Paediatric Hepatocellular carcinoma

1. HEPATOCELLULAR
CARCINOMA
Dr Arka Banerjee
M.Ch. Resident
Paediatric Surgery
MAMC
Moderator: Dr Sujoy Neogi

2. INTRODUCTION
 Ishak and Glunz [1967]
 1st identified childhood HCC as a separate entity
 Exelby [1974]
 Analysed clinical course
 Dismal outcome
 Is classical (adult-type) HCC in the pediatric age group the same or a different
disease with respect to HCC in adult patients?
 Is it a variant of adult-type HCC?
 Its a tumor family
 Fibrolamellar variant of adult-type HCC
 A novel entity occurring in older children and young adolescents, transitional liver cell tumor
(TLCT)

3. EPIDEMIOLOGY
 2nd MC (19-23%) paediatric liver
tumor
 Peak incidence at 10-15 yrs age
 > ⅔ occur in children older than
10yrs
 Very rare in < 5yrs age group
 0.5-1% of HCCs manifest before
20yrs age
 M > F [3:1]
 20-35% have an underlying chronic
liver disease

5. PRESENTATION
 Abdominal mass/pain
 Nausea/vomiting
 Anorexia/malaise
 Wt loss
 Hemoperitoneum d/t tumor rupture (10%) – catastrophic
 Hypovolemic shock
 Acute RUQ pain
ꝶ – Trans arterial embolization after stabilization of pt f/b early resection
 Most commonly, multinodular

6. LABORATORY STUDIES
 ed AST, LDH
 ed AFP (50-70%)
 Indicates ed recurrence risk poor prognosis
 Mildly elevated/Normal in FL variant

7. BIOPSY
 Complications
 Hemorrhage
 Tumor seeding
 Uninvolved liver segment
 Abdominal wall
 Peritoneal cavity
 Molecular biology
 Mutation of c-met proto-oncogene
 Low levels of cyclin D1 expression
 LOH of Chr 13q

8. IMAGING
 CT/MRI
 Non-invasive diagnosis of HCC – In nodules < 2 cm diam in cirrhotic livers, the
diagnosis of HCC can be made without biopsy of the lesion if two coincidental dynamic
imaging studies (e.g., CT/MRI) reveal arterial-phase hypervascularity followed by wash-
out in the portal venous phase + unequivocal rise in AFP
 FL-HCC
 Hypodense, single or multilobed mass on CT that tends to be hypervascular;
sometimes showing a central scar [D/D: FNH]

9. PATHOLOGY
 Gross
 Solitary
 Expanding (or pushing) mass lesions
 Pedunculated (or hanging) lesions
 Invading tumors with poor delineation
 Multiple/multifocal
 Microscopy
 Trabecular growth pattern with
intervening sinusoid-like vascular
channels and a reduced reticulin
network

10. MICROSCOPY
 The larger trabeculae display central necrosis
 Large pleomorphic cells with nuclear
hypochromasia and frequent and bizarre mitosis
 Surrounding liver exhibits cirrhosis in upto 60%
cases
 As the tumor enlarges, its blood supply becomes
more dependent on newly formed arterial vessels
and less dependent on the portal circulation. This
imbalance between the hepatic arterial and portal
venous supply leads to the hypervascular pattern
that is the radiologic hallmark for HCC

11. GRADING

12. GRADING
 Modified Edmondston-
Steiner grading criteria

13. FIBROLAMELLAR HCC
 < 10% of all HCCs [15-50% of HCCs in  20 yr age group]
 Arises in noncirrhotic livers of adolescents or young adult patients
 Biologically similar to adult-type HCC
 Vascular invasion (upto 35% of cases)
 Metastasizes into locoregional lymph nodes (~50%)
 Tends to show unusual spreading patterns, including intraperitoneal spread
 Solitary lesion
 Predilection for left lobe (unusual for primary hepatic lesions)
 Slow growth

