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Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 112-120
An update on subtypes of hepatocellular carcinoma: From morphology to molecular

1 Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2 Department of Pathology, Yale School of Medicine, New Haven, CT, USA

Click here for correspondence address and email

Date of Submission20-Jun-2020
Date of Decision29-Jul-2020
Date of Acceptance30-Aug-2020
Date of Web Publication7-Jun-2021


The morphologic spectrum of hepatocellular carcinoma (HCC) is quite broad. While in about one-third of cases, the neoplasms can be categorized into meaningful subtypes based on morphology, a vast majority of these neoplasms are morphologically heterogeneous. With extensive tumor profiling, data has begun to emerge which can correlate specific morphologic features with underlying molecular signatures. A true morphologic subtype not only has reproducible H & E features, further supported by specific immunohistochemical or molecular signatures, but also has specific clinical implications and prognostic associations. Eight such morphologic subtypes are recognized by the 2019 WHO classification of tumors with a few more additional subtypes described in the literature. The goal of this review is to familiarize the reader with the morphologic subtypes and elaborate on the clinical and molecular associations of these neoplasms.

Keywords: Carcinoma, hepatocellular, molecular, subtypes

How to cite this article:
Vyas M, Jain D. An update on subtypes of hepatocellular carcinoma: From morphology to molecular. Indian J Pathol Microbiol 2021;64, Suppl S1:112-20

How to cite this URL:
Vyas M, Jain D. An update on subtypes of hepatocellular carcinoma: From morphology to molecular. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Sep 21];64, Suppl S1:112-20. Available from: https://www.ijpmonline.org/text.asp?2021/64/5/112/317923

   Introduction Top

Hepatocellular carcinoma (HCC) is the malignant neoplasm of hepatocytic lineage and its diagnosis requires good clinical and radio-pathological correlation. While histologic confirmation is not always necessary for the diagnosis, it is important to realize that HCC shows considerable heterogeneity and a wide spectrum of morphology that can lead to diagnostic challenges and pitfalls. Thus, it is important to recognize this morphologic spectrum. Proper sub-classification of HCCs into various sub-types not only requires identification of distinct morphologic features, but also associated molecular alterations and its clinical significance. Massive parallel sequencing of HCC has given invaluable insights into the genomic underpinnings of HCC.[1],[2] A by-product of such studies has been a significantly improved understanding of various molecular alterations and their association with certain specific morphologic features.[3] These recent advances in the field have led to the recognition of new HCC sub-types which have now been included in the 2019 WHO classification of liver tumors.[4] The focus of this review is to elaborate on the morphologic subtypes of HCC which will help the readers to recognize these subtypes in their routine practice.

   Subtypes of Hepatocellular Carcinoma Top

HCC, as mentioned above, has a morphologic spectrum with different growth patterns and cytologic features with frequent morphologic heterogeneity. The major architectural growth patterns include trabecular, solid, pseudo-glandular (acinar), macrotrabecular, and diffuse. The cytologic features that can be seen in HCC include cytoplasmic fat vacuoles, cytoplasmic glycogen/clearing, cytoplasmic eosinophilia or oncocytic change, cytoplasmic inclusions (Mallory hyaline, pale bodies, Alpha-1 antitrypsin, and others), pigments (bile, lipofuscin, hemosiderin), etc., The stroma of the HCC can also show a variety of morphologic changes that range from minimal to extensive fibrosis/desmoplasia (diffuse or lamellar), myxoid/mucoid degeneration, and inflammatory infiltrate (lymphocytes, neutrophils, histiocytes/granulomas). While some tumors are very uniform with regards to the growth pattern, cytologic features, and stromal changes, these can also occur in different combinations in a given tumor leading to heterogeneity. While tumor morphology that includes architectural, cytologic, and/or stromal features is an important consideration in defining HCC subtypes, the recognition of a subtype extends beyond morphology alone. Only when these morphologic features combine in a certain way to impart a distinct clinical implication (clinical presentation, molecular phenotype, prognosis, and/or therapy), it provides the basis for creating a sub-type. The criteria proposed by Wood et al., to characterize a distinct histologic subtype include (a) distinct histomorphology on H & E sections, (b) supported by specific immunohistochemical stains or specific molecular alterations, and (c) have specific clinical correlates.[5],[6] Based on such clinicopathologic associations, 8 HCC sub-types have been recognized in the current 2019 WHO classification[4] [Table 1], [Figure 1].
Figure 1: Subclassification of hepatocellular carcinoma subtypes based on cyto-architectural features

