Pancreatic Carcinoma

Slide 1 · Pancreatic Carcinoma

Ductal adenocarcinoma

Ductal adenocarcinoma: molecular pathogenesis, morphology and clinical implications

Molecular pathogenesis | Morphology | Clinicopathologic correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What this lecture will establish

Identify the defining pathologic features of pancreatic ductal adenocarcinoma (PDAC).

Explain major risk factors, precursors and molecular alterations.

Connect tumor location and invasive behavior with clinical presentation.

Interpret the limits of detection and the importance of resectability.

Slide 3 · Pancreatic ductal adenocarcinoma: The entity

Infiltrating ductal adenocarcinoma is the most common exocrine malignancy of the pancreas.

Neoplastic epithelium forms malignant glands and often produces mucin.

Deep invasion, marked desmoplasia and late diagnosis dominate its behavior.

Exocrine ductal phenotype + infiltrative growth + fibrotic stroma

Slide 4 · Exocrine versus endocrine pancreatic tumors

DUCTAL / EXOCRINE

The subject of this lecture

Gland-forming, mucin-producing epithelial malignancy

Typically marked desmoplasia

ENDOCRINE

Distinct pancreatic neoplasm group

Discussed elsewhere

Do not equate with PDAC

Scope: Infiltrating exocrine ductal adenocarcinoma, not pancreatic neuroendocrine neoplasms.

Slide 5 · A high-fatality malignancy

12%

Five-year survival reported

Textbook estimate refers to the population reflected by its data.

This is not a stage-specific or individual prognostic estimate.

Late presentation is the dominant explanatory factor.

Slide 6 · Most patients present beyond surgery

>80%

Unresectable at initial presentation

Vascular/adjacent-structure involvement can prevent resection.

Some patients already have distant metastatic disease.

Earlier detection before dissemination is therefore critical.

Slide 7 · Pancreatic cancer: Anatomic distribution

Site

Approximate proportion

Pathologic/clinical implication

Head

60%

Often obstructs the distal common bile duct

Body

15%

May enlarge before causing biliary symptoms

Tail

5%

Usually no early biliary obstruction

Diffuse pancreatic involvement

20%

Disease extends through the pancreas

Percentages are approximate and come from the source morphology section.

Slide 8 · Anatomic location predicts obstruction

Bile duct

Head

Body

Tail

Head mass

Original editable schematic — not a clinical or histologic specimen

Carcinoma in the head lies near the intrapancreatic common bile duct.

Distal common bile duct obstruction causes upstream biliary dilatation.

Body and tail tumors may remain clinically occult longer.

Slide 9 · Age distribution

Pancreatic carcinoma is predominantly a disease of older adults.

That 80% of cases occur after age 60.

Age influences pretest probability but is not a stand-alone diagnostic criterion.

Slide 10 · Cigarette smoking as an established exposure

Smoking is described as the strongest environmental influence.

The source reports approximately twice the risk among smokers.

Smoking is a risk factor; Most smokers do not develop pancreatic cancer.

Risk ≠ diagnosis; Population associations should not be applied deterministically.

Slide 11 · How chronic pancreatitis increases risk

Chronic inflammation

Tissue injury and repair

Increased neoplastic risk

Association grounded in the source; This diagram is not a deterministic progression.

Slide 12 · Adiposity and metabolic risk

Visceral obesity and high body mass index are associated with greater risk.

Established diabetes mellitus is a modest risk factor.

These associations complement inherited and smoking-related susceptibility.

Slide 13 · Diabetes: Risk factor or early consequence?

PRE-EXISTING DIABETES

Modest epidemiologic risk factor

May precede malignant transformation

Not diagnostic of pancreatic carcinoma

NEW-ONSET DIABETES

Can precede recognition of occult carcinoma

Especially relevant in older patients

Requires clinical context, not indiscriminate screening

The temporal direction of the association is crucial.

Slide 14 · A possible preclinical metabolic signal

≤2 years

Diabetes or abnormal glucose tolerance before clinical signs

The source states that up to half of patients show this abnormality within this interval.

It is a possible opportunity for earlier recognition.

It is not sufficiently specific to diagnose PDAC alone.

Slide 15 · Population differences in incidence

The source reports increased incidence in African Americans, Japanese Americans, Native Hawaiian Islanders and Ashkenazi Jewish people.

Population patterns do not define causation in an individual.

Clinical assessment still depends on symptoms, inherited risk and diagnostic findings.

Slide 16 · Hereditary contribution

~10%

Patients with a deleterious germline predisposition or a first-degree family history

Family history and germline mutation status are overlapping—but not identical—concepts.

