China is a region with high incidence of viral hepatitis and hepatocellular carcinoma (HCC), and the incidence of HCC has jumped to the 2nd-3rd place of malignant tumors. Most hepatocellular carcinomas occur in the basis of cirrhosis, especially after hepatitis B and C. The differential diagnosis of hepatocellular nodular lesions is a major challenge for both clinicians and pathologists because, with the widespread availability of ultrasound-guided puncture biopsies and interventions, it is very difficult to clarify the benignity or malignancy of the tiny tissue punctured. Hepatocellular nodular lesions can occur in both cirrhotic and non-cirrhotic livers, but the lesions vary widely.
Hepatocellular nodular lesions in non-cirrhotic liver mainly include.
1. liver cell adenoma (LCA) Hepatocellular adenoma is rare and often occurs in women taking oral contraceptives. Other factors associated with the development of hepatocellular adenoma include: taking metabolic steroids, anti-fertility drugs such as clomiphene and danazol; metabolic disorders such as type Ia glycogen storage disease, tyrosinemia, lactosemia, and familial diabetes mellitus.
Hepatocellular adenoma often comes to attention due to acute abdominal pain caused by bleeding within the tumor. Some patients present with only abdominal pain or discomfort. Occasionally, they are found unexpectedly on clinical or imaging studies. Drug-induced hepatocellular adenomas often resolve when the drug is withdrawn. Some hepatocellular adenomas often require surgical removal because of the risk of bleeding. It has also been reported that a small number of hepatocellular adenomas have the potential to transform into hepatocellular carcinoma.
Differential diagnosis: Hepatocellular carcinoma, focal nodular hyperplasia (FNH), and large regenerative nodules (LRN) should be differentiated from LCA. It is easy to distinguish between surgically resected specimens of the above lesions from each other, but it is more difficult to distinguish between specimens obtained by fine needle aspiration.
Focal nodular hyperplasia (FNH) FNH often occurs in the normal liver, with no significant effect of gender or age on the onset of the disease. It is lighter in color and harder in texture than the surrounding liver tissue. Typically, the nodule is a central stellate scar surrounded by a nodule of liver parenchyma, which is divided by a fibrous septum radiating from the central scar. Broadly speaking, FNH nodules are similar to cirrhotic nodules. FNH has been shown to be caused by reactive hyperplasia of the liver parenchyma in response to a prior arterial spider-like malformation.
In addition to the solid type described above, a rare capillary-dilated type of FNH exists, in which the central scar described above is replaced by dilated blood cell-filled vessels. Broadly speaking, this part of the area is reminiscent of a hemangioma or purpura, and the arteries supplying this type of FNH are small and abundant compared to the solid type of FNH. About 1/3 of patients with FNH present with multiple lesions, and some present with multiple FNH syndromes, where FNH coexists with 1 or 2 other lesions, such as hepatic hemangiomas, structural defects of the arteries, vascular malformations of the central nervous system, meningiomas, and astrocytomas. Capillary dilated FNH is more commonly seen in multiple FNH syndromes.
Differential diagnosis: FNH should be differentiated from cirrhosis, LRN, LCA. it is difficult to differentiate between FNH and cirrhosis in biopsy specimens, especially when the wrong specimen is taken and no abnormal arteries are present. Since most of these biopsy specimens are obtained under imaging guidance, it is often possible to clarify in advance whether the lesion originates from the surrounding normal liver or from a liver that has undergone cirrhosis. When no hepatic triadic structures are seen in the fibrous septa surrounding a substantial hepatic nodule, then the diagnosis of FNH should be questioned.
3. nodular regenerative hyperplasia (NRH) NRH, also known as “diffuse nodular transformation”, has been thought to be a neoplastic lesion of the liver, but it has been shown to be a proliferative response of the liver parenchyma to abnormal blood vessels or blood circulation. NRH is often associated with diseases such as vascular collagen disease, myeloproliferative disorders, malignant lymphoma, bone marrow transplantation, chronic bruising, and primary biliary cirrhosis. The occurrence of NRH has been reported in 5% of autopsy cases in the elderly, but the incidence of the disease is higher in patients with the above mentioned systemic diseases.NRH is often found incidentally in surgery, autopsy, biopsy or as a cause of portal hypertension.