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Table 1: Clinicopathologic, molecular features and differential diagnoses of various HCC subtypes (based on 2019 WHO classification of liver tumors)

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It is important to know that since many HCCs can exhibit significant intra-tumoral heterogeneity, the accurate classification is best achieved on resection specimens, although many decisions have to be made on pretreatment biopsies. Also, when confronted with an HCC with features of more than one subtype, the subtype which portends a worse prognosis is the one that should dictate clinical management.[5] About ~35% of the HCCs encountered in practice can be classified into distinct subtypes, while the remaining tumors are considered conventional/HCC-NOS.[5] It is clear that the group of “conventional/HCC-NOS” still has a wide range of morphology combining various histologic changes discussed above, but not meeting the criteria for a sub-type.

With regards to HCC, it is also important to evaluate the status of the background liver and etiology of any underlying disorder. Chronic liver disease is an important risk factor for the development of HCC, and the nature of the underlying disease may influence its management and prognosis. Most morphologic subtypes can be seen in both cirrhotic and non-cirrhotic livers. However, few subtypes are seen more commonly (or exclusively) in non-cirrhotic livers.

Steatohepatitic HCC

This is a common variant of HCC, occurring at a frequency of 20% among resection specimens, although the incidence varies widely amongst studies due to the variability of selection criteria.[5] This variant of HCC was originally described in patients with hepatitis C virus (HCV), however, subsequent studies showed that steatohepatitic variant is most commonly seen in patients with non-alcoholic fatty liver disease (NAFLD) or alcoholic steatohepatitis (ASH), either with or without cirrhosis.[7] Subsequently, Yeh et al. showed that a subset of these may be seen without NAFLD or ASH and may be associated with specific genetic correlations such as loss of 9q12-q31.1.[8]

