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Tumors of the Liver and BiliaryTree¶

Hepatocellular Carcinoma and Anal Cancer | Part 4 – Oncology: Solid Tumors · Part 4 – Oncology: Solid Tumors · Chapter 87

Key Clinical Points¶

HCC is the third leading cause of cancer mortality globally; 85% of primary liver cancers are HCC.
Risk factors for HCC include chronic HBV/HCV infection (50–70%), alcohol/MASH (30%), and Aflatoxin B1 (leading to TP53 mutations).
Molecular drivers of HCC: TERT promoter mutations (56%), CTNNB1 (26%), and TP53 (27%).
Surveillance for HCC in cirrhotics: Ultrasound + AFP every 6 months; LI-RADS 5 indicates ≈95% probability of HCC.
BCLC staging system integrates tumor burden, liver function (Child-Pugh), and performance status (ECOG) to guide treatment selection.
First-line systemic therapy for advanced HCC: Atezolizumab + Bevacizumab or Durvalumab + Tremelimumab.
Anal cancer is primarily HPV-driven (subtypes 16/18); standard treatment is concurrent chemoradiation (5-FU + Mitomycin C).
Cholangiocarcinoma classification: iCCA (10–20%), pCCA (50–60%), and dCCA (20–30%).
Milan criteria for transplant eligibility: ≤1 nodule <5 cm or ≤3 nodules ≤3 cm without vascular invasion.
Advanced HCC systemic therapy options include TKI's such as Sorafenib, Lenvatinib, Regorafenib, Cabozantinib, and Ramucirumab.

1. ANAL CANCER¶

• Overview: Accounts for 1–2% of large bowel malignancies; predominantly squamous cell carcinomas arising in the anorectal region. • Etiology: Primary driver is HPV infection (especially subtypes 16/18); higher incidence in immunocompromised states (HIV, transplant recipients). • Risk Factors: ◦ Immunocompromise (HIV, transplant) ◦ Smoking ◦ Anal intercourse ◦ Note: 5–10% of cases are adenocarcinomas indistinguishable from rectal cancer.

1.1 CLINICAL MANIFESTATIONS¶

• Presentation: ◦ Rectal bleeding (70%) ◦ Perianal mass (40%) ◦ Pruritus ◦ Pain • Lymphadenopathy: Inguinal lymphadenopathy is common at diagnosis (unlike rectal cancer's iliac node metastasis). • Complications: 20–30% present with obstruction or fistulas.

1.2 MANAGEMENT & TREATMENT¶

Standard Treatment: Concurrent chemoradiation. ◦ Regimen: 5-FU + Mitomycin C with external beam RT.
Outcome: Complete response rate ≈80–90% at 6-month follow-up.
Salvage Therapy: Surgery (APR) for local recurrence or refractory disease.
Metastatic Disease: Carboplatin/paclitaxel; note that PD-1 inhibitors show limited activity.

2. HEPATOCELLULAR CARCINOMA (HCC)¶

• Epidemiology: 3rd leading cause of cancer mortality globally; 85% of primary liver cancers are HCC. • Risk Factors: ◦ Chronic HBV/HCV infection (50–70%) ◦ Alcohol/MASH (30%) ◦ Aflatoxin B1 (leads to TP53 mutations) ◦ Cirrhosis: 1% of population develops HCC annually.

2.1 ETIOLOGY & PATHOPHYSIOLOGY¶

• Development: Multistep process from LGDN → HGDN → HCC from hepatocytes or progenitor cells. • Molecular Drivers (Table 87-1): ◦ TERT promoter mutations: 56% ◦ TP53: 27% (associated with ATM, RB1) ◦ CTNNB1: 26% (associated with AXIN1) ◦ Other pathways: Wnt/β-catenin, Ras/PI3K/mTOR, Oxidative stress. • Molecular Subtypes: ◦ Proliferative: HBV-related, AFP+, poor prognosis. ◦ Nonproliferative: CTNNB1 mutations, better outcome. ◦ Immune-inflamed: 35% of cases, PD-1 expression.

