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Semelhante a Updates in Hepatocellular Carcinoma Subtypes and Diagnosis
Semelhante a Updates in Hepatocellular Carcinoma Subtypes and Diagnosis (20)
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Updates in Hepatocellular Carcinoma Subtypes and Diagnosis
- 1. Updates in Hepatocellular Carcinoma
- 2. Updates in Hepatocellular Carcinoma
- 3. Epidemiology • 5th most common • 3rd cancer-related death
- 4. Clinical Features and Etiology • Effects of the mass or signs and symptoms of underlying chronic liver disease, abdominal enlargement and hepatomegaly with or without a palpable mass. • Signs of decompensated liver disease, such as jaundice, ascites, variceal haemorrhage, hepatic encephalopathy or obstructive jaundice. • High levels of serum alpha fetoprotein (AFP) • CT and MRI are the most common modalities • Enhancement in the arterial phase of imaging and hypointesity compared with surrounding liver in venous phase. Risk Factors Cirrhosis Viral Hepatitis: HBV, HCV Aflatoxin B1 Alcohol Metabolic syndrome, NASH Inherited Metabolic syndrome Others: Anabolic steroids and contraceptives
- 5. HBV and HCC
- 6. Wnt- B catenin Pathway Transcriptional activation of several downstream target genes, one of which is GLUL, which codes for glutamine synthetase
- 7. HCV and HCC Robbin’s 10th ed
- 8. NASH and HCC
- 11. Molecular Changes in Multi-step Carcinogenesis
- 12. Dysplastic Foci • <1mm in size Small Cell Change Large Cell Change Iron Free Foci
- 13. Dysplastic Nodules Low Grade Dysplastic Nodule
- 14. Dysplastic Nodules High Grade Dysplastic Nodule
- 15. Non-triadal arteries Sinusoidal Capillarisation LG Nodule HG Nodule Early HCC Progressed HCC
- 16. Small HCC measures less than 2.0 cm in diameter.
- 17. Early HCC Progressed HCC
- 18. Role of Biopsy • Needle-tract seeding of HCC may deter liver biopsy; incidence varying in the between 0% and 7.69%, with a median of 2.7%.
- 20. HSP 70 Glypican3 Glutamine synthetase Application of a panel of these 3 markers had 100% specificity and 72% sensitivity in detecting well diff HCC.
- 22. • 242 cases consecutively resected solitary primary HCC • Gross classification an independent predictor of both overall and disease-free survival by multivariate analysis • Infiltrative type had the worse prognosis whereas vaguely nodular and expanding nodular had a better prognosis.
- 24. Tumor focality Size of nodules Macrovascular invasion • Less than 2 cm distant from the main tumor should be categorized as “satellite nodules” • Arise within the drainage area of the larger nodule and typically represent intrahepatic metastasis • Solitary nodules that are far from the main tumor are typically synchronous in origin, better differentiation. • Patients with intrahepatic metastases have worse outcome, poor histological differentiation and similar mutation profile.
- 27. • Suggested that for a tumor with specific morphologic variation to qualify for a subtype 1. The tumor should have reproducible microscopic pattern throughout 2. Immuno-histochemical and molecular tests that help in the subcategorization of the tumor preferably be available
- 30. • micro- trabecular pseudoglandular pattern. • Poor differentiation • Activation of angiogenesis with ANGPT2 upregulation • Areas of compact histology, sarcomatous pattern • High AFP, adverse clinical outcome.
