carcinoma pancreas

CARCINOMA PANCREAS

byprof/ gouda ellabban

prof of surgery , hepatobiliary and laparoscopy scu hospital/ Egypt

Embryologic devt.

• Dorsal and ventral pancreatic buds.

dorsal ventral

larger Smaller

Arise from foregut destined to be duodenum

Buds off from CBD as hepatic evagination

Develops into head, body and tail of pancreas

Develop into uncinate process.

Anatomy

CA pancreas

• 13th MC cancer worldwide

• 8th MC cause of cancer death

• 23% live after 12 months• 5% live after 5 years

• <10% presents with local disease

• 25% has regional disease• >50% metastatic• Median age of diagnosis-

72 years.

Aetiology• Tobacco• Infectious diseases- H. Pylori,

Hep-B• Occupation- Organochlorine

compounds• Demographic and host risk

factors- older age, African American, Low SES, Jewish.

• Diabetes mellitus• Obesity, physical inactivity

and metabolic syndrome

• Pancreatitis• Genetic predisposition• Inherited syndromes

Genetics

• K-ras- 95%• p16- 90%• p53- 55 to 75%• DPC4 50%• BRCA2-70%

Syndrome Gene alteration

Hereditary pancreatitis

PRSS1

HNPCC(LynchII variant)

hMSH2, hMLH1

Hereditary breast and ovarian CA

BRCA2

Familial Atypical Multiple Mole melanoma syndrome (FAMMM)

P16

Peutz Jegher’s LKB1/STK11

Ataxia Telangiectasia

ATM

PathologyIntraepithelial Neoplasm

Microscopy Genetic mutations

PanIN 1 A Columnar transitionRetention of apical nucleiIntracellular mucin near the luminal aspect

K ras and Her-2-neu

PanIN 1 B Micro papillary or papillary transition

-do-

PanIN 2 Nuclear atypia/ crowding/ enlargementLoss of nuclear polarity

P16

PanIN 3 Apical mitosisProminent nucleoliDystrophic goblet cellsCribriform architectureLuminal necrosis

P53, DPC4, BRCA2

Screening

• Incidence is low for using screening in general population.

• High Risk1. Family history2. Genetic syndromes3. Obese with new onset DM

>60yrs.

• Endoscopic Ultrasound (EUS) is the Ix of choice.

• Multi detector dynamic Phase CT.

• EUS:1. Excellent visualization of

gland.2. Detect small <1cm lesions3. Can get EUS guided FNA.

Presenting complaints

• Initial symptoms vague, non- specific

• Jaundice• Preceded by episodes of

biliary colic, anorexia and GI distress.

• Pain – s/o unresectable, metastatic and worse survival.

• Steatorrhoea• a/c pancreatitis• Glucose intolerance/

overt DM- 70%• Superficial or DVT• Weight loss- MC in some

studies.• Late: GOO, Ascites, skin

manifestations.

Physical Exam and Lab.

• Usually unremarkable• Icterus• Cutaneous excoriations• Muscle wasting• Hepatomegaly/ nodular

liver• Virchow s node• Sr mary Joseph’s nodes• Blumer’s shelf

• Mild to mod. Hyperglycemia

• Deranged LFT• Amylase, Lipase (IPMN)• Anaemia- NCNC• Hypoalbuminemia• Coagulation profile:

prolonged PT.

Evaluation• Confirm the diagnosis of

pancreatic mass• Re establish biliary patency.• Determine the extent of

disease• Resectability?• Histological diagnosis

• In past combined diagnostic and therapeutic laparotomy.

• Separate diagnostic evaluation advantages:

1. laparotomy required for only resectable.

2. Objective criteria to decide on resectability

3. Pre-op plan for venous reconstruction

4. NACT

Diagnostic Imaging• Multi phase multi detector

helical CT• Coordinating IV contrast

administration with subsequent rapid thin cut CT through pancreas during arterial, portal venous and parenchymal phases.

• SMA, celiac axis, SMV-PV, contiguous structures, mets.

• MRI• Not widely used• Longer scanning times• Artefact d/t organ motion.• Dynamic MRI with rapid

scanning sequence has sens. and spec. similar to CT.

• USG• High sens and spec although

lower than helical CT• Better in identifying primary

lesion, but CT better for defining resectability.

• EUS• Non contributory when CT has

characterized the tumor as resectable.

• Used when a tumor not seen on CT

• And to obtain FNA in unresectable tumors before chemo or borderline resectable before NACT.

• Endobiliary stent can be placed.