Besides steatosis, which is often seen in HCC, the diagnosis of steatohepatitic variant also requires evidence of injury in the form of inflammation and ballooning with pericellular fibrosis and the pattern must involve at least 50% of the neoplasm [Figure 2]a.[5] Pericellular fibrosis can be highlighted by trichrome stain.[5] The distinction of HCC from background steatohepatitis, when present, may be rather challenging. Contrary to conventional HCC, reticulin stain is of limited utility as the presence of pericellular fibrosis can confound the interpretation of liver plate thickness, and foci of reticulin loss may be present in NAFLD.[9] The presence of unpaired arterioles and CD34 to demonstrate arterialization may be helpful.[7] Immunohistochemical stains can also help. Majority of the tumors show positivity for glypican-3 (GPC-3) and the use of a three stain panel with GPC-3, glutamine synthetase (GS), and HSP (heat shock protein)-70 has been reported to increase the diagnostic accuracy to 100%.[10],[11] Some studies suggest that this subtype may be arising more commonly in non-cirrhotic livers compared to conventional HCC, but the issue remains unresolved. As a result, it's prognostic significance also remains unclear. One study has shown no difference in survival or metastatic potential, while other studies show a slightly better prognosis when compared to conventional HCC.[7] The immunohistochemical profile of this subtype is similar to conventional HCC, however, it shows increased staining with inflammatory markers such as C-reactive protein (CRP) due to activation of IL6/JAK/STAT pathway.[4],[12] These neoplasms are less likely to show beta-catenin mutations as compared to conventional HCC. Other than steatohepatitis, the differential diagnoses also include focal nodular hyperplasia (FNH) and steatotic hepatocellular adenomas (HCA).[5],[12] The presence of fibrous septa with thick-walled arterioles, ductular reaction highlighted by CK7/CK19, and geographic staining with Glutamine synthetase (GS) favor a diagnosis of FNH.[13] Differentiation from a steatotic HCA can be challenging and lack of staining for GPC3, CD34, GS, and HSP70, lack of cytologic atypia, lack of thick hepatic cords (>2 cell plates), young age, female gender, and non-cirrhotic background tend to favor a diagnosis of HCA. However, the diagnosis can be very challenging on biopsy specimens. It needs to be highlighted that CRP, B-catenin, LFABP, and GS should not be used to differentiate HCA from HCC. Angiomyolipoma (AML) can also be a differential diagnosis when fat-containing lesions are encountered; however, the presence of varying proportions of thick-walled blood vessels, distinctive epithelioid “spider cells” and spindle cell components can help make a diagnosis of AML. Confirmatory immunohistochemical stains include HMB45, Melan A and Cathepsin K, which are all negative in HCC.[14],[15] One needs to be aware that AMLs can be positive for glutamine synthetase (GS) which can be misleading when trying to differentiate these from HCC.[16]
Figure 2: (a) Steatohepatitic HCC showing extensive steatosis, focal ballooning, and Mallory-Denk bodies (H&E, ×400), (b) Macrotrabecular variant showing thickened hepatocellular cell plates (>10 cell thickness) (H&E, ×400), (c) Lymphocyte-rich HCC showing florid infiltration by lymphocytes (H&E, ×400), (d) Clear cell HCC composed of predominantly of cells with clear, glycogen rich cytoplasm (H&E, ×400), (e) Chromophobe HCC shows pale, granular to eosinophilic cytoplasm and pleomorphic nuclei (H&E, ×400). (f) Fibrolamellar HCC showing large neoplastic cells with abundant granular, eosinophilic cytoplasm, large nucleus with prominent nucleolus. Pale bodies and rare cytoplasmic hyaline globules are seen (H&E, ×400)

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Macrotrabecular HCC

While macrotrabecular growth pattern in HCC has been recognized for a while, macrotrabecular HCC (MT-HCC) as a unique subtype has been recognized only recently and has become a focus of several studies due to the proposed aggressive behavior and worse prognosis.[3],[17],[18] This variant seems to constitute about 10–12% of all resected HCCs.[18] This subtype is more common in males and often seen in non-cirrhotic background, especially in a setting of viral hepatitis, particularly hepatitis B (HBV).[17] While originally macrotrabeculae were defined as those with >6 cell plates in thickness, based on the current WHO classification, macrotrabeculae are defined as hepatic trabeculae with ≥10 cell plates in thickness and need to constitute >50% of the HCC [Figure 2]b.[4],[18] However, Jeon et al. have suggested at a threshold of 30% may have the same prognostic implications and hence, may be sufficient to make a diagnosis of MT-HCC.[17] These tumors are often associated with higher AFP levels, larger tumor size, higher rate of vascular invasion, and higher stage and grade. MT-HCC has a higher recurrence rate and worse recurrence-free survival.[17],[18] Ziol et al. have shown that this subtype of HCC is associated with activation of both angiopoietin 2 and Vascular Endothelial Growth Factor A (VEGF-A).[18] Based on more recent studies, detection of ESM1 (endothelial-specific molecule-1) is being touted as a promising immunohistochemical marker for the detection of this variant.[19]

Neutrophil-rich HCC

This category has been recognized in the recent WHO classification, albeit it is very rare and not very well studied.[4] Only a handful of cases have been described so far. First described by Yamamoto et al. in 1999, these neoplasms are poorly differentiated with heavy infiltration by neutrophils.[20] Since then several authors have recognized this entity and, in some cases, they are accompanied by extensive sarcomatous differentiation.[21],[22] The patients tend to present with leukocytosis and paraneoplastic symptoms due to the production of G-CSF and IL-6 by the neoplastic cells.[23] G-CSF producing neoplasms are not specific to the liver and have been described in other organs such as the lung, tubular gut, thyroid, and pancreas.[24],[25],[26] Irrespective of the site, these neoplasms show a poorly differentiated or sarcomatous morphology and abundant infiltrating neutrophils. The production of G-CSF by the tumor cells can be confirmed by immunohistochemistry.[27] This subtype has been associated with a worse overall prognosis.[4]