DNA repair genes are prominent among inherited predisposition genes.

Identifying a familial mutation has implications for relatives.

Slide 17 · DNA repair genes in familial pancreatic cancer

BRCA2 and ATM are highlighted as common known familial predisposition genes.

BRCA1 and PALB2 are additional DNA repair-related susceptibility genes.

These inherited defects are distinct from acquired tumor mutations.

Slide 18 · Inherited predisposition: Selected syndromes

Context

Selected genes

Teaching significance

Peutz–Jeghers syndrome

STK11

Strong predisposition in textbook

Hereditary pancreatitis

PRSS1, SPINK1

Pancreatic injury plus inherited susceptibility

Familial atypical multiple-mole melanoma

CDKN2A

Hereditary tumor-suppressor predisposition

Hereditary breast/ovarian cancer

BRCA1/2, PALB2, ATM

DNA repair pathway involvement

Selected inherited predisposition syndromes; Comparison not exhaustive.

Slide 19 · Additional inherited risk settings

Setting

Molecular/family basis

Clinical implication

Lynch syndrome

DNA mismatch-repair genes

Pancreatic risk and possible mismatch-repair deficiency

Strong pancreatic family history

Several affected relatives

Elevated inherited risk even without an identified gene

First-degree relative of a mutation carrier

Shared familial variant possible

Genetic counseling/cascade assessment

Slide 20 · From index case to familial risk recognition

Pancreatic cancer diagnosis

Germline testing

Pathogenic variant detected

Counseling and cascade testing

Robbins recommends germline testing for all patients with pancreatic cancer.

Slide 21 · Genetic results can inform therapy

Germline and tumor DNA repair defects may define therapeutic vulnerabilities.

Mismatch-repair deficiency and microsatellite instability are potentially actionable.

Do not confuse a susceptibility marker with proof of a particular treatment response.

Slide 22 · Precursor lesions establish a progression model

Most pancreatic cancers are believed to arise from microscopic PanIN lesions.

A smaller fraction arise from recognizable mucinous cystic precursors.

The distinction is important for interpreting precursor morphology and early detection.

Slide 23 · PanIN is the dominant precursor

>85%

Estimated pancreatic cancers arising from PanIN

PanIN develops in small pancreatic ducts and is often microscopic.

Low-grade PanIN can be encountered in older individuals.

High-grade PanIN is uncommon without associated invasive carcinoma.

Slide 24 · Low-grade versus high-grade PanIN

LOW-GRADE PanIN

Microscopic intraductal epithelial atypia

Formerly classified as PanIN-1A/1B/2

May be isolated, particularly in older patients

HIGH-GRADE PanIN

Markedly dysplastic precursor epithelium

Formerly termed PanIN-3 / carcinoma in situ

Often found with invasive carcinoma

Both are noninvasive; Invasion is a separate decisive event.

Slide 25 · Evidence connecting PanIN with carcinoma

PanIN and PDAC share multiple genetic and epigenetic alterations.

PanIN often occurs in non-neoplastic pancreas adjacent to PDAC.

Engineered mouse models and rare longitudinal human reports support progression.

Slide 26 · PanIN progression: Conceptual stages

Normal small duct

Low-grade PanIN

High-grade PanIN

Invasive carcinoma

Model of cumulative alterations; Not every lesion necessarily progresses.

Slide 27 · Telomere erosion occurs early

The source describes striking telomere shortening in PanIN epithelial cells.

Short telomeres may favor chromosomal instability and accumulation of alterations.

Telomere shortening is a pathobiologic feature—not a routine diagnostic assay.

Slide 28 · Cumulative mutation burden matters more than order

A general sequence of molecular events.

Individual lesions need not acquire alterations in a rigid chronological order.

Progressive loss of regulatory safeguards facilitates invasion.

Progression model: A framework, not an obligatory genetic itinerary.

Slide 29 · KRAS: Early oncogenic activation

KRAS activation

Increased growth-signaling input

Clonal expansion

Original editable schematic — not a clinical or histologic specimen

Activating KRAS mutations are the most frequent oncogenic event.

KRAS functions as a growth-signal transducer.

Early KRAS activation alone does not establish invasive cancer.

Slide 30 · KRAS alteration is exceptionally common

>90%

PDACs with activating KRAS mutation

KRAS is located at chromosome 12p.

Mutation frequency refers to pancreatic carcinomas, not all pancreatic tumors.

Ongoing trials targeting mutant RAS proteins.

