This document summarizes key information about hepatocellular carcinoma (HCC). It discusses the etiology and pathogenesis of HCC. It describes the role of tumor tissue analysis in diagnosing HCC and assessing prognosis. Gross morphology, histological subtypes, and morphological parameters are reviewed. The importance of distinguishing HCC from other nodular lesions and metastases is covered. Biomarkers and the role of liquid biopsies are also mentioned.

1. Topic: Hepatocellular Carcinoma
Moderator: Dr Jatindra Deka
Associate Professor, Dept of Pathology
Tezpur Medical College Hospital
Presenter: Dr Lekhraaj Gautam
PGT3, Dept of Pathology
Tezpur Medical College Hospital

2. Hepatocellular Carcinoma:
It is the most common primary liver tumor with
hepatocytic differentiation.
Its pathogenesis is a multistep process involving the
progressive accumulation of molecular alterations
involving different molecular and cellular events.

4. ETIOLOGY

5. Role of tumor tissue analysis in hepatocellular carcinoma
Diagnostic
Distinguishing HCC from metastasis
Distinguishing benign/preneoplastic lesions from HCC
Diagnosis confirmation of small HCC
Diagnosis of liver nodules in non-cirrhotic background
Diagnosis of atypical variants of HCC, which have atypical
Imaging findings
Combined HCC-CC
Diagnosis confirmation of HCC in trials of new drugs.

6. Role of tumor tissue analysis in hepatocellular carcinoma
Prognostic/theragnostic
Prognostic histomorphological parameters
Identification of Histological variants of prognostic
importance
Tissue biomarkers for prognostication and assessing
presence of therapeutic targets and drug development
Modification of risk/benefit ratio

7. GROSS MORPHOLOGY OF HCC

8. Importance of Gross Pathology
Independent predictor of overall and disease free survival
regardless of tumor size
Lee Y- The clinicopathological and prognostic
significance of HCC- J Pathol transi Med 2017
Study of 242 resected
Infiltrative type- worst prognosis
Vaguely nodular and expanding nodular- More favourable
prognosis

9. Most common patterns in histopathology of HCC
Microtrabecular
pattern: thin tumor
trabeculaes with not
more than ten cells in
thickness
Pseudoglandular
pattern: glandular-
like or acinus-like
structures with
minimal atypia.
Macrotrabecular
Pattern: trabecular
structures with more
than 10 cells in
thickness

10. Hepatocellular carcinoma variants, subtypes
Steatohepatic Sarcomatoid Fibrolamellar
Clear cell Combined HCC-CC Scirrhous

11. Role of morphological parameters and histological subtypes
Macrotrabecular pattern:
 Defined by the presence of a predominant(≥50%) macrotrabecular architecture
 This phenotype is associated with poor prognostic factors like tumor size, AFP level,
satellite nodules and vascular invasion. Also therefore found to be an independent
predictor of early and overall recurrence.
Clear cell HCC:
 Smaller, better differentiated with lower rate of vascular invasion
Sarcomatoid HCC:
 Poorly differentiated subtype
Prognostic information derived from phenotypes re-emphasizes the potential
benefits of Histopathology

12. Role of tissue analysis for small Hepatocellular carcinoma
 Small suspicious nodules are difficult to detect as vascular characteristics and
capsule formation are not completely developed and hence lack typical imaging
characteristics.
 Histopathology evaluation is required in around 60% cases, for early and correct
diagnosis.
 Hepatocellular nodules are classified by the International consensus group as:
●Early HCC: well differentiated, small size <2cm, poorly defined margins,
vaguely nodular type
●Progressed HCC: >2cm, small size <2cm but moderately differentiated,
distinctly nodular type.
Gross morphology of small distinctly nodular HCC and
small vaguely nodular HCC.

13. Pathology based differentiation of HCC from other nodular
lesion found in chronic liver disease such as large regenerative
nodule, low grade dysplastic nodule(LGDN) and high grade
dysplastic nodule(HGDN) is the most important indication of
biopsy.
Biopsy is often recommended for nodules 1.0 cm or larger to
make a differential diagnosis between early HCC and a DN.

14. Dysplastic foci
 By definition, these clusters are <1mm in size and do not
fulfil criteria for malignancy i.e, no invasive growth
 Small cell dysplasia. These are round foci of small dysplastic
cells with an increased nuclear/cytoplasmic ratio. They are
usually seen in cirrhotic livers and also considered
premalignant lesions due to their increased proliferation
index and low rate of apoptosis.