- 31. Gluconeogenisis, Urea Synthesis Lipogenesis, Glycolysis Ng CKY, Piscuoglio S, Terracciano LM. Molecular classification of hepatocellular carcinoma: The view from metabolic zonation. Hepatology. 2017;66(5):1377-1380. doi:10.1002/hep.29311
- 32. CTNNB1 Mutated HCC Calderaro J, Couchy G, Imbeaud S, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017; • 343 surgically resected HCC • 2 groups- p53 and CTNNB1 • CTNNB1 mutations in 40% • CTNNB1 mutations define a specific cholestatic well- differentiated subtype of HCC
- 34. Glutamine synthetase staining was classified into one of three patterns: (a) diffuse homogeneous: moderate to strong cytoplasmic staining in more than 90% of lesional cells, without a map-like pattern, (b) diffuse heterogeneous: moderate to strong staining in 50– 90% of lesional cells, without a map-like pattern, (c) patchy: moderate to strong staining in <50% of lesional cells (often perivascular), weak staining irrespective of extent, and all other staining patterns • due to missense mutation or small in-frame insertion or deletions in exon 3 of the CTNNB1 gene,
- 35. Steatohepatitic HCC • Alcoholic or non-alcoholic steatohepatitis, • G4 subclass, which is known to share a gene expression profile similar to that of non-tumour liver • Upregulation of interleukin-6, a key regulator of JAK STAT pathway • Inflammatory infiltrates, cell ballooning peri-cellular fibrosis and Mallory-Denk bodies
- 37. Attenuated reticulin in SH
- 38. Macrotrabecular Massive HCC • Novel subtype: 10% of all tumours • Predominant (50%) macrotra-becular growth pattern • TP53, ATM mutations, FGF19 amplifications,ANGPT2 • Progenitor phenotype (CK19 +) • Exhibits aggressive phenotype, with frequent satellite nodules and macrovascular and/or microvascular invasion • Early tumour relapse, poor overall survival (>10 cells thick)
- 39. ESM1 staining helped to identify the macrotrabecular architecture of HCC, by revealing the sinusoidal stromal cells surrounding the macrotrabeculae.
- 40. Fibrolamellar Subtype • Younger patients, <5% • Non cirrhotic background • large polygonal cells with oncocytic cytoplasm and prominent nucleoli separated into trabec-ulae and cords by dense parallel bands of collagen • Activation of protein kinase A, most commonly as a result of the DNAJB1- PRKACA fusion transcript.
- 41. Scirrhous Subtype • 5% of tumour types • Abundant, dense fibrous stroma in which clusters of neoplastic cells are embedded • Genetic studies have highlighted TGF-β signalling • TSC1/TSC2 mutations • Expression of stem cell markers- CK7, CK19 • Poor sensitivity for Hepar-1 D/D • Fibrolamellar HCC • Intra hepatic cholangiocarcinoma
- 42. Hepar1 CD68 CK7
- 43. Lymphoepithelioma like Subtype • <5% of tumour types, chronic HBV or HCV • Large undifferentiated epithelial cells with a predominant lymphoplasmacytic component. • T cells predominant, with a uniform distribution of CD4 and CD8 (>) positive cells • Cholangiolar differentiation seen by K19 positivity. • Not associated with chromosomal instability • Better prognosis- dense lymphocytic infiltrate reflects effective of antitumour immunity
- 44. Clear Cell type Subtype Clear cell HCC showed higher frequency of IDH1 mutation rate than other variants of HCC. Presence of IDH1 mutation was related with poor survival in clear cell HCC patients • >80% of tumour shows clear morphology • Glycogen accumulation • Steatosis may also be seen. • No molecular alteration detected • Better prognosis
- 45. Chromphophobe Subtype • Association with HBV (50% of cases) • 5% of HCC cases • Cases of chromophobe hepatocellular carcinomas with abrupt anaplasia found that they were positive for the ALT phenotype
- 47. Combined hepatocellular-cholangiocarcinoma Subtype • Unequivocal presence of hepatocytic and cholangiocytic differentiation within the same tumour regardless of percentage of each component- IHC alone not sufficient. • Bidirectional differentiation potential of both hepatocytes and biliary epithelium • Post trans-arterial chemo-embolization.