Slide 31 · CDKN2A: Impaired cell-cycle restraint

CDKN2A / p16 loss

Reduced cell-cycle restraint

Proliferation permitted

Original editable schematic — not a clinical or histologic specimen

CDKN2A at 9p encodes p16/INK4a and ARF tumor suppressors.

Its loss weakens normal safeguards against inappropriate proliferation.

Inactivation in approximately 30% of PDAC.

Slide 32 · TP53: Compromised response to DNA damage

TP53 loss

Impaired damage response

Abnormal cells persist

Original editable schematic — not a clinical or histologic specimen

TP53 at 17p encodes p53, a tumor suppressor.

Its inactivation undermines cellular responses to DNA damage.

The source reports alteration in 70–75% of carcinomas.

Slide 33 · SMAD4: Defective TGF-β growth regulation

SMAD4 loss

Perturbed TGF-β signaling

Reduced regulatory restraint

Original editable schematic — not a clinical or histologic specimen

SMAD4 at 18q participates in TGF-β pathway signaling.

It is inactivated in approximately 55% of PDAC.

Loss is relatively uncommon across other cancer types, but not exclusive to PDAC.

Slide 34 · Core molecular alterations in PDAC

Gene

Role

Approximate alteration frequency

KRAS

Oncogenic signal transducer

>90%

TP53

DNA damage response

70–75%

SMAD4

TGF-β pathway tumor suppressor

55%

CDKN2A

Cell-cycle restraint (p16/ARF)

30%

Frequencies are textbook estimates; A tumor may harbor several alterations simultaneously.

Slide 35 · Less-common molecular events

Group

Selected genes

Interpretation

DNA damage response

ATM, BRCA2

Subset with DNA repair defects

Chromatin regulation

ARID1A, KMT2C, KDM6A

Altered transcriptional control

Growth signaling

AKT2, BRAF, MYC

Additional oncogenic mechanisms

Wnt-associated restraint

RNF43

Disrupted pathway regulation

Selected molecular alterations; Not an exhaustive diagnostic panel.

Slide 36 · Epigenetic dysregulation

Promoter hypermethylation

Tumor-suppressor silencing

Reduced growth control

Example: CDKN2A silencing. Hypomethylation can have the opposite transcriptional effect.

Slide 37 · Two transcriptomic phenotypes

BASAL-LIKE

Transcriptomic subtype

More aggressive behavior reported

Can coexist with classic subtype elements

CLASSICAL

Transcriptomic subtype

Relatively more favorable prognosis

May shift under treatment pressure

Basal-like/classic phenotypic heterogeneity and plasticity; Clinical selection is still under investigation.

Slide 38 · Tumor heterogeneity changes interpretation

Different molecular phenotypes may coexist within one tumor.

Expression programs can show plasticity during chemotherapy.

A subtype assignment need not represent every tumor cell at every time point.

Slide 39 · Microscopic versus cystic precursor routes

PanIN ROUTE

Small ducts; Usually microscopic

Histologic low-grade/high-grade progression

Major presumed source of PDAC

CYSTIC MUCINOUS ROUTE

Macroscopic lesions may be detectable

IPMN and mucinous cystic neoplasm

Subset progresses to invasive carcinoma

Related topics are used only to explain the origin of invasive ductal cancer.

Slide 40 · IPMN: A duct-centered precursor

Intraductal papillary mucinous neoplasm involves main or branch pancreatic ducts.

Neoplastic epithelium secretes mucin and can progress to invasion.

GNAS mutations are characteristic of IPMN relative to other cyst types.

Slide 41 · Mucinous cystic neoplasm as a precursor

Mucin-producing cystic epithelium sits above ovarian-type stroma.

These neoplasms tend to occur in the pancreatic tail and in women.

An invasive adenocarcinoma can arise within a mucinous cystic neoplasm.

Slide 42 · Gross carcinoma: A firm ill-defined mass

Bile duct

Head

Body

Tail

Firm, ill-defined

Lesion

Original editable schematic — not a clinical or histologic specimen

Tumor invasion and stromal collagen produce a hard mass.

Gray-white, stellate, poorly demarcated lesions.

A duct-centered infiltrative mass can blend into adjacent pancreatic parenchyma.

Slide 43 · Why the pancreatic mass becomes desmoplastic

Atypical glands

Fibrotic stroma

Original editable schematic — not a clinical or histologic specimen

Cancer-associated fibroblastic response deposits dense collagen.

Malignant duct-like glands are embedded in abundant non-neoplastic stroma.

The fibrotic component may dominate a small needle biopsy.