Lymphocyte-rich HCC

Lymphocyte rich or lymphoepithelioma-like (LEL) carcinomas are characterized by the presence of sheets or nests of poorly differentiated carcinoma cells admixed with dense lymphocytic infiltrate. This entity has been recognized in the recent WHO classification. Different diagnostic criteria have been used in the past. Wada et al. proposed using >100 lymphocytes per high power field in at least 10 high power fields.[28] Understandably, this criterion may be cumbersome to apply in practice. The recent WHO classification requires the lymphocytes to outnumber tumor cells in most fields in the neoplasm [Figure 2]c.[4] The tumor-infiltrating lymphocytes are predominantly CD8+ T lymphocytes, while the peritumoral infiltrate is rich in CD4+ T cells.[29],[30] Majority of reported cases are seen in non-cirrhotic livers and many in the context of viral hepatitis.[30] The HCC component in the majority of cases is poorly differentiated; however, well and moderately differentiated histology may be rarely encountered.[31] These tumors have an overall favorable outcome compared to conventional HCC.[32] Classically, lymphocyte rich or lymphoepithelioma like histology is seen in the context of Epstein Barr Virus (EBV) related neoplasms. While that certainly holds true for LEL cholangiocarcinomas, it is not so clear for HCC.[33] EBV positivity and higher degree of microsatellite instability (MSI-high) have been described only in a minor subset of cases.[34],[35] Hence, using the term “lymphoepithelioma-like” maybe a misleading to some and current practice is to use the term “lymphocyte rich”. One theory suggests that the cytotoxic T-lymphocytes may be responsible for antitumor response and favorable prognosis seen in this subtype.[28] More recent studies have shown increased expression of programmed cell death ligand-1 (PD-L1) in the carcinoma and PD1 in the inflammatory component which could present a potential for targeted therapy with PD1 inhibitors.[3],[36] The differential diagnosis of lymphocyte rich HCC includes LEL-cholangiocarcinoma, metastatic lymphoepithelial carcinoma of other sites such as nasopharynx, lungs or stomach, and lymphoma. Demonstration of hepatocellular differentiation with the help of IHC markers can easily distinguish this entity from other mimics.[32]

Clear cell hepatocellular carcinoma

Although clear cells are seen in many HCCs and any of the subtypes, the tumor needs to have >80% clear cells to be designated as clear cell HCC, per the new WHO criteria.[37] This variant is observed in about 7% of the resection specimens.[5] A female preponderance is seen when compared with conventional HCC.[38] The clearing of the cytoplasm is attributed to glycogen accumulation [Figure 2]d; however, this has not been well-established as some tumors have admixture of clear cytoplasm with steatosis, while in some this distinction is difficult.[5] These are usually well to moderately differentiated tumors and show robust staining with hepatocellular markers. Some studies suggest these to be more common in non-cirrhotic livers and associated with better prognosis compared with conventional HCCs.[5],[12] However, this issue is not entirely resolved and requires further studies. When they arise in cirrhotic livers, diagnosis may not be challenging. In cases where the lesions are seen in non-cirrhotic livers or small biopsy specimens, metastases from other clear cell neoplasms, such as of renal and gynecologic origin and localized hepatic glycogenosis need to be considered in the differential diagnosis.[12] Immunohistochemical stains for hepatocellular differentiation, such as Arginase, HepPar1, and polyclonal CEA, can help make the distinction.[39] It has been postulated that clear cell HCC may be an intermediary in the path of conventional HCC, but more studies are needed before definite conclusions can be made.[40] Lee et al. showed that clear cell histology in HCC was enriched in mutations in the IDH1 R132C gene, however, these findings await further validation.[41]