- 48. Combined hepatocellular-cholangiocarcinoma Subtype • EpCAM, CD56, CD117, CD133- Markers of stem cell differentiation • latest (5th) edition9 published in 2019 omits the subcategorization • “stem cells” may potentially be found in all forms of cHCC-CCA. • Not necessary to subtype cHCC- CCA, but recommended mentioning “stem/progenitor cell features present” in the comments, when it is observed. Komuta M, Yeh MM. A Review on the Update of Combined Hepatocellular Cholangiocarcinoma. Semin Liver Dis. 2020
- 49. Brunt E, Aishima S, Clavien PA, et al. cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation. Hepatology. 2018 • Monotonous morphological features intermediate between those of hepatocytes and cholangiocytes at the cellular level • Diagnosis reserved for PLC in which such features are present in the entire tumour.
- 50. Vyas M, Jain D. A practical diagnostic approach to hepatic masses. Indian J Pathol Microbiol. 2
- 51. Arg-1 Hep Par-1 GPC-3 p-CEA IHC
- 52. Albumin ISH • Branched chain albumin ISH offers a robust means of detecting a tumor of liver origin, and is particularly valuable when confronted with a poorly differentiated HCC. However, the assay cannot distinguish HCCs from intrahepatic cholangiocarcinomas.
- 53. Nguyen T, Phillips D, Jain D, et al. Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiatio for the Diagnosis of Hepatocellular Carcinoma. Arch Pathol Lab Med. 2015;139(8):1028-1034. D/D Well differentiated D/D Poorly differentiated Arginase-1 and Hepar-1 – highest sensitivity HSP-70, GS, GPC-3 Arginase-1 and Glypican -3 sensitivity >80% CK 19- r/o cholangiocarcinoma >50% Arginase
- 54. ARGINASE-1 CK-19Two stain approach Arg-1+, CK-19- Arg-1-, CK-19+ Arg-1+, CK-19+ Arg-1-, CK-19- • Adenocarcinoma with aberrant Arg-1 positivity (rare) • Combined HCC-cholangiocarcinoma • HCC with stem cell features- GPC-3 to rule out HCC Choi WT, Kakar S. Immunohistochemistry in the Diagnosis of Hepatocellular Carcinoma. Gastroenterol Clin North Am. 2017
- 55. Arg-1-, CK-19+
- 56. Arg-1-, CK-19-
- 57. CK19 BAP1 Intra-hepatic cholangiocarcinoma Arginase-1 Negativity for the hepatocytic markers (HepPar1 antigen, Arg1 and GPC3, AFP, CD10, and pCEA) helps distinguish CC from HCC.
- 58. Vascular Invasion • Includes gross as well as microscopic invasion of vessels. • Macroscopic venous invasion is generally accompanied by microscopic invasion.Both - lower survival. • Microscopic vascular invasion is defined by tumor within a vascular space lined by endothelium, identified only on microscopy in the capsule or noncapsular fibrous septa, or liver tissue surrounding the tumor. • Different studies have graded MVI based on the number of vessels invaded Distance of embolized 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
- 59. Tertiary Lymphoid Structures • Intra-tumoral TLS are associated with a lower risk of early recurrence after surgical resection for HCC. • TLS located within the tumors may contribute to effective anti-tumoral immune responses by promoting local antigen presentation and lymphocyte differentiation.
- 60. Molecular targeted therapies Sorafenib, Regorafenib show anti-tumoral activity by blocking various receptor tyrosine kinases of the growth factors, including VEGF, PDGF, and c-Kit Everolimus Selumetinib Pembrolizumab, an anti-PD-1 monoclonal antibody, Anti-Angiogenic Agents mTOR Inhibitors MEK Inhibitors Immunotherapy
- 61. Biomarkers • Annexin A2 is significantly increased in the serum of patients with HCC when compared to patients with chronic liver disease • Additional biomarkers, such as osteopontin, Golgi protein-73, squamous cell carcinoma antigen, soluble urokinase plasminogen activator receptor, thioredoxins, multifucosylated α-1-acid glycoprotein, • Vascular endothelial growth factor, angiopoietin, survivin and alpha-1 antitrypsin, have shown potential for diagnostic and/or prognostic utility.
