Hepatocellular Carcinoma

Slide 1 · Hepatocellular carcinoma

Pathogenesis · morphology · diagnosis · clinical correlation

Pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Relate chronic liver injury and etiologic exposures to tumor development

Explain β-catenin, TERT and TP53 alterations in HCC

Recognize major precursors and architectural tumor patterns

Interpret characteristic imaging and key management constraints

Slide 3 · HCC in the spectrum of hepatic malignancy

HCC is a primary malignant hepatocellular neoplasm

Intrahepatic cholangiocarcinoma is the other major primary epithelial malignancy

Metastatic cancers may also produce malignant masses in the liver

Primary liver cancer

Hepatocellular / biliary

Conceptual comparison

Slide 4 · The clinical–pathologic problem

HCC often arises against a background of chronic liver disease

Both the neoplasm and the residual liver function influence outcomes

A minority arise in a liver without cirrhosis

Tumor burden (size, invasion, spread)

Background liver function (cirrhosis / reserve)

Independent but interacting clinical burdens

Slide 5 · Geographic burden

HCC is particularly frequent where chronic hepatitis B is common

More than 85% of cases in parts of Asia and sub-Saharan Africa

These estimates describe the textbook source, not an independently updated 2026 registry

Slide 6 · Epidemiologic transition

HBV vaccination is associated with decreasing HCC incidence in parts of Asia

Rising metabolic syndrome is contributing to increasing burden in Western countries