14. FIBROLAMELLAR HCC
 Well-defined margins with central scar (70%)
 Gross – cut surface shows firm, tan to brown tissue with radiating
septa, resembling FNH
 Microscopy
 The leading cell is a large and polygonal, hepatocyte-like cell with a granular
cytoplasm of large vesicular nuclei
 These cells form strands embedded in the typical fibrosclerotic stroma that
may form a central stellate scar
 Pale bodies – large, ground glass–like inclusions helpful in bioptic diagnosis
 PAS-positive globular inclusions contain alpha-1-antitrypsin and other
glycoproteins
 Cells show marked immunostaining for cytokeratin 7

15. TRANSITIONAL LIVER CELL
TUMOR
 Intermediate position of the tumor cells between hepatoblasts and more
mature hepatocyte-like cells
 Large solitary tumor
 Right lobe
 Associated with very high serum AFP levels
 Highly aggressive
 Expanding growth pattern
 Gross - Large central necrosis
 Microscopy
 The tumor cells vary between HCC-type cells and cells found in hepatoblastoma, sometimes
with formation of multinuclear giant cells
 Marked expression of beta-catenin, typically in a mixed nuclear and cytoplasmic pattern

16. STAGING
 COG recommendation
 Staging same as hepatoblastoma
 No risk stratification
 Extent of tumor involvement of the liver based upon PRETEXT
 Aids in decision-making regarding surgical resectability

19. TREATMENT STRATEGY
 Complete surgical resection – gold standard
 Main prognostic factor – Resectability
 Primary radical tumor resection has to be attempted whenever possible
 Sampling of LNs from HDL is mandatory as it has a significant impact on
prognosis
 Recurrence – 20-65%
 Primary resection not always possible [10-20% are resectable at
diagnosis]
 Advanced at diagnosis
 Bilobar tumor
 Extensive hepatic resection risks leaving the patient with insufficient FLR

20. PROGNOSTIC FACTORS
 Tumor size(< 2 cm)
 No of tumor nodules
 Histologic increase in tumor microvascular density
 Fibrolamellar variant [No survival benefit in children]
Slow growth
Non-cirrhotic liver
 Child-Pugh class
 Elevated angiogenic markers [VEGF, bFGF]

21. PROGNOSIS
 Very poor prognosis
 Relapse-free survival → 25-30%
 Chemoresistant
 Advanced at diagnosis
 No improvement in outcome despite progress in surgical
techniques, chemotherapy delivery and patient support
 Childhood FL-HCC
 Similar resection rates
 5-yr EFS – 30% [Longer median survival]

22. SURVIVAL
 5-yr EFS
 Stage I/II (with complete, microscopically-free radical resection) – 80%
 Stage III – 23%
 Stage IV – 10%
 Overall – 14-18% [All long term survivors had complete tumor excision]
 Adjuvant chemotherapy may have a role after ‘complete resection’
[Stage I/II]
 Current consensus: Routine use of chemotherapy with cisplatin and doxorubicin
may benefit children with completely resected HCC
 NACT to improve resectability?
 Partial response noted in 45-50%
 No RCTs

23. LIVER TRANSPLANT
 Survival – 53-89% [after primary OLT]
 Indications
 Multifocal PRETEXT IV
 Unifocal PRETEXT IV (who do not downstage to POSTTEXT III after NACT)
 Intrahepatic relapse/residual tumor (Rescue transplantation)
 Contra-indications
 Metastatic disease (Extrahepatic spread/Angioinvasion)
 Tumor progression on chemotherapy
 POSTTEXT III +V
 POSTTEXT III +P

24. MILAN CRITERIA
 Criteria for LT in adult HCC
 Single tumor <5 cm diam.
  3 foci of tumor, each one  3 cm.
 No angioinvasion
 No extrahepatic involvement

25. MILAN CRITERIA
 Use in children ?
 50% to 70% of children present with large de novo tumors
 Large tumor burden in otherwise healthy livers
 Milan criteria were developed in adults with small tumors and underlying cirrhotic liver
disease
 No. of nodules not considered a c/i to transplantation in children as long as the disease is
confined to the liver
 TLCT have a favourable biology compared to adult HCC
 Adherence to Milan criteria is not recommended in children who present with large de novo
tumors, no cirrhosis, and no evidence of extrahepatic disease
 Criteria for LT in pediatric HCC
 Unilobar tumor
 Tumor < 2 cm
 No angioinvasion