Chromophobe HCC

This variant of HCC was first described by Wood et al. in 2013 and described as “chromophobe HCC with abrupt anaplasia”, but the data on this sub-type is still scant.[6] This entity has been recognized in the current WHO classification and occurs at a frequency of 3% approximately.[4] The tumor as the name suggests has some histologic similarity with its namesake renal neoplasm (chromophobe renal carcinoma). It is composed of cells with partly clear and partly eosinophilic cytoplasm, clear cell borders, and bland nuclear features, with foci of abrupt pleomorphism and atypia [Figure 2]e. Wood et al. further showed that this variant is associated with defects resulting in alternative lengthening of telomeres (ALT) which can be detected by FISH (fluorescence in situ hybridization).[5],[6],[42] While details of prognosis are not well-known, it seems their behavior is similar to conventional HCCs.[43]

Fibrolamellar hepatocellular carcinoma (FLHCC)

FLHCC is a unique hepatocellular neoplasm in many ways. It is the only variant of HCC which almost exclusively arises in non-cirrhotic livers.[44] It is commonly seen in younger patients and the median age described is 22 years (range: 4–65 years).[45] It is now known that the distinct morphology of this neoplasm is associated with a specific molecular alteration. In 2014, Honeyman et al., detected a unique DNAJB1-PRKACA fusion transcript in FLHCC.[46] This fusion results in constitutional activation of PRKACA which plays an important role in tumorgenesis. While this fusion is the mechanism of PRKACA activation a vast majority of cases, rare cases of PRKACA amplification, and FLHCC in patients with Carney complex (germline PRKAR1A mutations) have been reported.[47]

Grossly, these tumors are larger than conventional HCCs and appear tan-white with often a central scar with/without calcifications.[42] The scar and fibrosis are microscopically distinct as lamellar fibrosis. The tumor cells are large, polygonal with abundant eosinophilic granular cytoplasm (oncocytic), large nuclei with a single prominent nucleolus. Hyaline globules and pale bodies (made of fibrinogen inclusions) are often seen [Figure 2]f. Taken together, all these features are diagnostic of FLHCC, but may not be seen in every case.[42],[48],[49],[50] Morphologic variations such as solid growth (devoid of intervening fibrosis), pseudoglandular architecture, intracytoplasmic mucin, and intermixed fat, can make the diagnosis challenging.[45],[47] These tumors are positive for HepPar-1, polyclonal CEA (canalicular pattern), and arginase.[42] Granular cytoplasmic staining with CD68 is sensitive but not specific and the cells frequently express CK7 and CK19.[42],[51] This immunoprofile suggests that FLHCC has some biliary differentiation.[52] Additionally, it is now known that the novel DNAJB1-PRKACA fusion, which was once considered diagnostic of FL-HCC, is also shared by a set of pancreaticobiliary neoplasms with distinct oncocytic morphology, which may suggest a probable common origin of these neoplasms and FLHCC.[53],[54] While not entirely specific, demonstration of this gene fusion (using fluorescence in situ hybridization for PRKACA gene rearrangement) is still considered the gold standard for making the diagnosis[55] and presents a potential target for future therapies.