Slide 44 · Microscopy: Infiltrative malignant gland formation

Atypical glands

Fibrotic stroma

Original editable schematic — not a clinical or histologic specimen

Abortive, irregular tubular structures and small cell clusters infiltrate tissue.

Cells range from cuboidal to columnar with nuclear pleomorphism.

Glands are surrounded by dense fibrotic stroma.

Slide 45 · Architectural clues to invasion

Malignant glands are irregularly distributed rather than neatly organized around preserved ducts.

Deep infiltration into peripancreatic tissue supports invasive behavior.

Perineural, lymphatic or vascular invasion supplies additional evidence.

Slide 46 · Carcinoma versus chronic pancreatitis

DUCTAL CARCINOMA

Haphazard atypical invasive glands

Perineural / vascular invasion may be present

Desmoplastic tumor-associated stroma

CHRONIC PANCREATITIS

Benign ducts can show reactive atypia

Fibrosis can resemble desmoplasia

Requires careful architectural correlation

Source explicitly cautions that well-differentiated PDAC can be difficult to distinguish from benign glands in chronic pancreatitis.

Slide 47 · Needle biopsy sampling is vulnerable to error

Dense stroma means the sampled tissue may contain relatively few malignant cells.

Well-differentiated malignant glands can resemble reactive epithelium.

Interpret biopsies in clinical and imaging context; Do not assume a sparse sample excludes cancer.

Slide 48 · Perineural invasion: Biologic and clinical relevance

Nerve

Infiltrative tumor glands

Original editable schematic — not a clinical or histologic specimen

Pancreatic carcinoma commonly tracks along and invades nerves.

Perineural infiltration is an indicator of invasive growth.

Perineural involvement demonstrates spread beyond ductal epithelium.

Slide 49 · Vascular invasion governs spread and resectability

Vessel

Infiltrative tumor glands

Original editable schematic — not a clinical or histologic specimen

The tumor may encase or infiltrate major abdominal vessels.

Vascular invasion contributes to surgical unresectability.

Hematogenous dissemination can lead to distant metastasis.

Slide 50 · Routes of tumor dissemination

Direct local invasion

Lymphatic spread

Blood-borne metastasis

These are parallel potential routes, not necessarily sequential stages.

Slide 51 · Direct extension into neighboring structures

Retroperitoneal extension is common.

The spleen, adrenal glands, stomach and transverse colon may be directly involved.

Local extension can make a small anatomically strategic tumor unresectable.

Slide 52 · Regional lymphatic spread

Peripancreatic nodes are commonly involved.

The source also lists gastric, mesenteric, omental and portohepatic nodal groups.

Lymphatic spread is part of the characteristic invasive phenotype.

Slide 53 · Metastatic targets

Primary pancreatic

Carcinoma

Liver

Lungs

Original editable schematic — not a clinical or histologic specimen

Distant spread occurs chiefly to liver and lungs.

Metastases document spread outside the primary pancreatic site.

Documented distant metastasis makes curative surgery unrealistic.

Slide 54 · Less common histologic variants

Adenosquamous and colloid carcinomas are recognized variants.

Medullary, hepatoid and signet-ring cell patterns are described.

Undifferentiated carcinoma may occur with or without osteoclast-like giant cells.

Slide 55 · Head versus body/tail presentation

HEAD OF PANCREAS

Common bile duct obstruction

Obstructive jaundice may reveal the tumor

Palpable nontender gallbladder can occur

BODY OR TAIL

Often no early biliary obstruction

Can grow substantially before symptoms

May be disseminated at recognition

Anatomic effects help explain presentation; These patterns are not absolute.

Slide 56 · Mechanism of obstructive jaundice

Pancreatic head mass

Distal bile duct obstruction

Upstream ductal distention

Clinical jaundice

The pathway is causal; Jaundice does not prove malignant obstruction.

Slide 57 · Courvoisier sign in pancreatic carcinoma

Describes a palpably enlarged, nontender gallbladder associated with painless jaundice.

It follows distal bile duct obstruction in a compatible clinical setting.

It is a classic clue rather than a definitive test for carcinoma.

Slide 58 · Pain and the silent interval

Pancreatic carcinomas often remain asymptomatic until obstruction or invasion.

Pain is frequently the first symptom.

By the time pain occurs, disease is often beyond curative treatment.

Slide 59 · Why systemic decline accompanies advanced cancer

Advanced tumor burden

Anorexia and metabolic disturbance

Loss of muscle and visceral fat

Cachexia and weakness

Schematic clinical relationship described in the source.