Etiologic patterns vary strongly by population

HBV prevention

Regional decrease in HBV-linked HCC

Metabolic burden rising

Schematic / conceptual relations

Slide 7 · Demographic clues

Textbook describes marked male predominance in high-incidence regions

In perinatally acquired HBV infection, HCC can arise in young adulthood

Age alone cannot exclude HCC in an appropriate risk context

Slide 8 · Cirrhosis is common—but not universal

Most tumors occur in chronic liver disease with cirrhosis

Approximately 15%–20% occur in noncirrhotic livers

Fibrolamellar carcinoma is a prominent noncirrhotic exception

Most HCC

Cirrhotic background

Conceptual comparison

Slide 9 · Major etiologic settings

Viral hepatitis

Metabolic / alcohol

Inherited disease

Aflatoxin

Distinct contributors converge on hepatocarcinogenesis

Slide 10 · Hepatitis B: Major carcinogenic context

Chronic HBV infection is strongly associated with HCC

Perinatal HBV acquisition underlies early-adult HCC in some endemic populations

Population prevention through HBV vaccination can reduce future HCC burden

Chronic HBV infection

At-risk hepatocytes

HCC

Schematic / conceptual relations

Slide 11 · Hepatitis C and long-term hepatic injury

Chronic hepatitis C is a frequent antecedent condition

Ongoing inflammation, hepatocyte loss and regeneration support carcinogenesis

Cirrhotic livers require particular attention to evolving nodules

Slide 12 · Alcohol-associated liver disease

Alcohol-associated chronic liver disease is a recognized HCC risk setting

Repeated injury and regeneration contribute to accumulation of somatic changes

Aflatoxin may act synergistically with alcohol in exposed populations

Alcohol-associated injury

Chronic damage / regeneration

Driver selection

Schematic / conceptual relations

Slide 13 · MASLD-related risk

MASLD is an increasingly important background disease for HCC

The text explicitly notes HCC can develop without cirrhosis in MASLD

Therefore, absence of established cirrhosis does not imply zero risk

Slide 14 · Inherited metabolic diseases

Hemochromatosis

α₁-antitrypsin deficiency

Slide 15 · Other cirrhosis etiologies

Wilson disease and chronic biliary diseases may increase HCC risk

Robbins characterizes these risks as lower than those of common etiologies

These risks remain above the general-population baseline

Slide 16 · Aflatoxin exposure

Aflatoxin is produced by Aspergillus species

Contamination of crops is an exposure pathway in parts of Africa and Asia

It is a mycotoxin associated with hepatocarcinogenesis

Contaminated crops

Aflatoxin exposure

Hepatocarcinogenic risk

Schematic / conceptual relations

Slide 17 · Risk factors can act together

Synergistic effects between aflatoxin, HBV and alcohol

Carcinogenesis should not be reduced to a single mutually exclusive exposure

Regional disease patterns reflect interacting biologic and exposure contexts

HBV / alcohol

Aflatoxin exposure

Amplified risk

Schematic / conceptual relations

Slide 18 · A causal framework for HCC

Repeated hepatocyte damage drives inflammation and regeneration

Cell proliferation provides opportunities for selection of altered clones

Driver mutations confer growth or survival advantages

Progression eventually yields invasive malignant neoplasia

Cell injury / inflammation

Hepatocyte regeneration

Driver selection

HCC

Schematic / conceptual relations

Slide 19 · Tumor development is multistep

Chronic liver disease creates a permissive tissue environment

Mutated hepatocyte populations may be clonally selected

Dysplastic lesions can precede overt HCC

Not every chronically damaged liver develops carcinoma

Chronic injury

Altered clones

Dysplastic nodules

Carcinoma

Schematic / conceptual relations

Slide 20 · Three common classes of driver change

β-catenin

TERT

TP53

Distinct contributors converge on hepatocarcinogenesis

Slide 21 · β-catenin pathway activation

Activating β-catenin gene mutations in ~40% of HCCs

Activation of Wnt/β-catenin signaling supports neoplastic growth

This pathway also links some hepatocellular adenomas with malignant transformation

CTNNB1 activation

Wnt/β-catenin signaling

Neoplastic growth advantage

Schematic / conceptual relations

Slide 22 · TERT promoter alterations

Promoter mutations in TERT are reported in 50%–60% of HCCs

Promoter activation increases telomerase activity

This is a molecular route toward sustained proliferative capacity

TERT promoter mutation

Telomerase up-regulation

Sustained proliferation

Schematic / conceptual relations

Slide 23 · TP53 loss of function

Inactivating TP53 mutations are reported in up to 60% of tumors

Loss of this tumor-suppressor pathway weakens cellular protection against malignant progression

This genetic event can cooperate with other driver alterations

TP53 inactivation

Tumor-suppressor impairment

Malignant progression

Schematic / conceptual relations

Slide 24 · Interpretation of mutation frequencies

The reported percentages are not exclusive disease subtypes

Different drivers may coexist in the same malignancy

Do not add their frequencies to derive the prevalence of HCC

These are textbook figures; Sequencing cohorts vary

Slide 25 · Convergence on cancer hallmarks

Growth signaling: Activation of β-catenin pathway

Replicative capacity: Increased telomerase activity

Tumor suppression: Loss of TP53 function

Different genomic routes converge on a malignant phenotype

β-catenin / TERT / TP53

Complementary hallmarks

Malignant HCC

Schematic / conceptual relations

Slide 26 · Recognized routes to HCC

In chronic liver disease: Altered hepatocytes and dysplastic nodules

In noncirrhotic liver: Malignant progression can occur within an adenoma

The precursor context depends on the underlying disease

Chronic disease

Dysplastic nodule → HCC

Conceptual comparison

Slide 27 · Large cell change

Hepatocytes are larger than adjacent normal cells

Nuclei may be enlarged, pleomorphic or multiple

Nuclear-to-cytoplasmic ratio is not increased

This is a morphologic alteration in the at-risk liver

Schematic · not a specimen

Slide 28 · Small cell change

Hepatocytes have increased nuclear-to-cytoplasmic ratio

Mild nuclear hyperchromasia and/or pleomorphism may occur

The change is particularly relevant in dysplastic nodules

Schematic · not a specimen

Slide 29 · Large cell versus small cell change

Feature

Large cell change

Small cell change

Cell size

Enlarged

Relatively small

N:C ratio

Not increased

Increased

Nuclear finding

Enlarged / pleomorphic

Mild hyperchromasia / pleomorphism

Slide 30 · Dysplastic nodules in cirrhosis

Nodules differ from neighboring cirrhotic nodules in size or appearance

Color and vascularization may also differ

Dysplasia and clonal molecular abnormalities can be present

Higher-grade lesions may contain early carcinoma

Cirrhotic nodules

Dysplastic nodule

Focal HCC

Schematic / conceptual relations

Slide 31 · Nodule-in-nodule evolution

A focus of HCC may develop within a pre-existing dysplastic nodule

This produces a recognizable nodule-in-nodule configuration

A distinct subnodule should prompt evaluation for malignant transformation

Inner focus within larger nodule

Schematic · not a specimen

Slide 32 · Adenoma as a precursor in some settings

HCC may arise within hepatocellular adenoma in noncirrhotic liver

β-catenin–activated adenomas are an important higher-risk subgroup

Exon 3 CTNNB1 activation is particularly associated with malignant transformation