Scirrhous hepatocellular carcinoma

This variant is seen in about 4% of cases.[5] Scirrhous HCC is characterized by nests of tumor cells surrounded by a markedly fibrous stroma, which by recent WHO criteria should constitute >50% of the tumor.[4] The incidence of scirrhous HCC is estimated to be about 4.0%. This subtype is more often seen in non-cirrhotic patients but a history of chronic viral hepatitis is often present.[5],[12],[56] The abundance of fibrous stroma may impart a nested appearance to this tumor [Figure 3]e. The morphologic features are similar to a well to moderately differentiated HCC. Clear cell change, hyaline bodies, and lymphocyte infiltration may be present.[56] Common hepatocellular markers like Hep Par 1 and polyclonal CEA may be negative in more than 50% of scirrhous HCC, while markers commonly used to identify adenocarcinoma like CK7, CK19, and EPCAM are positive in nearly two-thirds of cases.[57] This variant is often misdiagnosed as cholangiocarcinoma due to the dense fibrosis and its immunophenotype.[12] The newer hepatocellular markers, glypican-3 and arginase-1 are more reliable for the identification of scirrhous HCC and are positive in >90% of cases. A sensitivity of 100% has been reported with their combined use.[58] Scirrhous HCC can also mimic of fibrolamellar HCC. While patient demographics are likely to be different in the two groups, immunohistochemical stain for CD68 and molecular testing for DNAJB1-PRKACA fusion can be applied in challenging cases.[12],[51] Other differential diagnoses include therapy-related changes (such as radiation, embolization), cholangiocarcinoma and metastatic adenocarcinoma, and positivity for hepatocellular immunohistochemical markers will be helpful in making a diagnosis. While the long-term outcome of patients with this subtype of HCC is similar to conventional HCC, the prognosis seems variable.[4],[12] Molecular profiling data has shown that this variant is enriched in TSC1/TSC2 mutations and alteration in the transforming growth factor-beta (TGF-B) pathway.[3]
Figure 3: (a) Gross image of fibronodular HCC - Multinodular, yellow-tan tumor in a non-cirrhotic liver, (b) Fibronodular HCC is composed on multiple nodular tumor nests separated by bands of fibrosis (H&E, ×40), (c) Gross image of cirrhotomimetic HCC – Multinodular neoplasm showing pale parenchymal nodules and fibrosis which cannot be separated from the background cirrhotic nodules, (d) Cirrhotomimetic HCC showing few cirrhotic nodules and nodules of tumor separated by thick bands of fibrosis and inflammatory cells in the same field (H&E, ×40), (e) Scirrhous HCC – Tumor shows extensive, densely fibrotic stroma with fibrosis around smaller nests and tumor individual cells (H&E, ×100), (f) Sarcomatoid HCC showing extensive dedifferentiation and spindle cell morphology (H&E, ×100)

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Cirrhotomimetic HCC

This is considered a growth pattern of HCC rather than a sub-type. It has also been referred to as diffuse-type or infiltrative HCC in the literature. The importance of recognizing this growth pattern is two-fold; one, it can often evade diagnosis based on imaging and gross examination, and second, they are associated with worse outcomes after liver transplantation.[59] Diagnosis of cirrhotomimetic subtype requires macroscopic correlation as the characteristic features are best appreciated on gross examination. The tumor forms multiple small nodules (usually >20) that are intimately admixed with the background nodules of a cirrhotic liver and cannot be differentiated based on gross examination [Figure 3]c and [Figure 3]d.[5] It is often diagnosed in the explants.[42] This entity does not have distinctive histologic features and is not a specific histologic subtype. The majority of patients have no, or minimal, elevation in AFP, and the individual tumor nodules show well or moderately differentiated HCC with frequent Mallory–Denk bodies and cholestasis.[42] While it is possible that the nodules represent extensive seeding of the liver by tumor due to spread via portal veins, it is distinct from peritumoral satellite nodules which are usually <10 in number.[5] Clayton et al. have shown that among the limited cases of this entity which were studied, the ones which had clear cell histology and involvement of <50% of the liver, were associated with better prognosis.[59]

Fibronodular HCC

This is the most recently described unique growth pattern of HCC. This variant is characterized by an extremely nodular appearance due to multiple bands of fibrosis that traverse the tumor mass. This variant is more commonly observed in non-cirrhotic liver, which makes the lesion stand out [Figure 3]a and [Figure 3]b). Viral Hepatitis C was the most common underlying liver disease in this cohort. While scirrhous HCC also shows extensive fibrosis, FN-HCC differs from it due to paucity of fibrosis between individual tumor cells or cell clusters. This gives FN-HCC a more cirrhosis-like appearance on low power microscopy, in contrast to scirrhous HCC which appears more uniformly fibrotic. This lesion exhibits a distinct “popcorn” appearance on contrast imaging, in addition to nodular contour, capsular enhancement, and has a nodular appearance on the cut surface. As compared to conventional HCC, FN-HCC seems to presents at an earlier stage, has a lower rate of disease progression, and longer time to progression.[60]