2.2 PREVENTION & EARLY DETECTION¶

• Primary Prevention: ◦ Universal HBV vaccination ◦ HCV DAA therapy (leads to >90% SVR). • Surveillance for Cirrhotics: ◦ Ultrasound + AFP every 6 months. • LI-RADS Classification: ◦ LI-RADS 5: ≈95% probability of HCC. ◦ LI-RADS 4: 60–70% probability (biopsy indicated). ◦ CT/MRI used for atypical cases or obesity/fatty liver.

2.3 DIAGNOSTIC APPROACH¶

Initial Screening: Ultrasound and AFP every 6 months for patients with cirrhosis.
Imaging Assessment: Multiphasic CT or MRI to identify hallmark features (arterial uptake + venous washout).
Risk Stratification (EASL Algorithm):
If mass/nodule <1 cm → Repeat US in 3–6 months.
If mass/nodule >1 cm AND (AFP ≥ 20 ng/mL or rising) → Multiphasic CT or MRI.
If 1 positive technique (Radiological hallmark OR LI-RADS 5) → Diagnosis: HCC.
If LI-RADS 3 or 4 → Use alternative imaging or Biopsy.
Biopsy Criteria: Perform if: ◦ No cirrhosis present ◦ Atypical imaging on both modalities ◦ LI-RADS 4 lesion identified.
Histopathology: Use GPC3, glutamine synthetase, and HSP70 immunostains.

2.4 MANAGEMENT & TREATMENT¶

Staging Determination (BCLC System):
Very Early (0): Single nodule ≤ 2 cm, Child-Pugh A, ECOG 0.
Option 1: Ablation.
Option 2: Resection.
Early (A): ≤3 nodules ≤ 3 cm, Child-Pugh A–B, ECOG 0.
If "Optimal surgical candidate" = Yes → Resection.
If "Optimal surgical candidate" = No AND "Transplant candidate" = Yes → Transplantation (LT).
If "Transplant candidate" = No → Ablation.
Intermediate (B): Multinodular, Child-Pugh A–B, ECOG 0.
If "TACE candidate" = Yes → Chemoreembolization (+ systemic therapy) or TACE (TARE, SBRT).
If "TACE candidate" = No → Ablation.
Advanced (C): Portal invasion, N1, M1, Child-Pugh A–B, ECOG 1–2.
Treatment: Systemic therapy.
Terminal (D): Child-Pugh C, ECOG >2.
Treatment: Best supportive care.
Surgical & Locoregional Outcomes:
Resection: 5-year OS 50–70% for solitary tumors in noncirrhotics; 35–55% if suboptimal (multinodular/portal hypertension).
Transplantation: Milan criteria (≤1 nodule <5 cm or ≤3 nodules ≤3 cm) yields 5-year survival 70–80%.
Ablation: RFA median 50–60 months for ≤3 cm tumors.
TACE: Median OS 20–32 months; TACE + Durvalumab + Bevacizumab improves PFS to 15.2 months.
Systemic Therapy (Advanced HCC):
First-line:
Atezolizumab + Bevacizumab (IMbrave150): Median OS 19.2 months.
Durvalumab + Tremelimumab (HIMALAYA): Median OS 16.4 months.
Sorafenib or Lenvatinib (if not candidate for immunotherapy).
Second/Third-line:
Regorafenib: Median OS 10.6 months.
Cabozantinib: Median OS 10.2 months.
Ramucirumab (for AFP >400): Median OS 8.5 months.
Nivolumab + Ipilimumab or Pembrolizumab.

2.5 PROGNOSIS & COMPLICATIONS¶

• Survival by Stage: ◦ Early (0/A): >60 months. ◦ Intermediate (B): ≈25–30 months. ◦ Advanced (C): ≈19 months (immunotherapy) or ≈10 months (TKI). ◦ Terminal (D): <3 months. • Recurrence: 50–70% after resection/ablation; improved by adjuvant atezolizumab-bevacizumab.