β-catenin adenoma

Clonal progression

HCC can emerge

Schematic / conceptual relations

Slide 33 · Major patterns of gross growth

Solitary mass

Multiple nodules

Diffuse infiltration

Schematic configurations · not gross specimens

Slide 34 · Why HCC masses differ in color

Yellow coloration may reflect fatty change

Green coloration may result from cholestasis

Gross color can suggest tumor composition but is not diagnostic by itself

Fatty change

Cholestasis

Schematic · not a specimen

Slide 35 · Tumor size and invasive potential

Tumors larger than 2 cm are more likely to show vascular invasion

Larger tumors are also more likely to show intrahepatic metastases

This is a pathologic association, not a stand-alone staging algorithm

Larger tumor

Vascular invasion

Intrahepatic spread

Schematic / conceptual relations

Slide 36 · Venous invasion is a defining concern

HCC may invade veins and propagate within vascular channels

Extension into the portal vein and inferior vena cava can occur

Rarely, tumor may extend to the right side of the heart

Tumor invades venous channel

Portal vein / IVC extension

Possible right-heart extension

Schematic / conceptual relations

Slide 37 · Differentiation modifies cytologic appearance

Well-differentiated tumors closely resemble hepatocytes

Moderately differentiated tumors retain partial hepatocellular characteristics

Poorly differentiated tumors show pronounced atypia

Well differentiated

Poorly differentiated

Conceptual comparison

Slide 38 · Thickened trabeculae

Neoplastic hepatocytes may form thick plates or trabeculae

Normal hepatic cell plates are comparatively thin

Architectural expansion is an important diagnostic clue

Normal thin plate

Thickened neoplastic trabecula

Schematic · not a specimen

Slide 39 · Pseudoglandular architecture

HCC may produce pseudoglandular or pseudoacinar spaces

These are distorted hepatocellular structures, not necessarily true glands

Bile plugs may be present in these spaces

Central lumen / bile plug

Schematic · not a specimen

Slide 40 · Solid growth pattern

HCC may consist of confluent sheets of malignant hepatocytes

This pattern is one of several microscopic growth architectures

A single tumor may show architectural variability

Schematic · not a specimen

Slide 41 · How the patterns relate

Pattern

Architectural hallmark

Trabecular

Thickened hepatocellular plates

Pseudoglandular

Lumen-like spaces; May contain bile

Solid

Confluent cell sheets

Slide 42 · Morphology must be interpreted in context

Atypia, architecture and the underlying liver all contribute

Well-differentiated HCC can resemble nonmalignant hepatocellular lesions

Histologic assessment should not rest on one isolated feature

Slide 43 · Fibrolamellar carcinoma is a distinct HCC subtype

Younger age

Noncirrhotic liver

Characteristic fusion

Slide 44 · Fibrolamellar: The diagnostic triad

Large polygonal tumor cells with granular oncocytic cytoplasm

Vesicular nuclei bearing conspicuous nucleoli

Parallel lamellae of dense collagen separating tumor cell groups

Parallel collagen + large oncocytic cells

Schematic · not a specimen

Slide 45 · The oncocytic cytoplasm has a mechanism

Abundant mitochondria account for granular eosinophilic cytoplasm

Dense collagen lamellae create a distinctive stromal compartment

These features explain the term “fibrolamellar”