26. NEWER TREATMENT MODALITIES
 Anti-angiogenesis
 Chemo-embolization
HACE/TACE
Theraspheres
 Portal venous embolization
 Percutaneous ablation
RFA
PEI
Cryotherapy

27. ANTI-ANGIOGENIC THERAPY
 Sorafenib
 Indications
 Post-transplant adjuvant therapy
 Pts with high risk for tumor relapse
 Advantages
 Broad spectrum of activity
 Decreased resistance (as endothelial cells are genetically stable)
 Improved drug access to targets
 Tolerable side effects
 Combination of angiostatic agents has better effect
 Purely cytostatic action and hence, should be combined with cyttoxic
chemotherapy for maximum effect

28. METRONOMIC CHEMOTHERAPY
 For optimal effect, anti-angiogenic treatment has to be given in small doses
at frequent intervals to avoid recovery of endothelial cells from therapy insult
 Effective in treating tumours in which cancer cells have developed resistance
to the chemotherapeutics
 Less acutely toxic, therefore making more prolonged treatments possible
 Some metronomic-chemotherapy regimens induce sustained suppression of
circulating endothelial progenitor cells and increase the levels of the
endogenous angiogenesis inhibitor thrombospondin 1, both of which can
suppress neovascularization

29. CHEMO-EMBOLIZATION
 Intra-arterial administration of
 Chemotherapeutic and vascular occlusive agents (Gelatin or Lipiodol)
 Along with cytotoxic drugs (Doxorubicin/Mitomycin/Cisplatin)
 MOA
 Intra-arterial injection of cytotoxic agents results in higher local concentration of
drugs with reduced systemic side effects
 Intra-arterial embolization causes ischemic necrosis of the tumor

30. CHEMO-EMBOLIZATION
 Uses
 As bridge therapy till a donor is available
 Neo-adjuvant therapy to facilitate tumor resection/transplantation
Multinodular tumors or large tumors not responding to systemic chemotherapy are the best
candidates provided there is preserved liver function without any vascular invasion or
extrahepatic spread
 Disadvantage
 Acute liver failure
 Does not improve survival

31. THERASPHERES
 Combined Radiotherapy + Angioembolization
 Intra-arterial injection of Yttrium-90 radioactive microspheres

32. PORTAL VENOUS EMBOLIZATION
 To induce hypertrophy of the remaining liver remnant
 Experimental use in children
 Procedure
 Portal venous branch on the side of the tumor is cannulated percutaneously and polyvinyl
alcohol and coils are inserted to induce portal vein occlusion under fluoroscopic control
 MOA (Dual effect)
 Alcohol thrombosis of the embolized tumor
 Compensatory hypertrophy of the unharmed opposite liver lobe, increasing the potential
hepatic functional reserve in preparation for hepatic resection

33. PERCUTANEOUS ABLATION
 RFA [Radiofrequency Ablation]
 90% complete tumor necrosis
 Contraindicated in lesions located adjacent to the major biliary ducts or bowel loops
 PEI [Percutaneous Ethanol Injection]
 80% complete tumor necrosis
 Requires more sessions than RFA
 More side effects
 Cryotherapy
 Cold injury produced by cryoprobe delivery of liquid nitrogen
 Inferior results compared to RFA and PEI

34. PERCUTANEOUS ABLATION
 Uses
 Palliative therapy for smaller tumors (< 3-4 cm diam)
 Advantages
 Low risk
 Repeatable
 Do not damage non-neoplastic tissue (esp important in cirrhotic livers)
 Combination of techniques can be applied
 Complications
 8-9%
 Pain, fever, bleeding
 Tumor seeding
 Gastrointestinal perforation

35. What to do with a HCC child??
 Admit
 Routine investigations
 Tumor markers
 Imaging
 ?NACT (based on stage and resectability)
 Plan for surgery (Complete resection)
 Chemotherapy (based on institutional protocol)
 Put name on transplant list early in the treatment to prevent delays and unwanted
extended chemotherapy while awaiting resection and transplantation

36. THANK YOU