• ERCP• Delineates CBD & PD anatomy• Brushings and ductal lavage

(low yield).• Reserved for:1. Endoscopic stenting2. Equivocal findings on std.

evaluation3. Tissue diagnosis requiredComplications- pancreatitis, Hrg.,

Perforation.

• CT guided FNAC• Per cutaneous• Operator dependent• Cannot be done for lesions not

visible on CT• Complications: 1. Hrg.2. Pancreatitis3. Fistula, Abscess4. Tumor seeding along the

needle tract.

• Staging laparoscopy:• Few(8%) adnl. tumors

than detected by CT.• No routine use1. >3cm primary tumor2. CA 19-9 > 100 U/L3. In body or tail.4. Equivocal findings of

mets on CT

• STAGING• T1: <2cm; limited to

pancreas.• T2: >2cm; limited to

pancreas.• T3: Extend beyond

pancreas; No involvt. Of coeliac axis or SMA.

• T4: involves coeliac axis or SMA.

• Resectable

Locally advanced

Metastatic

T1,T2,T3 --- ResectableT4 -------Locally advanced

• Resectability Definition:1. Absence of mets outside

pancreas and nodal basin.

2. Patency of SMV-PV3. Presence of definable fat

plane btw SMA, celiac A. and pancreatic mass.

4. “SMV-PV invasion”

Treatment of Resectable disease

• 5 year survival 18%• Justified to prolong

survival: No cure.• Whipple- 1934.• Earlier days: 2 stage

procedure- biliary bypass ---pancreatectomy.

• Vitamin K in pre-op regimen to treat coagulopathy.

• Evans et al: 6 steps of resection.

• foll by 4 steps of reconstruction.

• Post surgery use of IP drains is decreasing.

• Studies show more chance of sepsis, fluid collection or fistula.

Whipple’s surgery• 6 Steps of resection:1. Exposing SMV2. Extended kocher’s

maneuvre.3. Portal dissection4. Transect stomach5. Transect jejunum and

dissect ligt of treitz, rotating duodenum under mesenteric vessels.

6. Transect pancreas.

• 4 steps of reconstruction:1. End to side pancreatico

jejunostomy2. End to side

choledochojejunostomy3. End to side

gastrojejunostomy4. Gastrostomy tube,

jejunostomy tube, drains.

• Biliary stents• 70% cases indicated• 2 types:1. Metallic: durable2. Soft silastic: do not last full

course of NACT.• 2 methods:1. percutaneous transhepatic2. endoscopic

• Older studies show increased morbidity and mortality.

• But in recent studies, only increased chance of wound infection

• Relatively safe procedure.• Not to be avoided to palliate

patients or while referral to higher center.

Extended Lymphadenectomy

• Adnl nodes removed are: hepatic hilar, periaortic from diaphragm to inf mesenteric, incld renal hilar, coeliac and SMA.

• No benefit except in node positive cases--- improved survival.

Adjuvant therapy• Chemotherapy alone better

than observation.• 5FU/ Leucovorin Ca (ESPAC-

1 2004)• Gemcitabine(CONKO-001)• Gemcitabine slightly better

than 5FU(p>0.05)[RTOG9704 and ESPAC3]

• ChemoRT• Did worse than

control(ESPAC-1)• Gem > 5FU in ChemoRT

(RTOG-9704)(p=0.033).

• The current standard is Adjuvant Chemo with Gemcitabine 1000mg/m2 weekly x 3 every 4 weeks x 6 cycles.

Indications of RT

1. Adjuvant CRT in resectable disease.

2. Pre-operative CRT3. For locally advanced

lesions with good PS4. In metastatic disease

for palliation of pain and obstructive symptoms.

5. For recurrence after resection, if previous RT has not been given.

RT techniques• Four field technique• Weighted: AP twice as

lateral.• Lat fields restricted to 20 Gy

[limit dose to liver and kidney]

• Coeliac axis at T12• 2 cm margin sup• 2cm margin inferiorly• 2 cm margin to the L

vertebral edge

• 2 cm margin from R vertebral edge.

• Pre op location of duodenum defines the right border and ant extent of lateral fields.

Pre-op Chemo RT• Advantage:1. Initiation of Rx shortly

after Δsis2. Rx of relatively well

perfused tumor bed.3. Time to assess aggressive

tumor biology.4. Assess pt’s potential to

undergo rigors of Sx.

• Against:1. Local progression (No

proof for significant risk.)

BORDERLINE RESECTABLE1. Confined to pancreatic

bed and nodes without distant mets.