Mitochondria-rich oncocytic cell

Schematic · not a specimen

Slide 46 · DNAJB1::PRKACA gene fusion

Strongly associated with fibrolamellar carcinoma

The fusion is linked to increased protein kinase A activity

It distinguishes this subtype from common driver patterns of conventional HCC

DNAJB1::PRKACA

Protein kinase A activation

Fibrolamellar carcinoma

Schematic / conceptual relations

Slide 47 · Fibrolamellar versus conventional HCC

Feature

Conventional HCC

Fibrolamellar HCC

Background

Often chronic liver disease

Often noncirrhotic

Molecular

β-catenin / TERT / TP53

DNAJB1::PRKACA

Morphology

Varied hepatocellular patterns

Oncocytic cells + collagen

Slide 48 · Clinical presentation is nonspecific

Abdominal pain

Systemic symptoms

Hepatomegaly

Slide 49 · α-fetoprotein: A limited biomarker

Serum AFP is frequently elevated in advanced HCC

Sensitivity is inadequate for screening early-stage HCC by AFP alone

The fibrolamellar subtype generally lacks AFP elevation

Advanced HCC: Often elevated

Early disease: May be normal

Conceptual comparison

Slide 50 · Ultrasound in at-risk livers

Ultrasound as a screening method in high-risk patients

Cirrhosis is a central high-risk setting

A suspicious observation requires further characterization

At-risk patient

Ultrasound surveillance

Characterize suspicious nodule

Schematic / conceptual relations

Slide 51 · Dynamic imaging: Arterial enhancement

HCC commonly exhibits early enhancement after contrast delivery

The arterial-phase behavior reflects the tumor’s vascular phenotype

This is only one phase of a multiphasic examination

Arterial phase

Early enhancement

Venous phase

Relative washout

Schematic contrast behavior · not a scan

Slide 52 · Dynamic imaging: Venous washout

Rapid washout after arterial enhancement

Arterial uptake followed by venous washout is strongly characteristic

Interpretation depends on the entire imaging context

Arterial phase

Early enhancement

Venous phase

Relative washout

Schematic contrast behavior · not a scan

Slide 53 · Imaging pattern as an integrated sequence

First identify an at-risk patient or a hepatic mass

Characterize enhancement during arterial phase

Assess behavior during the venous phase

Integrate with clinical condition and other findings

Arterial phase

Early enhancement

Venous phase

Relative washout

Schematic contrast behavior · not a scan

Slide 54 · Resection depends on hepatic reserve

Surgery is favored for resectable HCC in noncirrhotic liver

Patients with cirrhosis require adequate residual liver function

Anatomical tumor extent and hepatic function must both be considered

Resectable tumor

Adequate hepatic function

Conceptual comparison

Slide 55 · Transplantation addresses two problems

For HCC associated with advanced cirrhosis, transplantation may be considered

It removes the tumor-bearing liver together with the diseased parenchyma

Selection criteria are not specified in this textbook excerpt

Tumor-bearing liver

Advanced cirrhotic substrate

Liver transplantation

Schematic / conceptual relations

Slide 56 · Local ablation

Image-guided alcohol ablation or radiofrequency ablation may be used

These for unresectable tumors or non-transplant candidates

Ablation is a local tumor-directed approach

Selected unresectable HCC

Image-guided local therapy

Tumor ablation

Schematic / conceptual relations

Slide 57 · Hematogenous and regional spread

Metastases may occur late in the course

The lung is a particularly important distant hematogenous site

The excerpt reports lymph-node metastasis in fewer than 5% of cases

Venous invasion

Bloodborne dissemination

Pulmonary metastasis

Schematic / conceptual relations

Slide 58 · Outcome is driven by tumor and host liver

Underlying cirrhosis can independently worsen prognosis

Conventional chemotherapy resistance contributes to poor outcomes

Noncirrhotic patients may tolerate more extensive resection

Tumor extent

Residual hepatic reserve

Conceptual comparison

Slide 59 · Textbook-reported survival contrasts

Disease extent

Robbins-reported 5-year survival

Confined to liver

~30%

Extrahepatic spread

~5%–10%

Slide 60 · Why fibrolamellar outcomes may differ

Absent chronic liver disease often permits larger resections

Up to 40% with survival of 10 years or longer

Prognosis is not favorable for every individual patient

Often preserved liver

Extensive resection possible

Potentially improved outcomes

Schematic / conceptual relations

Slide 61 · Case: A nodule in a cirrhotic liver

A patient with longstanding chronic hepatitis has a new distinct hepatic nodule

Its architecture contains an emerging internal subnodule

Interpretation: Consider dysplastic nodule with evolving HCC

Inner focus within larger nodule

Schematic · not a specimen

Slide 62 · Case: Dynamic enhancement of a liver mass

A high-risk patient has a liver mass with arterial enhancement

The lesion subsequently becomes relatively hypoenhancing during venous imaging

Interpretation: Imaging phenotype strongly characteristic of HCC

Arterial phase

Early enhancement

Venous phase

Relative washout

Schematic contrast behavior · not a scan

Slide 63 · Case: Young patient without cirrhosis

Young adult with a hepatic mass and no chronic liver disease

Tumor shows oncocytic hepatocytes and dense lamellar collagen

Interpretation: Fibrolamellar carcinoma; Consider DNAJB1::PRKACA association

Young / noncirrhotic

Oncocytic cells + collagen

Fibrolamellar HCC

Schematic / conceptual relations

Slide 64 · HCC versus hepatocellular adenoma

Feature

Hepatocellular adenoma

HCC

Biologic class

Benign neoplasm

Malignant neoplasm

Architecture

Typically thin plates

Often thick plates / pseudoacini

Vascular invasion

Not a benign feature

May be extensive

Slide 65 · HCC versus intrahepatic cholangiocarcinoma

Feature

HCC

Intrahepatic cholangiocarcinoma

Cell lineage

Hepatocellular

Biliary epithelial

Primary malignant liver tumor

Major category

Other major category

Primary teaching emphasis

Trabecular / pseudoacinar

Biliary adenocarcinoma

Slide 66 · Integrating pathology with clinical decisions

Risk context identifies patients in whom a new liver nodule is consequential

Morphology and multiphasic enhancement support diagnostic classification

Cirrhosis and tumor spread shape management feasibility

Etiologic risk

Tumor evidence

Hepatic reserve / spread

Treatment feasibility

Schematic / conceptual relations

Slide 67 · Core concepts for recall

Chronic injury

Driver mutations

Morphologic progression

Invasive / metastatic tumor