**4. Pathological features**

HCC is a highly heterogeneous tumor. Heterogeneity is both molecular and morphological [64, 65]. Understanding the heterogeneity is important for the diagnosis, treatment and follow-up of the disease [64].

HCCs below 2 cm are called small HCC (s-HCC) and early HCC (e-HCC) [1, 64, 66]. These tumors are divided into two as prominent nodular or indistinct nodules [64]. Early-HCC is in the form of nodules with indistinct borders and usually develops from a dysplastic nodule background. They are well differentiated, develop from the background of fibrosis-cirrhosis, and are radiologically hypovascular and rarely vascular invasion (5%) [1, 64]. Small-HCC has a prominent pseudocapsule, is well-moderately differentiated, radiologically hypervascular, and invades more frequently (40%) [1, 64]. Pedinculated HCC has a growth pattern protruding from the capsular surface [67]. Diffuse HCC is in the form of proliferation of small tumor nodules and resembles cirrhotic nodules (cirrhotomimetic) [64]. SH-HCC is more solid than other HCC subtypes and has more golden-yellow color due to the lipid contains. When the macroscopic specimen is carefully examined, fibrotic bands that divide the tumor into lobules can be seen. The tumor usually tends to be well-circumscribed or nodular and may range in diameter from 0.5 cm to 11 cm [68]. The prognosis of SH-HCC is similar to that of classical HCC [40, 57, 69, 70]. Although nontumoral liver can be cirrhotic or noncirrhotic, it is usually yellowish-brown in color suggestive of fatty liver (**Figure 1**).

After these macroscopic definitions and macroscopic heterogeneity, it is necessary to mention microscopic heterogeneity. This heterogeneity is also reflected in the histopathological subtyping of HCC [71]. In the 5th edition of WHO classification of the tumors of the digestive system (2019), the subtypes of HCC are as follows; fibrolamellar, scirrhus, cear cell type, steatohepatitic, macrotrabecular massive, chromophobe, neutrophil-rich, lympocyte-rich [1]. More on SH-HCC will be mentioned here. SH-HCC is a newly identified subtype of HCC. It accounts for approximately 5–20% of all HCCs [1]. It is characterized by steatohepatitic features such as steatosis in tumor cells, balloon degeneration, inflammation, Mallory-Denk bodies and pericellular fibrosis [58, 72]. Tumor is usually related to MetS and steatohepatitis is detected in the background [22, 39, 57, 61, 69, 72]. Some studies have shown that steatosis and interstitial fibrosis are the main findings for SH-HCC [22, 40]. However, the minimum amount of steatosis in the steatohepatitic area in some tumors *Histopathological Features of the Steatohepatitic Variant of Hepatocellular Carcinoma… DOI: http://dx.doi.org/10.5772/intechopen.99842*

#### **Figure 1.**

*Tumor with nodular border is seen in the brown-yellow noncirrhotic liver. The tumor is lobulated by fibrotic bands and has yellow areas.*

that are histomorphologically SH-HCC, the presence of only steatosis in some cases, the presence of steatotic areas or cells in HCC are confusing points in the diagnosis of SH-HCC. Despite all this confusion, the steatohepatitic area in HCC is diagnostic for SH-HCC. For the histopathological diagnosis of SH-HCC, the cut-off for steatohepatitic features was described more than 5% of the tumor before but later moved to 50% [10, 39, 64, 72]. Hepatocellular carcinoma morphologically has 4 histological growth patterns: trabecular, solid (compact), pseudoaglandular (pseudoacinar), and macrotrabecular (trabecular thickness consisting of more than 10 cells) [1]. When SH-HCC is examined microscopically, a steatotic tumor is seen, separated from the generally steatotic liver (cirrhotic or non-cirrhotic) by a nodular or infiltrative margin. Large fat droplets are detected in tumor cells. Mallory-Denk bodies are detected in most tumors. Thin connective tissue growth (pericellular fibrosis), trabecular fibrosis, and randomly distributed collagen bundles surrounding tumor cells can be easily selected. Trabecular fibrosis, including randomly distributed collagen bundles in the tumor, and fibrosis surrounding tumor cells (pericellular) can be easily distinguished. Inflammation in the tumor is also remarkable. The inflammation is lymphocyte predominant with sparse plasma cells. More prominent neutrophil and lymphocyte infiltrations can be detected around tumor cells which contains Mallory-Denk bodies. The nuclei of tumor cells have atypia. This atypia is mild in well-differentiated tumors and quite pronounced in poorly differentiated tumors. They may even have bizarre nuclei suggested of sarcomas or pleomorphic carcinomas. However, mitotic activity is very low. Again, as in classical HCC and other subtypes, the tumor does not contain portal tracts and unpaired arteries can be seen (**Figures 2**–**4**) [1, 10, 45, 68, 72, 73]. The differentiation of SH-HCC is the same as that of classical HCC and is graded as well differentiated (Grade1: Tumor cells resemble mature hepatocytes with minimal to mild atypia), moderately differentiated (Grade 2: Distinctly malignant and histomorphology strongly suggests hepatocellolar differentiation) and poorly differentiated (Grade 3: Clearly malignant, but histomorphology strongly suggests spectrum of

#### **Figure 2.**

*The tumor (pale area) is located in the center of the figure, surrounded by cirrhotic nodules (a, Hematoxylin and Eosin-H&E). Masson's trichrome (b) and reticulin (c) stains, both the tumor and its surrounding micronodular cirrhotic background are more prominent.*

#### **Figure 3.**

*The parenchymal invasion area of steatohepatitic HCC is seen (arrows) (a), the tumor is seen adjacent to the fatty cirrhotic nodule (stars) (b), presence of large lipid droplets and chronic inflammation (arrows) (c), Masson's trichrome stain shows thick fibrous septa (arrows) (d).*

poorly differentiated carcinomas) [1]. Most SH-HCCs are moderately differentiated and have a trabecular pattern and a pseudoglandular pattern [52].

Immunohistochemical antibodies are helpful and supportive in the diagnosis of HCC [74]. Although heppar-1, glypican-3, glutamine synthetase, arginase, heat shock protein-70 (HSP-70), β-catenin and sinusoidal staining with CD34,

*Histopathological Features of the Steatohepatitic Variant of Hepatocellular Carcinoma… DOI: http://dx.doi.org/10.5772/intechopen.99842*

canalicular staining pattern with polyclonal carcinoma embryogenic antigen (pCEA) and CD10 antibodies are used in the diagnosis of HCC, immune studies for SH-HCC are limited (**Figure 5**) [22, 68, 72, 75].

#### **Figure 4.**

*Dense inflammation and fibrosis (a), pleomorphism (b), Mallory-Denk bodies (arrows) (c), and ballooning (cells with pale cytoplasm) (d) are seen in different areas of the tumor.*