2. Tumor involvt of SMV-PV incld. Abutment, constriction of lumen or encasement.

3. Arterial Involvt.- gastroduodenal and hepatic without coeliac axis. SMA with <180o

• Gem chemo 50.4/28F CCRT with Gem 400mg/m2 weekly resection.

• Survival 40 months.• 40% cases after CCRT could

undergo resection• 90% R0 resection.• Response to therapy:

Decrease in mass size, CA-19-9, decraese in pain.

LOCALLY ADVANCED DISEASE• Defn: >180o SMA or coeliac

axis invasion without gross disease outside the pancreatic primary.

• FOLFIRINOX• CCRT with 5FU is a

recommended Rx.

• Gemcitabine or capecitabine also used as radiosensitizers.

• CCRT – more fatigue• More GI toxicity• Novel radiosensitizers:

mCCNU+ 5FU +/- testolactone

• Hycanthone.

RT techniques• LA disease pt do not benefit

from LN irradiation• Would only lead to more GI

toxicity• RT fields confined to gross

tumour.• Respiratory motion: axial

motion negligible.• So Cranio caudal 1cm extra.

• 3 or 4 field technique• Equally weighted ant, post

and opposed lat fields.• 2cm block margin in radial

directions• 3 cm block margin in CC

directions.• Delivery >50.4 Gy requires

IMRT or ABC to spare duodenum, stoamch and jejunum.

• Incidence of converting a LA disease to resectable is 1 in 25.

• For them survival is similar to resectable disease.

• Palliative surgeries:1. Hepaticojejunostomy2. Choledochojejunostomy or

choledochoduodenostomy3. Gastrojejunostomy.

• Antecolic- MC used • Retrocolic• Less morbid techniques:1. Endoscopically placed

metal stent.2. Percutaneous endoscopic

gastrostomy.

• Initial chemo for 2 to 4 months

• re assess by CA19-9 and radiological assessment.

• then 5FU based chemoRT• If progressive Palliative

chemoRT to 30 Gy.• If no Progression, Then

CCRT 50.4 Gy/5.5week.

• After chemo RT:• If good PS- Chemo alone

with 5FU/ Gem.• If poor PS- Best

Supportive care.

Metastatic disease

• Bolus 5FU: RR 0%• Infusional 5FU: 8.6%• 5Fu+MMC- 17.1%(No diff

in OS)• Gemcitabine: RR 5.4% Survival 5.65 months vs

Bolus 5 FU 4.1 months.• Peak ICF accumulation

when given at 10 mg/m.sq./min.(FDR)

• FDR(Fixed dose rate) 1500mg/m.sq. over 150 min. vs standard Gemcitabine 2200mg/m.sq over 30 min.

• OS was 8 months against 5 months.

• Gem-Ox vs Std. Gem.• RR and PFS significant,

but not OS.• Gem-Ox and FDR Gem

had similar RR 0f 9 to 10% vs Std Gem has only 6%.

• With Molecular agents:• Marimastat• Tipifarnib• Erlotinib [RR and OS- p

0.025]• Cetuximab• Bevacizumab

• Gemcitabine effective at lower dose 300 to 700 mg/msq [MDACC trial]

• Max tolerated dose 790mg/msq.

THANK YOU ☺

• Comprises several different molecular distinct subtypes that collectively represent the MC form of sarcomas of the GIT.

• 1 to 3% of all malignant GI tumors.

• Neural crest antigens NSE and S-100 Positive

• CD34 Positive• Also it was proposed that

GIST cells differentiate from:

• 1. smooth muscle lineage• 2. neurogenic• 3. “Null” Phenotype.

• Older eponyms:1. Leiomyoblastoma2. GI leiomyosarcoma3. GI autonomic nerve

tumor4. GI pacemaker cell

tumor5. Plexosarcoma6. GI neurofibrosarcoma

• Ultra structural similarities with ICC(Interstitial Cells of Cajal) combining neural and myogenic differentiation.

• Both arise from mesenchymal precursor cells.

• Both express KIT RTK.

• ICCs are unique pace maker cells in the myenteric plexus, that link the smooth muscle of the gut with the ANS

• Origin of neoplastic GIST cells are believed be from CD34+ stem cells, which can differentiate to ICC phenotype.

• KIT exon-9 mutant GIST found in small bowel primary

• PDGFRA mutant found in gastric primary

• Due to differential migration and distribution of these cells along the length of the GI tract.

Molecular mechanisms

• KIT protein normally serves as a transmembrane receptor tyrosine kinase.

