—  SHORT COURSE #22  —

Tumors In The Liver - Diagnostic Problems

Case 3 - Small Hepatocellular Carcinoma

Linda D. Ferrell, M.D.
Wendy L. Frankel, M.D.


Clinical history:
45 year old man with cirrhosis who underwent a liver transplant. In his explant, a 1.5 cm nodule was found in the background of a cirrhotic liver.


Case 3 - Figure 1 - Cirrhotic liver with a dominant nodule (arrow), low power
Case 3 - Figure 2 - Atypical hepatocytes with thickened cell plates, medium power

Case 3 - Figure 3 - Atypical hepatocytes with thickened cell plates, hight power
Case 3 - Figure 4 - Cell plates greater than 2-3 cells thick, H&E and reticulin stains, medium power


Pathologic findings:
Cut section of the liver showed a cirrhotic liver with a 1.5 cm dominant nodule that was poorly circumscribed from the surrounding liver. Microscopic sections showed atypical hepatocytes with an increased nuclear to cytoplasmic ratio. The cell plates were thickened and some areas showed cell plates greater than 2-3 cells thick, while others showed complete loss of the reticulin framework.

Diagnosis- Small Hepatocellular Carcinoma


Comment
A brief overview of the currently recommended terminology used for the cytologic changes is necessary as a prelude to the discussion of nodules within the cirrhotic liver. The cirrhotic nodule very frequently contains scattered enlarged hepatocytes with abundant cytoplasm and atypical, enlarged nuclei, but the ratio of nucleus to cytoplasm is relatively normal. This cytologic feature was designated as "large cell dysplasia" in the past, but now the International Working Party has recommended the terminology of large cell change for this finding as there is a consensus that this lesion is likely to not be truly dysplastic in nature, and this cellular change is too frequently present to be assumed to be a premalignant process. Similarly, cirrhotic nodules may also contain hepatocytes smaller than normal with normal, slightly smaller, or slightly larger nuclei and scant cytoplasm that results in an overall increase in the nuclear/cytoplasmic ratio. This cytologic feature was previously designated as "small cell dysplasia", but the International Working Party has recommended the terminology of small cell change for this process. Again, there is currently a consensus that small cell features in cirrhotic livers could be regenerative rather than dysplastic, and may only be preneoplastic in certain instances when the cells are arranged in clusters within a cirrhotic nodule. These clusters of small cells can be present in any nodule in the cirrhotic liver, may be a focus of no more than 1-2 mm in diameter, and appear like a nodule within a nodule. This type of change has been designated a "dysplastic focus" without further grading into low or high grade by the International Working Party, and has been noted to have a high prevalence in diseases such as chronic hepatitis B and C, alpha-one-antitrypsin deficiency, and tyrosinemia. Dysplastic foci may also contain cells with enlarged nuclei with hyperchromasia, with the spectrum of nuclear atypia varying from minimal to severe. Cytoplasmic fat or glycogen may differ in content from the surrounding liver. The same International Working Party also recommended that the term "dysplasia" be used only in the description of nodules or the above described "dysplastic foci" rather than for more generalized cytologic changes within the liver.

Large Regenerative Nodule (Macroregenerative nodule) and Low-Grade Dysplastic Nodule

Nomenclature. In the cirrhotic liver, benign nodules that are larger than the typical cirrhotic nodule have been referred to by various names including large regenerative nodule, macroregenerative nodule, or adenomatous hyperplasia. For similar nodules in the noncirrhotic liver, the International Working Party has recommended that they be designated as multiacinar regenerative nodules or adenomatous hyperplasia. These latter nodules tend to occur in the setting of Budd-Chiari syndrome, portal vein thrombosis, or as a sequelae of necrosis with regeneration. These large regenerative nodules and multiacinar regenerative nodules are thought to be a reactive process rather than a clonal, preneoplastic lesion.

In contrast, the low-grade dysplastic nodule in the cirrhotic liver is thought to represent a clonal proliferation of hepatocytes, although the gross and standard microscopic features can be indistinguishable from the large regenerative nodule. For this reason, the remainder of the descriptions generally apply to both lesions, and in practice, many do no try to distinguish these as clonality studies may be the only mechanism to do so. Rather, in practice, the terms are almost used interchangeably to represent a nodule that lacks the cytologic or architectural abnormalities seen in the high-grade dysplastic nodule.

Clinical Features. Large regenerative nodules/low-grade dysplastic nodules occur in the setting of cirrhosis, with a few exceptions when they are noted in the setting of chronic liver disease without fully developed cirrhosis. They are often found as incidental findings at autopsy or at the time of transplantation, but can also be noted on radiographic studies. Serum AFP is normal or within the same range as the underlying chronic liver disease/cirrhosis.