Carcinosarcoma/Sarcomatoid HCC

Carcinosarcoma is considered a type of primary hepatic carcinoma with distinct carcinomatous and sarcomatous component, where the epithelial component can be either HCC or cholangiocarcinoma, or both. Sarcomatoid HCC is characterized by the presence of a component of malignant spindle cells [Figure 3]f. This component may be focal or predominant but there should be some evidence of hepatocellular differentiation.[5] Some use the terms sarcomatoid HCC and carcinosarcoma synonymously. In fact, sarcomatoid HCC as an individual category is not recognized as a specific subtype in the recent WHO blue book, while carcinosarcoma is briefly discussed under primary hepatic carcinomas. The epithelial component in these tumors is often poorly differentiated requiring IHC to prove the epithelial/hepatocellular nature of the malignancy. When definite mesenchymal or heterologous elements are present, the carcinoma is often categorized as carcinosarcoma.[5] This subtype of HCC is rare and the terms sarcomatoid and carcinosarcoma have been used interchangeably in the past, However, sarcomatoid carcinoma is considered to be a dedifferentiation in a carcinoma (with retention of epithelial markers) while carcinosarcoma has distinct sarcoma and epithelial components. There is no significant prognostic difference between the two entities, and both exhibit aggressive behavior and poor outcomes.[61] Sarcomatoid HCC shows lower serum AFP, higher incidence of extra-hepatic disease, and a worse prognosis compared to conventional HCC. Hepatocellular markers are typically negative in the malignant spindle cell component, while keratin positivity has been observed in 23–63% of cases.[42] Some of the sarcomatoid/undifferentiated carcinoma may have associated numerous osteoclast-like giant cells. These giant cells are histiocytic in nature, are not malignant, and stain with CD68.[62] Molecular studies have shown that tumors with sarcomatoid features are enriched in TP53 mutations.[3]

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA)

This entity has been subject to a lot of controversy in recent years, both in terms of diagnostic criteria and subcategories. Per the 2019 WHO classification, diagnosis of a combined hepatocellular-cholangiocarcinoma requires unequivocal features of both hepatocellular and cholangiocellular differentiation in the same neoplasm, based on H & E staining.[63] The 2010 WHO classification recognized two iterations in this entity; a. classic and b. with stem cell features; the latter included carcinoma with intermediate cell features and cholangiocellular carcinoma.[64] However, stem cell features are no longer recognized as unique and hence were abandoned by the new WHO schema. Similarly, the 2019 WHO classification of tumors of the digestive system, separated the cholangiocellular variant from this subtype and placed it under the small duct intrahepatic cholangiocarcinoma.[63],[65]

Based on the 2018 consensus guidelines, the diagnosis of mixed HCC-CCA can be made when there are both hepatocytic and cholangiocellular components present, either intermixed or juxtaposed.[66] The possibility of a collision tumor must be excluded (based on the absence of uninvolved liver parenchyma between the two components).[5] The WHO defines intermediate cell carcinoma is defined as a neoplasm in which the individual epithelial cells are not characteristic of either HCC or CCA but show overlapping features, hence termed “intermediate” cell carcinoma.[63],[66] It has been shown that cHCC-CCA is closer to CCA even though they can harbor common mutations seen in both of these neoplasms. Similarly, the prognosis of these combined neoplasms is worse than that of HCC alone.[63]

   Conclusions Top

Pathology of HCC has come a long way, from a time when tissue diagnosis was not even required in a majority of cases to the present day when pathology reports can offer much more than confirmation of diagnosis. As we continue to learn more about the molecular associations of HCC, we are likely to discover more morphologic associations that will be useful to describe new variants or subtypes. Pathologists will be able to include this information in their reports which can drive further confirmatory testing for the suspected molecular alterations. The information on subtypes will also help in prognostication and management decisions. Hence, pathologists will play a bigger role in the management in patients with HCC with the exciting current and future developments in this field.

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Conflicts of interest

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Correspondence Address:
Dhanpat Jain
310 Cedar Street, Department of Pathology, Yale University School of Medicine, New Haven, CT – 06510
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_751_20

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