• CD117 is marker for KIT

• Normal cell signalling:1. KIT binds its ligand- stem

cell (steel) factor.2. 2 molecules of KIT together

forms a homodimer.3. Activate signal transductoin

pathways downstream.4. Cell proliferation and

survival.

• Mutation in KIT protooncogene

• Uncontrolled activation of KIT signaling enzyme

Clinical features• Median age 58 years.• More in males• Stomach 60 to 70%• Small intestine 20 to 30%• Esophagus, colon and

rectum <10%.• Non specific symptoms• Occur only when tumor is

large or in critical location e.g. GOO

• Abdominal pain, mass, N, V, Anorexia, wt loss.

• A/c hrg into peritoneal cavity d/t rupture of tumor

• Metastasis- liver, omentum or peritoneal cavity.

• Extra abd mets very rare.

INVESTIGATIONS

• CT essential for evaluating primary and for staging.

• MRI may be used.• OGD- smooth mucosa

lined protrusion of the bowl wall+/- ulceration.

• Submucosal, endophytic growth.

• Hence visual OGD very challenging.

• EUS is an ideal tool for localized GIST for assessment of lesion size and guided FNA.

• FDG PET- TKI therapy show rapid changes in PET scan

• Can detect lesion of 1cm size without difficulty

• This is because neither normal bowel nor omentum takes up FDG tracer with excess avidity.

Differential diagnosis• CD117+1. Normal ICC s and mast ells2. Desmoid tumors3. Ewing’s and angiosarcoma4. Rarely SCLC, melanoma,

seminoma, ovarian,adenoid cystic CA, AML

• CD34+1. Desmoid tumors2. Other vascular and

myoepithelial tumors.

• Leiomyosarcomas CD117 neg ; SMA and desmin+

• S100+ in schwannomas but CD117 –

• 5% of GIST are CD117 neg. they’re driven by PDGFRA kinase.

Prognostic featuresRisk level size Mitoses/50 hpf

Very low <2cm <5

Low 2 -5 cm <5

Intermediate >5 to 10cm <5

<5cm 6 to 10

high >10cm Any

>5cm >5

any >10

• Size• Mitotic rate• Small bowel and rectal

primary GIST worse.• Gastric GIST good.• KIT mutations found in

exon 11,9,13,17.• Exon 11 worse prognosis

• PDGFRA mutations favorable prognosis.

Management of metastatic GIST

• Chemoresistance• RR 0 to <5%• Anti apoptotic impact of

aberrant KIT signalling.• Increased PGP, product of

MDR-1 gene.• RT-rarely any role- liver

toxicity• IMRT or proton may be

used for palliation

1. Focal bleeding2. Pain control3. Bony involvement4. Fixed to the wall of

abdomen or pelvis

• Surgery also minimal role due to peritoneal and liver mets- unresectable.

IMATINIB mesylate

• 1 st molecular TKI therapy

• Serendipity while screening molecules for TKI function of BCR-ABL oncoprotein (CML)

• STI-571Imatininb

• Optimal dose is 400mg/day

• Max tolerated dose is 800mg/day.

• Median time to objective response is 3 months.

• Better response when KIT mutation is in exon11.

• Poor response in exon9.• Higher doses(800mg) later

was found to be beneficial in Exon 9 mutations.

• KIT neg pts also respond d/t action on PDGFRA mutations.

• No benefit with 600 mg/d in two trials.

• EORTC trial show benefit in PFS for 600 mg/d.

• Life long use• Periodic pulse therapy-

being evaluated.• Neo adjuvant/ preop use to

make tumor operable.• E.g. rectal GIST

• Adverse effects1. Nausea, vomiting2. Edema- Periorbital3. Myalgia- calves 40%4. Skin rashes- 30%5. Headache- 20%6. Diarrhoea- 45%7. Myelotoxicity-less common8. GI hrg.9. Potential of cardiac

impairment.

• Resistance to imatinib• Occurs in <15%• Second line therapy with

Sunitinib 50 mg orally daily for 4 weeks with 2 weeks gap- life long.

• Also inhibits VEGFR.• Nilotinib being evaluated.• Has better pharmacodynamic

and clinical inhibitory properties.

Early GIST: Adjuvant therapy

• After complete resection, the std of care is observation/ surveillance.

• FDA has approved Imatinib for adjuvant use without any qualifications.

• EMA- For those at high risk of recurrence.

• Phase 3 trial have confirmed the benefit of using adjuvant imatinib for 1 year.

• But increased recurrences on discontinuation.

• Targets for future research:

1. MAPK(mitogen activated protein kinase)

2. m-TOR(mammalian target of rapamycin.)

THANK YOU…