Pancreas Cancer & Surgery

Key Points for Revision: Genetic and Molecular Aspects

Insulin Resistance, Inflammation, Hemostasis, and Infection are associated with the development of various diseases, including cancer.
Hereditary vs. Sporadic Cases: < 3% is hereditary and 80% is sporadic.
Most Common Mutation (MC): KRAS
Key Genetic Mutations: ATM, BRCA1, BRCA2, MLH-1, MSH-6, p53, PALB2, CDKN2NA, PRSS-1, STK11.

Familial Pancreatic Cancer

Definition: Familial Pancreatic Cancer involves two or more first-degree relatives with Pancreatic Cancer (PC).
Prevalence: 5-10% of cases have a positive family history.
No Mendelian heritance.
Most Common Mutation (MC): Germline BRCA-2, found in 6-19% of cases.
Additional Genetic Mutation: PALB-2 gene is present in 3% of cases.
Distinction from Hereditary Pancreatic Cancer:
- Hereditary Pancreatic Cancer is associated with specific syndromes like Peutz-Jeghers Syndrome (PJS), Hereditary Pancreatitis (HP), Hereditary Nonpolyposis Colorectal Cancer (HNPCC), Familial Atypical Multiple Mole Melanoma (FAMMM), and Ataxia Telangiectasia.

High-Risk Genetic Disorders Associated with Familial Pancreatic Cancer [61.3 blg]

Peutz-Jeghers Syndrome
- Gene/Chromosomal Mutation: STK11/LKB1 (19p13)
- Estimated Increased Risk of PDA: 75-132 times
Hereditary Pancreatitis
- Gene/Chromosomal Mutation: PRSS1 (7q35)
- Estimated Increased Risk of PDA: 50-80 times
FAMMM Syndrome
- Gene/Chromosomal Mutation: p16 (9p21)
- Estimated Increased Risk of PDA: 20-34 times
Hereditary Breast and Ovarian Cancer
- Gene/Chromosomal Mutation: BRCA2 (13q12-q13)
- Estimated Increased Risk of PDA: 3.5-10 times
Hereditary Nonpolyposis Colorectal Cancer (Lynch II Variant)
- Genes/Chromosomal Mutations: hMSH2, hMSH1, hPMS2, hMSH3, hPMS1, hMSH6/GTBP
- Estimated Increased Risk of PDA: Undefined
Ataxia-Telangiectasia
- Gene/Chromosomal Mutation: ATM (11q22-23)
- Estimated Increased Risk of PDA: Undefined

Risk Factors for Pancreatic Cancer

Most Common Risk Factor: Smoking
Highest Risk: Peutz-Jeghers Syndrome
Lowest Risk: Familial Adenomatous Polyposis (FAP)

Pathophysiology of Pancreatic Cancer

Genetic Progression of Pancreatic Intraepithelial Neoplasia (PanIN) to Invasive Pancreatic Ductal Adenocarcinoma (PDAC)

PanIN Definition:
- PanIN is defined histologically by progressive abnormalities in the ductal epithelium:
  - PanIN-1A: Columnar, mucin-producing ductal epithelium with basally located homogeneous nuclei without atypia.
  - PanIN-1B: Development of papillary architecture, otherwise identical to PanIN-1A.
  - PanIN-2: Simple papillary growth with nuclear atypia, enlarged nuclei, nuclear crowding, and loss of polarity.
  - PanIN-3 (Carcinoma in situ): Prominent nuclear abnormalities with complete loss of polarity and marked cytologic atypia; clusters of abnormal cells within the duct lumen.
KRAS2 Oncogene:
- Activated in >95% of pancreatic cancers.
- Point mutations (codons 12, 13, or 61) lead to constitutive activation and loss of regulation of the mitogen-activated protein kinase (MAPK) signaling pathway.
- Mutation of KRAS2 is an early genetic abnormality:
  - Found in 36% of PanIN-1, 44% of PanIN-2, and 87% of PanIN-3 cases.
Tumor Suppressor Genes:
- CDKN2A/p16:
  - Encodes p16, which binds to CDK4/CDK6, resulting in cell cycle arrest.
  - Mutation leads to loss of p16, resulting in loss of cell cycle regulation.
  - Present in 30% of PanIN-1, 55% of PanIN-2, and 71% of PanIN-3 cases.
  - 90% of PDACs show loss of p16 function.
- P53:
  - Regulates cell proliferation through cell cycle arrest and pro-apoptotic mechanisms.
  - Rare in PanIN, but 79% of invasive PDACs show P53 mutations.
- SMAD4:
  - Functions as a downstream mediator in the TGF-β signaling pathway.
  - Loss of SMAD4 leads to decreased inhibition of cell growth and proliferation.
  - Observed in 20-30% of PanIN-3 and localized cancers, and 78% of widely metastatic tumors.