Slide 60 · Trousseau sign: Migratory thrombophlebitis

Migratory, episodic thrombosis can accompany pancreatic carcinoma.

This phenomenon in about 10% of patients.

Cancer-associated procoagulants and platelet-activating factors contribute.

Slide 61 · A symptom cluster requiring investigation

Upper abdominal or back pain, unexplained weight loss and jaundice can coexist.

New-onset diabetes in an older adult may be a separate early clue.

These features are nonspecific and require diagnostic evaluation, not assumed PDAC.

Slide 62 · What different investigations can and cannot do

Modality

Useful role

Key limitation

CT imaging

Assess suspicious mass and disease extent

Not recommended for general-population screening

Endoscopic ultrasound

Investigate suspected pancreatic lesion

Not general-population screening

CA19-9 / CEA

May aid longitudinal response assessment

Inadequate sensitivity/specificity for early screening

Circulating tumor DNA

Potential tumor-derived signal

Insufficient performance for general screening

Slide 63 · CA19-9 is not an early diagnostic solution

Serum CA19-9 may be elevated in pancreatic carcinoma.

Limited sensitivity for early disease and limited specificity for population screening.

It can be useful to follow treatment response in an individual patient.

Slide 64 · Circulating tumor DNA: Promise with limitations

Tumor cells can release DNA fragments into blood.

Detectable ctDNA can reflect tumor biology or burden.

Robbins does not support ctDNA as a stand-alone early-detection screening test.

Slide 65 · Population screening versus high-risk surveillance

AVERAGE-RISK ASYMPTOMATIC

Routine screening is not recommended

False positives and downstream harm are major concerns

No validated general screening strategy in source

INHERITED HIGH RISK

Longitudinal surveillance may be appropriate

Consider germline status and family history

Specialized risk assessment is necessary

Reproduces the textbook framework; Detailed surveillance protocols are not asserted.

Slide 66 · Why resection matters

Advanced disease is usually short-lived after recognition.

A subset who undergo successful resection may survive substantially longer.

Anatomic stage and ability to achieve resection are clinically decisive.

Slide 67 · Link morphology to clinical outcome

Ill-defined invasion

Vessels / nerves / nodes involved

Often unresectable at diagnosis

Poor population survival

Causal overview—not a formal staging or treatment algorithm.

Slide 68 · Case application: Obstructive presentation

Clinical vignette

A 67-year-old develops painless jaundice, a nontender enlarged gallbladder and recent weight loss. Imaging reveals a pancreatic head mass.

Which anatomic mechanism best explains the jaundice?

Discuss the mechanism before revealing the answer in presenter notes.

Slide 69 · Case application: A difficult core biopsy

Clinical vignette

A firm pancreatic mass is sampled. The core contains extensive fibrosis and a few atypical glands; Chronic pancreatitis is in the differential.

Which source-described problem makes histologic interpretation difficult?

Discuss the mechanism before revealing the answer in presenter notes.

Slide 70 · Case application: Inherited susceptibility

Clinical vignette

A newly diagnosed PDAC patient has several close relatives with cancer. Germline testing detects a pathogenic DNA repair gene variant.

What is the added clinical implication beyond the patient’s tumor?

Discuss the mechanism before revealing the answer in presenter notes.

Slide 71 · Case application: Screening biomarkers

Clinical vignette

An asymptomatic, average-risk adult requests a screening blood CA19-9 test because a family acquaintance developed PDAC.

What limitation should be explained?

Discuss the mechanism before revealing the answer in presenter notes.

Slide 72 · Synthesis: Recognize the pathologic phenotype

Infiltrative atypical glands plus intense desmoplasia are defining morphologic features.

Nerve, vessel and peripancreatic tissue invasion reveal the aggressive phenotype.

Head lesions are more likely to obstruct the distal bile duct.

Slide 73 · Synthesis: Connect precursors and mutations

Microscopic PanIN explains most of the proposed precursor sequence.

KRAS activation is early and common; Tumor-suppressor loss is cumulative.

Genetic susceptibility and rare mismatch-repair defects can have family and therapeutic implications.

Slide 74 · Synthesis: Clinical decision points

The prediagnostic interval is often silent.

Markers and imaging are useful in symptomatic workup or monitoring, not mass screening.

Inherited high-risk surveillance and assessment of resectability are distinct priorities.

Slide 75 · Primary reference and visual provenance

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026). Section: The Pancreas.

Illustrations in this lecture are original editable conceptual PowerPoint schematics. No synthetic microscopy, patient images or textbook figures are presented as clinical evidence.