Pathogenetic Features. These nodules are generally considered benign lesions and either may represent regenerative foci or presumed clonal proliferations in a liver with chronic disease. Nodules with this benign histologic pattern have been associated with an increased incidence of hepatocellular carcinoma, and in some instances may be predisposed to the development of hepatocellular carcinoma. However, it is important to point out that since almost all of the past studies of these nodules have not attempted to define the lesions as regenerative or clonal, but have rather defined the nodules by routine histologic examination as lacking features of high grade dysplastic nodules or hepatocellular carcinoma, one cannot definitively state at this time whether the regenerative nodules and the clonal nodules have similar risks for the association with hepatocellular carcinoma. Such nodules are more typically seen in cirrhosis due to HBV, HCV, alcohol, and hemochromatosis, but unlikely to be seen in primary biliary cirrhosis, so the risk factors tend to be the same as for hepatocellular carcinoma.

Gross features. Large regenerative nodules/low-grade dysplastic nodules are larger than other cirrhotic nodules. The lower limit for size is generally accepted as between 0.8 and 1 cm in diameter, and these lesions are almost always less than 3 cm in greatest diameter. These nodules may tend to bulge on cut section, the edges of the nodules are rounded and sharply circumscribed, and they may be more bile stained or paler yellow to tan than the other cirrhotic nodules.

Microscopic features. These nodules histologically resemble cirrhotic nodules. They have an intact reticulin framework similar to normal liver, and the cell plates are 1-2 cells in thickness. The hepatocytes typically have unremarkable cytology, although some focal variations in cell size, especially scattered large cell change similar to that seen in the other cirrhotic nodules, can be present in the large regenerative nodule. The low-grade dysplastic nodule would probably be expected to have a more uniform population of hepatocytes due to its clonal nature, but many of the specific features of this type of clonal nodule have not been definitively established. Findings such as Mallory bodies, bile stasis, clear cell cytoplasmic change, iron or copper deposits, a slight decrease in cell size [Ferrell, 1993 #101], and focal or diffuse fatty change may be present. Portal tracts are usually present within the nodule and bile ductular proliferation may be prominent, but fibrous septa without the complete triad of duct, vein, and artery may also be present [Ferrell, 1994 #365].

Special studies. Studies of the vascularity of these lesions have shown that they tend to have an increased number of arteries that lack the other components of a portal zone, the so-called "unpaired artery". However, staining for vascular markers such as CD34 or CD 31 as a marker for sinusoidal capillarization is essentially the same as that seen in cirrhotic nodules, which consists of some peripheral staining at the edges of the nodule. The nodules are negative for alpha-fetoprotein, and otherwise show the similar staining patterns expected in normal liver for cytokeratin and polyclonal CEA.

Differential diagnosis. The size of this nodule differentiates it from other cirrhotic nodules. Rarely, a nodule with this pattern of histology may lack portal zones, but this does not warrant a diagnosis of adenoma in the cirrhotic liver unless one of the risk factors discussed above is present. The features differentiating it from high-grade dysplastic nodules and small, well-differentiated HCC are outlined in Table 3.

High-Grade Dysplastic (Borderline) Nodules

Clinical features. The high-grade dysplastic nodule, also known as borderline nodule, type II macroregenerative nodule, atypical adenomatous hyperplasia, and atypical macroregenerative nodule almost always occurs in a cirrhotic liver. Serum AFP is normal or in the range seen with the underlying chronic liver disease/cirrhosis. Most recommend that these lesions should be excised or ablated since they are considered to be a premalignant process.

Pathogenetic features. This type of nodule typically occurs in the setting of cirrhosis and is considered to be a premalignant change on the pathway to the development of hepatocellular carcinoma.

Gross features. These nodules have essentially the same gross features of the large regenerative /low-grade dysplastic nodules with the exception that some of them may appear to be less well circumscribed or have irregular edges.

Microscopic features. When the dysplastic changes are noted uniformly throughout the nodule, then the nodule is designated as a high-grade dysplastic nodule. Alternatively, a nodule containing one of more dysplastic foci is also designated as a dysplastic nodule. The atypical features seen are not overtly diagnostic for HCC but are more atypical than expected in the usual cirrhotic nodule. The nodule is often recognized by zones of small cell change with increased nuclear:cytoplasmic ratio, also designated as increased nuclear density, which is defined as the estimated number of hepatocyte nuclei per microscopic field compared to the normal liver. Large cell change is rarely a feature of high-grade dysplastic nodules, but if it is, the focus must be a discrete zone of atypical cells rather than enlarged nuclei scattered singly throughout a nodule. Other common features are the focal zones of cell plates up to three cells thick, focal decrease in the reticulin framework, and mild dilation of sinusoids. These nodules can also contain foci of Mallory bodies, fat, clear cell change, cytoplasmic basophilia, bile, and portal tracts. Iron deposits may be present, but the high-grade dysplastic lesions tend to lack iron deposits in contrast to the low-grade nodules, where iron deposits are more common. The edges of the nodule may be irregular, and focal acini (pseudoglands) may be present.