Key Points for Revision: Pancreatic Intraepithelial Neoplasia (PanIN) and PDAC

High Grade Lesion: PanIN-3 (Carcinoma in situ)
Low Grade Lesions: PanIN-1 and PanIN-2 (Can be found in normal pancreas)
Histological Changes:
- Columnar metaplasia from cuboidal epithelium
Most Common Mutation: KRAS2
Earliest Mutation: KRAS2
Specific Mutation for PDAC: SMAD4 (Occurs late in PanIN-3)

Clinical Features:

Diagnosis of Pancreatic Ductal Adenocarcinoma (PDAC)

Investigation of Choice: Triple phase CT (Non-contrast, arterial, and portal venous phases)
Pancreatic Phase: [Late arterial phase]
- Hypodense lesion observed at 45 seconds
3 mm slices used for detailed imaging
Purpose:
- Assess local resectability and vascular invasion
Biopsy:
- Not mandatory for initial diagnosis
- EUS: Indicated for Biopsy
- Biopsy recommended for neoadjuvant chemotherapy (NACT)
EUS: Indicated when no mass on CT but with ductal dilatation

Staging Laparoscopy Indications in PDAC

Not Mandatory for all cases but only for High risk of peritoneal spread
Indications for Staging Laparoscopy:
- CA 19-9 > 100 U/ml
- Tumor size > 3 cm
- Weight loss, malnutrition, and pain
The strong determinant:
- For HCC and for PDAC: Size of tumor
- for Ca GB is LN’s
Staging Laparoscopy is Mandatory for:
- Ca GB
- Ca Stomach

PET Scan in PDAC

PET Scan:
- 10-30% of PDAC cases are PET negative
- Limited use in the diagnosis and staging of PDAC

Biopsy in PDAC

Biopsy:
- Not mandatory for diagnosis
- Highly fibrotic tumor increases the risk of sampling error
- EUS-FNA > ERCP brush cytology > Percutaneous Biopsy [ used in mets to liver with pancreatic head mass]

ERCP in PDAC

ERCP:
- Primarily used for biliary drainage
- Indicated in cases of cholangitis or prior to neoadjuvant chemotherapy (NACT) / NACRT
- Metallic stent preferred if NACT is planned
- Associated with higher postoperative infectious complications

CA 19-9 in PDAC

Sensitivity and Specificity:
- Most sensitive marker for PDAC: Sensitivity 79%, Specificity 82%
False Elevation:
- Can occur in cases of biliary obstruction
Lewis Antigen Negative:
- 10-15% of patients do not show CA 19-9 elevation due to being Lewis antigen negative
Prognostic Marker:
- Used to monitor progress after neoadjuvant chemotherapy (NACT)
- Important in follow-up assessments
Staging Indications:
- Consider staging laparoscopy or PET-CT if CA 19-9 > 100 U/ml

TNM Staging of Pancreatic Cancer (NCCN Guidelines Version 1.2022)

T: Primary Tumor

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ (Includes high-grade PanIN, intraductal papillary mucinous neoplasm with high-grade dysplasia)
T1: Tumor ≤2 cm in greatest dimension
- T1a: Tumor ≤0.5 cm
- T1b: Tumor >0.5 cm and ≤1 cm
- T1c: Tumor 1-2 cm
T2: Tumor >2 cm and ≤4 cm
T3: Tumor >4 cm
T4: Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size

N: Regional Lymph Nodes

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastases
N1: Metastasis in 1-3 regional lymph nodes
N2: Metastasis in 4 or more regional lymph nodes

M: Distant Metastasis

M0: No distant metastasis
M1: Distant metastasis present

AJCC Prognostic Groups

Stage 0: Tis, N0, M0
Stage IA: T1, N0, M0
Stage IB: T2, N0, M0
Stage IIA: T3, N0, M0
Stage IIB: T1, T2, T3; N1, M0
Stage III: T1, T2, T3; N2, M0 or T4, Any N, M0
Stage IV: Any T, Any N, M1

Resectability Status in Pancreatic Adenocarcinoma

(NCCN Guidelines Version 1.2022)

1. Resectable

Arterial:
- No arterial tumor contact with the celiac axis (CA), superior mesenteric artery (SMA), or common hepatic artery (CHA).
Venous:
- No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or ≤180° contact without vein contour irregularity.