2.6 SPECIAL CONSIDERATIONS¶

• Cholangiocarcinoma (CCA) Classification: ◦ iCCA (10–20%): Intrahepatic. ◦ pCCA (50–60%): Perihilar/periampullary. ◦ dCCA (20–30%): Distal common bile duct. • iCCA Management Strategy: ◦ Resectable: Surgical resection + adjuvant chemotherapy (Median survival 43 mo). ◦ Unresectable: Local-regional therapy (TACE, TARE) or Ablation (Median survival 15 mo). ◦ Advanced/Metastatic: Systemic therapies (e.g., Gemcitabine + cisplatin; targeted inhibitors like pemigatinib or ivosidenib).

Reference Tables¶

TABLE 87-1 Molecular Aberrations Common in Hepatocellular Carcinoma (HCC) a PATHWAY Mutations Telomere stability…¶

Harrison's 22e, p.661

PATHWAY	TARGET	PREVALENCE (%)
Mutations
Telomere stability	TERT promoter	56
p53/cell cycle control	TP53 ATM RB1	27 3 3
Wnt/β-catenin signaling	CTNNB1 AXIN1	26 5
Chromatin remodeling	ARID1A ARID2 KMT2A KMT2C	6 7 3 3
Ras/PI3K/mTOR pathway	RPS6KA3 TSC1/TSC2	3 3
Oxidative stress	NFE2L2 KEAP1	3 3
High-level focal amplifications
VEGFA
FGF19
CCND1 protein
Target with homozygous deletion
TP53/cell-cycle control	CDKN2A TP53 Retinoblastoma 1	5 4 4
Wnt/β-catenin signalling	AXIN1	3

TABLE 87-2 Summary of Key Results of Randomized and Cohort Studies in the Management of Hepatocellular Carcinoma¶

Harrison's 22e, p.664

TREATMENT OF EARLY AND INTERMEDIATE STAGE HCC
TREATMENTS	HCC STAGE	TREATMENT ARMS	OUTCOMES (OS)
Treatments for early HCC
Resection	Early	Optimal (single nodule; no portal hypertension)	5-year: 50–70%
		Suboptimal (multinodular or portal hypertension)	5-year: 35–55%
Resection + adjuvant	Early	Adjuvant atezolizumab + bevacizumab vs surveillance	12-month RFS: 78 vs 65%
Liver transplantation	Early	Milan (1 nodule <5 cm, 2–3 nodules ≤3 cm, no MVI, no EHS)	5-year: 70–80%
	Early/intermediate	Downstaged (1 nodule ≤6.5 cm, ≤3 nodules ≤4.5 cm and total diameter ≤8 cm, no MVI, no EHS)	5-year: 60–70%
Ablation	Early	RFA	Median: 50–60 months
Treatments for intermediate HCC
Intermediate	TACE
Intermediate	TACE + durvalumab + bevacizumab
TREATMENT OF ADVANCED STAGE HCC
STUDY NAME	TREATMENT	MEDIAN OS, MONTHS (HR 95% CI)	MEDIAN PFS, MONTHS (HR 95% CI)	ORR mRECIST/RECIST
First-line therapies
IMbrave150	Atezolizumab + bevacizumab	19.2 vs 13.5 (HR 0.66, 0.452–0.85)	6.9 (HR 0.65, 0.53–0.81)	35.4%/29.8%
HIMALAYA	Durvalumab + tremelimumab	16.4 (HR 0.78, 0.65–0.93)	3.7 (HR 0.90, 0.77–1.05)	NA/20%
SHARP	Sorafenib	10.7 (HR 0.69, 0.55–0.87)	10.7 (HR 0.69, 0.55–0.87)	NA/2%
REFLECT	Lenvatinib	13.6 (HR 0.92, 0.79–1.06)	7.4 (HR 0.66, 0.57–0.77)	24.1%/18.8%
Second-line therapies
Regorafenib	10.6 (HR 0.63, 0.5–0.79)	3.1 (HR 0.46, 0.37–0.56)
Cabozantinib	10.2 (HR 0.76, 0.63–0.92)	5.2 (HR 0.44, 0.36–0.52)
Ramucirumab	8.5 (HR 0.71, 0.53–0.95)	2.8 (HR 0.45, 0.34–0.6)