- 62. SUMMARY • HCC displays a high degree of molecular and histological heterogeneity. • Morphological subtypes of hepatocellular carcinoma are strongly associated with tumour subclasses and gene mutations • Development of a morpho-molecular classification - improve precision medicine for patients with this highly aggressive malignancy. • Although unlike lung or colorectal cancer, this increasing knowledge has not yet resulted in biomarker discovery and improved clinical care. • Integrative pathological and molecular studies should be encouraged with the aim of defining a consensus HCC morpho-molecular classification that could be used in ongoing therapeutic trials
Notas do Editor
- Highest rates are seen in Asia and Sub-Saharan Africa, where chronic viral hepatitis B infection and aflatoxin B are major risk factors North America and Western Europe, viral hepatitis C obese patients and patients with the metabolic syndrome are at increased risk for fatty liver disease and associated liver damage, Sixfth most frequent cancer worldwide and fourth highest cause of cancer-related death Accounts for 75-85% of primary liver cancers
- including upper abdominal pain, weight loss, Rarely, patients may present with distant metastases or paraneoplastic syndromes such as hypoglycaemia, erythrocytosis, hypercholesterolaemia, hypercalcaemia, isosexual precocious puberty (in children), gynaecomastia (in the absence of cirrhosis), carcinoid syndrome, hypertrophic pulmonary osteoarthropathy, osteoporosis, hypertension, hyperthyroidism, dysfibrinogenaemias, porphyria cutanea tarda and a variety of other cutaneous changes. ), an oncofetal antigen, can help in the screening, diagnosis and follow-up of HCC
- everal separate signalling pathways are deregulated in HCC including the Wnt/FZD/β-ca- tenin, PI3K/Akt/mTOR, insulin receptor substrate 1 (IRS1)/ insulin-like growth factor 1 (IGF), and the Ras/Raf/ mitogen-activated protein kinases (MAPK
- oxidation is often used by cancer cells to generate energy, exces- sive fatty acid oxidation due to high intracellular fat levels can lead to metabolic stress and eventually lipotoxic cell death, e.g. ballooning degeneration [5]. In patients with NASH, extremely high levels of fatty acids from dietary intake and lipolysis of vis- ceral adipose tissue can lead to lipotoxic hepatocyte death. This lipotoxic effect is an important promoter of NASH-associated HCC, and thus, HCC must adapt in order to survive in such a lipid-rich environment. In mouse models, the downregulation of carnitine palmitoyltransferase 2 (CPT2), the rate-limiting en- zyme of fatty acid oxidation, has been associated with lipotoxic- ity-resistant HCC cells and the accumulation of acylcarnitine [5, 15]. The resulting excessive accumulation of acylcarnitine was found to enhance STAT3 activation, thereby promoting hepato- carcinogenesis via the IL-6/STAT3 pathway [5]. Alternatively, SH-HCC arising in patients with non-ste- atotic chronic liver diseases may acquire steatohepatitic fea- tures secondarily to an inflammation-induced metaplastic phe- nomenon rather than an adaptation to high levels of fatty acids. A molecular study undertaken by Calderaro et al demonstrated that although the morphologic features of SH-HCC suggest dysregulation of metabolic pathways, no significant mutations were identified in genes associated with fatty acid synthesis, glycogenesis or neoglucogenesis [16]. However, an associa- tion was identified between the SH-HCC phenotype and acti- vation of the IL6/JAK/STAT3 pathway and C-reactive protein (CRP) immunohistochemical expression [16]. One interesting and important question that remains to be determined is the existence of a potential intermediate lesion or step that lies between non-neoplastic liver and SH-HCC such as a steatohepatitic adenoma or steatohepatitic dysplasia. One recent report suggested an association between inflammatory hepatocellular adenoma and sonic hedgehog hepatocellular ad- enoma with higher body mass index (BMI) [17]. Additional research is needed to answer this clinically and conceptually important question. A simple diagram outlining potential steps in the tumorigenesis of SH-HCC in NAFLD and other chronic liver diseases is illustrated in Figure 3.
