherapy selectively in hepatic artery
Then inject an embolic agent
Only in pt with early cirrhosis
No role for systemic chemotherapy

56. Systemic treatment for HCC
Sorafenib (Nexavar) Oral multitargeted tirozin kinase inhibitor (VEGFR, PDGFR, c-kit, Raf kinases) SHARP study only patients with godd PS, Child-Pough score max. 1.

57. Fibro-Lamellar Carcinoma
Presents in young pt (5-35)
Not related to cirrhosis
AFP is normal
CT shows typical stellate scar with radial septa showing persistant enhancement

58. Secondary Liver Metastases
The most common site for blood born metastases
Common primaries : colon, breast, lung, stomach, pancreases, and melanoma
Mild cholestatic picture (ALP, LDH) with preserved liver function
Dx imaging or FNA
Treatment depends on the primary cancer
In some cases resection or chemoembolization is possible