Differential diagnosis. This lesion is differentiated from overt HCC by features as described in Table 3. Features that are probably most helpful for the diagnosis of HCC are the presence of mitotic figures in moderate numbers, trabeculae, cell plates greater than 3 cells thick, nuclear density greater than 2 times normal, marked reduction in reticulin framework, numerous unpaired arteries, and absence of portal zones.

Hepatocellular Carcinoma

Clinical features. Hepatocellular carcinoma (HCC) is the most common malignant primary tumor in the liver, and is usually seen in the setting of cirrhosis (noted in approximately 85% of cases. Lesions less than 1.5 cm generally do not enhance on radiographic angiography, and HCC may be more or less echogenic than the adjacent liver. A high serum AFP level (>1000ng/ml) is seen in almost two-thirds of the cases of the larger tumors; tumors less than 2-3 cm in size are unlikely to have an elevated serum AFP. Elevations of serum AFP of less than 500 ng/ml can be seen in many liver disorders and levels between 500 and 1000 ng/ml are suspicious for HCC but not as reliably specific. Prognosis is typically correlated with staging for lymph node and distant metastases as well as histologic features that can be evaluated routinely on resection samples, such as vascular invasion, adequacy of surgical resection margins (with at least 1 cm typically recommended), number and location of lesions, and size of tumor. The relationship of histologic tumor grade or subtype of HCC to prognosis is considered by most to be not as important as the factors noted above, except when the histology is that of fibrolamellar HCC (see below). Liver transplantation has now been shown to be an effective form of therapy for HCCs less than 5 cm in greatest diameter and without evidence of large vessel invasion. Alternative therapies such as cryoablation, percutaneous ethanol injection, and transarterial chemoembolization have also been used, predominantly in inoperable cases, to improve length of survival.

Pathogenetic features. The major etiologic association for HCC is cirrhosis, but hepatitis B or C viral infections are also predisposing factors. Patients with cirrhosis due to hemochromatosis and alpha-1-antitrypsin disease may also have an increased risk of HCC over patients with cirrhosis due to other causes (excluding HBV and HCV). Other risk factors include exposure to thorotrast (thorium dioxide), aflatoxins, and estrogenic steroids.

Gross findings. Most HCCs arise in the cirrhotic liver. HCC may be more bile-stained or paler than the adjacent liver, and can have irregular borders or even satellite nodules. Large vein invasion and a fibrous capsule may be noted associated with the larger tumors. Small HCC is generally defined as HCC measuring less than 2 cm in diameter; these small tumors usually lack gross vascular invasion, necrosis or hemorrhagic zones.

Microscopic findings. Several typical histologic patterns of HCC have been described by the World Health Organization. The most common is the trabecular pattern, also known as the sinusoidal pattern. In this variant, the tumor morphology mimics the cell-plate architecture of normal liver, but with important differences. First, the cell plates in trabecular HCC are three cells thick or greater in comparison to the plates of normal or regenerative liver, which are only one to two cells thick. The tumor cell plates are lined by endothelial cells similar to normal liver, but with reticulin stain, the framework is often absent or may be markedly decreased or distorted, with irregular or absent staining of the edges of the trabeculae. The tumor cells often have features of small cell change. Large cell change can also be noted, but is probably less frequently seen except in the higher grade tumors. Often, foci of small or large cell change are admixed. Kupffer cells are typically absent.

The acinar, pseudoglandular, or adenoid pattern of HCC is less common than the trabecular type. The defining feature in this variant is gland-like spaces, or acini, lined by the hepatocytic tumor cells. These acinar structures are formed by the dilation or expansion of bile canaliculi and they often contain bile. Less frequently, the spaces are a result of central necrosis of the trabeculae and so may instead contain protein, cellular debris, or macrophages. Due to the formation of these gland-like spaces, one must not mistake this lesion for adenocarcinoma. The acinar pattern is frequently admixed with the trabecular pattern.

The solid, or compact, pattern of HCC is a relatively uncommon variant characterized by dense aggregates of tumor cells that may seem to lack the endothelial-cell-lined trabeculae or cell plates; however, careful examination with endothelial cell markers will often reveal the presence of compressed trabeculae. Loss of the reticulin framework is typically seen in the solid, crowded zones as well.