- everal immunosuppressive molecules are released from cancer cells and contribute to the establishment of immunosuppressive tumor environ- ment
- Archives of pathology
- Stromal invasion by tumor cells. Invasive tumor nests within fibrous septa and portal tracts in surgical resection (A) and liver biopsy (B). Stromal invasion should be considered when isolated nests of abnormal-looking hepatocytes are noted within a portal tract or fibrous septa (arrows). Invasive tumor nests are not surrounded by a ductular reac- tion as shown in Fig. 33-8A (right) after CK7/19 immunostaining. (c) High-grade dysplastic nodule bordered by a florid CK7/19-positive ductular reaction. (D) Invasive tumor nests in liver biopsy without ductular reaction (CK7/19 immunostaining).(e) In this ambiguous biopsy field, ductular reaction is documented by CK7/19 immunostaining and is diagnostically helpful to exclude stromal invasion
- Small HCC that are less than 2 cm distant from the main tumor are satellite nodules. These arise within the drainage area of the larger nodule and typically represent intrahepatic metastases. Moderate or poor histological differentiation and similar mutation profile compared to the main lesion. Solitary nodules that are far from the main tumor are typically synchronous in origin. They tend to show lower histo- logical grades (better differentiation) and share less molecular events with the main nodule. The distinction between synchronous tumors and intrahe- patic metastases has impact in patient prognosis. Intrahepatic metastases have worse outcome than those with synchronous tumors Intrahepatic metastasis has varying degrees of vascular invasion, while MO has no obvious vascular invasion
- Ng CKY, Piscuoglio S, Terracciano LM. Molecular classification of hepatocellular carcinoma: The view from metabolic zonation. Hepatology. 2017;66(5):1377-1380. doi:10.1002/hep.29311
- First described by Salomao et al in 2010 first recognized in ex- plant livers with chronic HCV infection Other associations are NASH and alcoholic steatohepatitis, metabolic syndrome. Usually well differentiated, belong to G4 subclass and share gene expression profile of non tumour liver. Characterised by upregulation of interleukin-6, a key regulator of JAK STAT pathway and overexpression of CAA on IHC. hallmark histological fea- tures of alcoholic or non-alcoholic steatohepatitis, namely inflammatory infiltrates, cell ballooning peri-cellular fibrosis and Mallory-Denk bodies This case of steatohepatitic HCC has a yellow colour due to intratumour steatosis. (D) Steatohepatitic HCC shows hallmark features of alcoholic or non-alcoholic steatohepatitis, with ballooned cells (black arrows), Mallory-Denk bodies and steatosis firmer and more golden-yellow in color compared to other HCC variants due to the relatively greater degree of fibrosis and steatosis [7]. Tumors are nodular, well-demarcated and range in size from 0. inflammatory infiltrates, cell ballooning, peri-cellular fibrosis and Mallory-Denk bodies
- Regardless of associated cytological features
- Inhibition of ESM1 or other key regulators of angiogenesis also upregulated in MTM-HCC, such as ANG2 (angiopoietin 2) or VEGFA (Vascular Endothelial Growth Factor A), has been shown to have strong anti-tumor effects in Morphological features and ESM-1 immunostaining of HCC in liver biopsy samples. A) This is a characteristic morphological aspect of MTM- HCC, with large trabeculae (>6 cells thick) separated by large empty spaces (left panel, HES, X200). ESM-1 shows a nearly continuous staining of stromal endothelial cells (right panel, X400). B) Microscopic examination of this MTM-HCC shows foci of clear cells (left panel, HES, X100). Stromal cells display ESM-1 expression (right panel, X400, higher magnification at bottom right). C) The macrotrabecular architecture of this sample is more difficult to diagnose on this HES section, because macrotrabeculae are closely packed together (left panel, HES, X200). F) ESM-1 staining however helps to identify the macrotrabeculae by lining their shapes (right panel, X200). G) This is an example of a non-MTM-HCC, classified as steatohepatitic HCC (left panel, HES, X200). H) No ESM-1 positive e
- unencapsulated solitary mass that ranges from 5 to more than 20 cm. On cut section, the tumor is gray to brown with scalloped bor- ders, and it has a solid consistency Prominent fibrous septa large solitary heterogenous mass with central scar and the background noncirrhotic liver. as a result of a microdeletion on chromosome 19, leading to a fusion between the DNAJB1 gene promoter and the PRKACA gene, which encodes a catalytic subunit of protein kinase A.