15. Dysplastic nodules
 Dysplastic nodules are defined as being larger than 1mm in size.
 Usually found in cirrhosis and are generally subdivided into low-grade
and high-grade lesions.

16. HGDN vs HCC: Clinical implication
High-grade dysplastic
nodule
Re-biopsy
? Ablation
Hepatocellular
carcinoma
Resection priority for
transplant

17. Small cell change + +
Pseudoglands + +
Trabeculae 1-3 1-3 or >3
Portal tracts + +
Unpaired arteries few few
Reticulin N or focal N or focal
Stromal Invasion - +
HGDN vs Early HCC

18. Stromal invasion in HCC
Earliest morphological feature of HCC
Invasion of neoplastic cells into portal tracts, septa, adjacent
parenchyma or blood vessels
In cirrhotic liver this feature can be difficult to distinguish
from small groups of hepatocytes entrapped within fibrous
septae.
Stromal invasion is difficult to assess in biopsy specimen

19. Ductular reaction and stromal invasion
CK7/CK19(to look for ductular reaction at nodular interface)
HGDN Largely present
HCC Absent(No DR in stromal invasion)
Ductular reaction should be present around 50% of
circumference of nodule and is absent in HCC

20. HCC immunohistochemistry
Hepatocellular differentiation
 Hep Par 1
 Polyclonal CEA
 Glypican-3
 Arginase-1
 Others: AFP, CD10, TTF-1
 CD34- sinusoids
 SMA- unpaired muscular artery

22. Corelate morphologically

23. Hepatic adenoma
The differential diagnosis between HCA and well differentiated HCC
arising in non cirrhotic liver can be challenging, especially when
tumors histologically similar to HCA occur in unusual
clinicopathological settings, such as in a man or an older woman and/or
display cytological or architectural atypia.

24. Combined hepatocellular-cholangiocarcinoma(cHCC-CC)
 Representing 0.4%-14.2% of primary liver cancers
 Aggressive tumor associated with poor outcome.
 Histopathological evaluation is crucial for diagnosis, as this entity lacks
the typical imaging characteristics thus often misdiagnosed by radiology
 In 2011, WHO classified it into classical subtype and subtypes with stem
cell features( intermediate cell type and cholangiolocellular type)
 Study has found CHCC-CC 1yr, 3yr and 5yr overall survival rates of
53%, 26% and 12% respectively, which suggest better prognosis then
CC but worse compared with HCC.
 Knowledge of mixed tumor by biopsy evaluation prior to surgery can
guide the type of resection including the lymph node dissection.

25.  Classical subtype – typical morphology of HCC + biliary
adenocarcinoma
 HCC- IHC: Hep-par1, CD10, pCEA
 Biliary component- DPSA or Mucicarmine stain to show mucin
production. Abundant desmoplastic stroma
 IHC- CK7/19, EMA- Positive

26. CASE:
60 year old Male
Liver lesion
NET? Fibrolamellar HCC?

29. HCC vs Metastasis
 MC primary sites that metastasize into liver are lung, colon, pancreas and
breast.
 The primary tumors resembling HCC are clear cell RCC, Clear cell
adenocarcinoma of female genital tract, adrenal carcinoma, hepatoid
adenocarcinoma of stomach and metastatic NET eith trabecular growth
pattern.

30. Biopsy for Prognostication
Histoprognostic features:
Grading of HCC cellular differentiation
Pathological tumor node metastasis stage
Vessel invasion

32. Macro vascular and Micro vascular(MVI) invasion is the major
predictor of prognosis of HCC and are associated with more advanced
tumor stage, disease progression, local invasion and distant metastasis.
Identification of MVI is feasible only on HPE of resected surgical
specimens.
Distance of embolised vessel from the main tumor has prognostic
significance with 1 cm cut off shown in studies to predict very poor
outcome.
MVI detection helps to identify patients at risk of development of
distant metastasis post resection and guides for the need of adjuvant
therapy.

33. Liquid Biopsy in HCC
A liquid biopsy, which entails the analysis of tumor components
released into the bloodstream, is minimally invasive procedure and
decreases the financial costs and potential complications od tissue
biopsies.
Most of the studies exploring circulating tumor cells(CTCs) in HCC
have shown a direct correlation between higher CTC number and poor
clinical outcome.
In addition, liquid biopsies could provide a valuable tool to overcome
tumor heterogeneity, which is particularly pronounced in multifocal and
advanced HCC, both at genomic and transcriptional level.