The final pattern is the scirrhous pattern, which contains focal to diffuse, prominent areas of fibrosis that can be associated with any of the patterns above. Occasionally, the tumor cell plates (or trabeculae), may be separated by increased amounts of connective tissue instead of by the endothelial-cell-lined sinusoidal spaces. In these instances, reticulin staining is usually increased in the bands of connective tissue rather than decreased as described above for the trabecular pattern of HCC. The thickened cell plates, which are separated by this prominent reticulin framework in these cases, often have a linear or ribbon-like arrangement. This pattern could be subclassified as a form of scirrhous HCC as well, although the overall amount of fibrous tissue may not be as prominent as typically described.

The cytologic features of HCC within any of these patterns also tends to resemble normal hepatocytes. The tumor cells often maintain a polygonal shape and have round vesicular nuclei and prominent nucleoli, typical features of hepatocytic differentiation. Intranuclear vacuoles (composed of cytoplasmic invaginations) and glycogenation of nuclei (another feature seen in normal liver) are fairly common findings. Small cell change (as described above) is probably the most common cytologic change, but large cell change and giant and/or pleomorphic cells may be present as either a diffuse or focal finding. The amount of cytoplasm may vary, and is often slightly more basophilic than in seen in normal hepatocytes. The cytoplasm may also have a granular appearance, or be exceptionally oxyphilic due to the presence of large numbers of mitochondria. Cytoplasmic inclusions such as Mallory bodies or globular acidophilic bodies composed of proteins including albumin, fibrinogen, alpha-1-antitrypsin, or ferritin may be present. Fat, glycogen, or even water can be prominent as well, giving the cells a "clear cell" appearance, which has been described as the clear cell variant of HCC. If the entire tumor shows this type of clear cell change and occurs in the noncirrhotic liver, it may be difficult to differentiate HCC from other clear cell tumors such as metastatic renal cell carcinoma. Other cytoplasmic changes that are seen much less frequently include the pale bodies (which are round to oval, lightly eosinophilic or clear cytoplasmic structures most frequently seen in the fibrolamellar variant of HCC, see below), ground glass cells containing HBsAg that are present in some patients with HBV infections, and dark-brown to black pigment like that seen in the Dubin-Johnson syndrome. Very rare forms of HCC with a prominent spindle cell component and a small cell type have been described.

Histologic grading of HCC. The grading of HCC has traditionally been based on three or four grades, based on the system developed by Edmondson and Steiner in 1954. They originally defined four grades as distinguished by proportional increases in nuclear:cytoplasmic ratio, variability in nuclear shape, hyperchromasia, and loss of cell plate architecture from low to high grade tumors. These grades are basically still used with some modifications, mostly in the low grade classifications. Some of Edmondson/Steiner's Grade I tumors with minimal cytologic atypia and architectural distortion were only recognized as malignant by their association with admixture of other higher grades of HCC or by the presence of metastatic lesions. With the current criteria now available as established by the International Working Party, stricter definition for Grade I lesions can possibly separate out some of these as dysplastic nodules. Grade II tumors are still well-differentiated, and still have a typical trabecular pattern but with increased nuclear size as compared to Grade I tumors. Grade II lesions can also contain acinar structures and bile. Grade III tumors are moderately differentiated, and have more cytologic and architectural variability than the Grade II lesions. Multinucleated and giant cells are often seen focally, and in contrast to grade II lesions, bile is often not present. When trabeculae are present, they are typically wider and/or more variable in structure than those in Grade II tumors. Grade IV consists of poorly differentiated tumors, or anaplastic lesions for which classification as HCC is difficult without the appropriate clinical setting such as cirrhosis or significantly elevated serum AFP. Grade IV lesions can include spindle cell and small cell components as well. An alternate three grade system is often used, with Grade I representing well-differentiated lesions (Grade I and II above combined); Grade II, the moderately differentiated lesions; and Grade III, the poorly differentiated and anaplastic lesions.

Differential diagnosis. Immunoperoxidase studies are not helpful to differentiate benign from malignant hepatocellular tumors; however, they can help to distinguish HCC from other tumors in the liver. Most of the diagnostic problems arise in differentiating the benign hepatocellular tumors such as adenoma or focal nodular hyperplasia from well-differentiated hepatocellular carcinoma, or poorly differentiated HCC from other primary or metastatic neoplasms. Well-differentiated HCC can be differentiated from large regenerative/low-grade dysplastic nodules and high-grade dysplastic nodules by features noted in Table 3.