- mmunohistochemistry (IHC) for fibrolamellar carcinoma. A, HepPar-1 IHC shows strong diffuse cytoplasmic staining. B, CD68 IHC shows diffuse weak to moderate granular cytoplasmic staining. C, CK7 IHC shows strong diffuse cytoplasmic staining (original magnifi- cations 3200 [A through C]). CD68, a transmembrane protein expressed in lysosomal and endosomal organelles prominent in macrophages, is char- acteristically expressed in FLCs.
- differentiated, composed of atypical cells with syncytial cytoplasm and nuclei with prominent nucleoli, and infiltrated by abundant lymphocytes
- A rare variant of primary hepatic cancer Reported incidence of this tumor varying between 0.4 and 4.7% Unequivocal presence of both hepatocytic and cholangiocytic differentiation within the same tumour Signs of HCC differentiation would include bile production and bile canaliculi as well as a pseudoglandular or trabecu- lar growth pattern, whereas signs of CC differentiation would include mucin-producing biliary epithelium forming true glan- dular structures surrounded by desmoplastic stroma Biliary cell stains include mucin, CK7, and CK19, while hep- atocellular stains comprise polyclonal CEA, Hep Par 1, and CD10
- Arg-1 shows diffuse cytoplasmic and nuclear staining, and it is the most sensitive and specific marker of HCC (original magnification 200). (B) Hep Par-1 demonstrates a diffuse cytoplasmic granular staining pattern (original magnification 200). (C) GPC-3 has high sensitivities for poorly differentiated HCC and scirrhous HCC, and it shows a diffuse cytoplasmic, membranous, or Golgi expression pattern (original magnification 200). (D) HCC shows a distinct canalicular staining pattern with pCEA (original magnification 200).
- LSs are defined as lym- phoid aggregates that form in non- haematopoietic organs in response to chronic inflammatory processes. Their role is to stimulate the in situ immunity by generating plasma cells and effector T cells. Interestingly, the impact on outcome was linked to the type of TLSs, with wer risk of relapse for tumours that bear full functional, mature TLSs (primary/secondary folli- TLS located within the tumors may contribute to effective anti-tumoral immune responses by promoting local antigen presentation and lymphocyte differenciation. This conventional HCC is infiltrated by numerous TLSs (white arrows, HES, 35). (B) High magnification of a TLS harbouring a germinal centre (HES, 130), an area where B cells proliferate, differentiate and undergo mutational processes involving antibody genes (200). (C) A focal, membranous expression of PD-L1 by neoplastic cells is observed in this progenitor HCC (400). (D) This lymphoepithelioma-like HCC is infiltrated by numerous PD-L1 expressing inflammatory cells (black arrows, 200). HCC, hepatocellular carcinoma; HES, hematein-eosin-saffron; TLS, tertiary lymphoid structure.
- Most HCC lack druggable genetic alterations, immunomodulating therapies are likely to play a significant role PDL1 Immunohistochemistry for PDL1 blocking agents
- vDCP is an abnormal prothrombin molecule induced by vitamin K absence (PIVKA II) and posttranslational carboxylation machinery is known as DCP. DCP is an abnormal prothrombin molecule overproduced in HCC patients AFP is a common biomarker for the diagnosis and surveillance for HCC
- Macrotrabecular-massive and progenitor subtypes are linked to adverse clini- cal outcomes.