2. Borderline Resectable:

Arterial:
- Pancreatic head/uncinate process:
  - Solid tumor contact with CHA without extension to CA or hepatic artery bifurcation, allowing safe resection and reconstruction.
  - Solid tumor contact with the SMA of ≤180°.
  - Solid tumor contact with variant arterial anatomy (e.g., accessory right hepatic artery) without significant impact on surgical planning.
- Pancreatic body/tail:
  - Solid tumor contact with the CA of ≤180°.
Venous:
- Solid tumor contact with SMV or PV >180° with suitable vessel proximal and distal to the site of involvement for resection and reconstruction.
- Solid tumor contact with the inferior vena cava (IVC).

3. Locally Advanced:

Arterial:
- Head/uncinate process:
  - Solid tumor contact >180° with the SMA or CA.
- Pancreatic body/tail:
  - Solid tumor contact >180° with the SMA or CA.
  - Solid tumor contact with the CA and aortic involvement.
Venous:
- Unreconstructible SMV/PV due to tumor involvement or occlusion.

Definition of Borderline Resectable Tumors (NCCN Guidelines) [Sabiston]

Definition: Borderline resectable tumors are those that exhibit one or more of the following characteristics:

1. Venous Involvement

Solid tumor contact with SMV or portal vein:
- >180 degrees contact or
- ≤180 degrees contact with contour irregularity or thrombosis of the vein.
Condition: There must be suitable vessel proximal and distal to the site of involvement to allow for safe and complete resection and vein reconstruction.

2. Arterial Involvement

Hepatic Artery Involvement:
- Solid tumor contact with the common hepatic artery (CHA), which may involve abutment or encasement, but without extension to the celiac axis or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction.
SMA Involvement:
- Solid tumor contact with the SMA of ≤180 degrees.

Neoadjuvant Therapy in Pancreatic Cancer

Indications:
- Borderline Resectable Pancreatic Cancer (BRPC) and Locally Advanced tumors.
- 30-60% response rate to neoadjuvant therapy.
Preoperative Steps:
- Initial preoperative biliary drainage is performed.
Treatment Regimen:
- Chemotherapy (CT) and/or Radiation Therapy (RT) is administered.
- 2-4 months of chemotherapy is typically given.
Post-Treatment Evaluation:
- CT scan is used to evaluate the tumor after treatment.
- Note: Post-treatment CT does not reliably assess resectability but to assess progression.
Outcome:
- If there is stable disease, proceed with operative exploration.

Trials on Neoadjuvant Therapy in Pancreatic Cancer

PREOPANC-1:
- Comparison: Neoadjuvant chemoradiotherapy (CRT) vs. surgery alone.
- Outcomes: 17.1 months survival with neoadjuvant CRT vs. 13.5 months with surgery alone.
APACT Trial:
- Regimen: Gemcitabine + Nab-paclitaxel.
NEOPA Trial:
- Focus: Neoadjuvant therapy in resectable pancreatic cancer.

PREOPANC Trial:

Trial Type: Only RCT to compare neoadjuvant versus adjuvant chemotherapy.

Patient Population: Included both resectable and unresectable pancreatic cancer.

Treatment Regimen: Chemoradiation with gemcitabine.

Survival Outcome:

No difference in survival on an intention-to-treat (ITT) basis.

Specific Benefit: More beneficial in patients with Borderline Resectable Pancreatic Cancer (BRPC).

Adjuvant Therapy:

Summary of Clinical Trials on Adjuvant Therapy After Pancreatic Cancer Resection

GITSG:
- Adjuvant chemoradiation with 5-FU and 40-Gy radiation therapy improves survival compared with observation alone.
ESPAC-1:
- Adjuvant chemotherapy improves survival.
- Chemoradiation is found to be deleterious.
CONKO-001:
- Adjuvant gemcitabine improves disease-free survival compared with observation.
RTOG 97-04:
- Gemcitabine before and after 5-FU-based chemoradiation provides similar overall survival compared with 5-FU but with significantly less toxicity.
ESPAC-3:
- Adjuvant chemotherapy alone with gemcitabine provides similar overall survival compared with 5-FU but with significantly less toxicity.
ESPAC-4:
- Adjuvant combination of gemcitabine and capecitabine is superior to gemcitabine alone.
PRODIGE 24:
- FOLFIRINOX versus gemcitabine: 54 months median survival with FOLFIRINOX compared to 35 months with gemcitabine.
  - FOLFIRINOX:
    - Combination regimen of 5-FU, leucovorin, oxaliplatin, and irinotecan.