Fibrolamellar Variant of HCC

Clinical features. The fibrolamellar variant of HCC (FLHCC) occurs in the noncirrhotic liver in young adults (mean age 26 years, females>males) and, with this strict definition (as is generally accepted), has a better prognosis than typical HCC of similar size. Lesions with similar morphology have been noted in the cirrhotic liver, but these HCCs should not be diagnosed as FLHCC by convention due to their much more variable outcome. Presentation may be accompanied by complaints such as abdominal pain or swelling, anorexia, weight loss, jaundice, and rarely, hemoperitoneum. No definitive risk factors have been identified. Nodular hyperplastic changes have been noted adjacent to FLHCC, but most concur that this is a secondary affect due to vascular changes within the liver adjacent to the tumor rather than suggesting that FLHCC arises in association with FNH. Serum AFP levels are usually normal; only rarely have high levels have been reported. Complete excision of the involved lobe is the current therapy of choice. When the tumor location precludes resection, liver transplantation has been done, but the outcome is not as favorable.

Gross features. FLHCC is a well-circumscribed, nodular, yellow to brown tumor with fibrosis. Rarely, a prominent central, fibrous zone similar to that of FNH can be present. The larger tumors can shows foci of hemorrhage and necrosis; satellite lesions are rare.

Microscopic features. The cellular component of FLHCC consists of small to large clusters or sheets of tumor cells separated by dense bands of lamellar fibrous tissue. The tumor cells tend to have a polygonal shape, and they routinely have eosinophilic and granular cytoplasm. Nuclei are large with prominent nucleoli easily identified. Other cytoplasmic features include the "pale body," which may contain fibrinogen and/or albumin and PASD-positive bodies, which probably represent various glycoprotein secretions. Other focal features that can be noted are acinar structures, bile, multinucleated tumor cells, copper, fat, epithelioid granulomas, and peliosis hepatis. Glandular differentiation with mucin secretion as well as zones of trabecular HCC have also been noted; it is not clear whether these variations result in poorer prognosis.

Combined Hepatocellular-Cholangiolar Carcinoma

Clinical features. Combined (or mixed) hepatocellular-cholangiolar carcinoma (HCC/CC)may account for up to 5% of all primary carcinomas of the liver. The risk factors are essentially the same as for HCC alone.

Diagnostic features. Combined HCC/CC contains a mixture of hepatocellular and ductular elements scattered throughout the tumor. Collision tumors, where each element is separated or side by side, are not considered to fall into this combined category by the World Health Organization classification.

Special studies. Cytoplasmic mucin and/or immunoperoxidase stains for keratin types such as AE1/AE3, cytokeratins 19 or 20 (as seen in ductular tumors) can be used to identify the cholangiocarcinoma component. CK7 also identifies ductular components, but this can also stain cells within HCC as well so caution should be used in interpretation of CK 7 alone. Bile production by tumor cells, or immunoperoxidase positivity for markers specific for hepatocytes such as AFP, polyclonal CEA, and hepatocyte antibody can help to identify the hepatocellular component.

Sclerosing Hepatic Carcinoma

This term has been used to refer to a mixture of hepatocellular, cholangiolar, or combined hepatocellular-cholangiolar carcinomas with tubular neoplastic structures embedded in a fibrous stroma that are typically associated with hypercalcemia.

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Table 3: Nodules in a Cirrhotic Liver

Macroregenerative Nodule Low Grade Dysplastic Nodule High Grade Dysplastic (Borderline) Nodule Well-Differentiated Hepatocellular Carcinoma
Hepatocyte Similar to cirrhotic nodules A uniform population of hepatocytes suggesting a clonal proliferation Variable, usually similar to normal size or slightly smaller Smaller or larger cells, diffuse type changes most common
Small cell change Absent or only scattered cells Absent or only scattered cells Occasional small foci, but nuclear density <2x normal, can be diffuse or prominent; dysplastic focus may have appearance of a nodule within the larger nodule Small foci to large zones commonly present
Cell plate architecture Less than 2-3 cells thick, reticulin intact Less than 2-3 cells thick, reticulin intact May see some plates > 3 cells thick, but no zones of trabeculae present, focal loss of reticulin Trabeculae commonly seen, zones of reticulin loss
Increased iron deposits Sometimes present Unknown May be present Almost always absent even in the setting of a siderotic liver
Periphery of nodule Well-circumscribed Well-circumscribed Some with irregular edge Common to see infiltrative or irregular edge
Portal zones or fibrous tissue zones Almost always present, focal bile ductular proliferation may be present Probably present Normal portal zones often seen within the larger dysplastic nodules No intact portal zones present unless entrapped near edge of tumor