Differential diagnosis: It should be differentiated mainly from normal liver and cirrhosis.
4. Partial nodular transformation (PNT) PNT is a rare disease associated with NRH but differs from NRH in the extent of liver involvement. Like NRH, PNT can cause non-sclerotic portal hypertension, but unlike NRH, which involves the liver diffusely, PNT mainly involves the liver parenchyma around the hepatic hilum. the nodal diameter of PNT is usually a few centimeters. The lesion is generally associated with obstruction of the medium and large veins of the portal system. Due to the focal features of PNT, its hepatocellular biopsy must be guided by imaging. the final diagnosis of PNT requires a triple combination of clinical, imaging and pathological findings to be made.
The term “compensatory hyperplasia” is used to describe the reactive hyperplasia of a lobe or segment of the liver due to atrophy or resection of an adjacent lobe or segment. often associated with thrombosis of the portal or hepatic veins. The hyperplastic response may form tumor-like nodules, which are evident on imaging. Histologic features of normal or near-normal lesion sites notwithstanding, altered widening of the liver plate may be seen.
6. focal fatty change Focal fatty change is sometimes seen in normal livers as well as in livers with chronic lesions, including cirrhosis. The areas of involvement are often isolated and are several centimeters in diameter. The diagnosis and identification of this lesion is a major challenge for the imaging physician, and therefore a liver biopsy is required to confirm the diagnosis.
The main hepatocellular nodular lesions in cirrhosis include.
The pathologic evaluation of nodular lesions in cirrhosis differs from that in the non-cirrhotic liver. First, in cirrhosis, the entire liver is nodular, so the main problem in diagnosis is to distinguish the diseased nodules from the surrounding nodules. Second, some nodular lesions, such as LCA and FNH, often occur in non-cirrhotic livers, and if they occur in cirrhosis, the lesions behave differently.
Since HCC is commonly found in cirrhosis, malignancy must be excluded even when a large nodule in the liver is suspected to be a possible adenoma. By convention, it is highly unlikely that adenoma will be diagnosed in the context of cirrhosis. Similarly FNH can theoretically occur in cirrhosis, but in practice it is difficult to recognize even if it does exist.
Thus, there are three main diseases that are easily confused in the diagnosis of cirrhosis. DN is considered to be a precancerous lesion and was previously diagnosed as adenomatous hyperplasia or giant regenerative nodule. For the sake of consistency and further accuracy in diagnosis, both of these terms were dropped at the 1994 World Congress of Gastroenterology. DN is now considered to be a neoplastic clonal lesion, and because the lesion may or may not have cellular or structural heterogeneity, DN can be further classified as either low or high grade, which are distinct.
1. RN According to the size of the nodules, cirrhosis can be classified as small nodule type, large nodule type, and mixed small and large nodule type. Most of cirrhosis belongs to mixed type of small and large nodules. Therefore, the diagnosis of the following diseases should not be based only on gross morphological features. If not only large nodules but also diffusely distributed nodules >1 cm in diameter are seen in the liver, the diagnosis of diffuse atypical hyperplastic nodules should be considered. In fact, such a liver does not have any pre-cancerous or heterogeneous features of HCC, is mostly post-hepatitis cirrhosis and is commonly seen in younger patients.
2. DN is a neoplastic lesion and may also be precancerous. Although DN can be detected early by ultrasound or MRI in some countries, by and large, DN is still commonly seen in cirrhosis and occasionally in chronic liver disease that has not fully developed cirrhosis. DN can form hepatocellular nodules that are well-defined from the surrounding cirrhotic parenchyma. It is clear that DN in imaging also includes HCC, so the final diagnosis depends on pathology. Most DN forms nodules with a maximum diameter >0.8 cm, so they are easily distinguished from nodules of surrounding cirrhosis, but some nodules are smaller in diameter. DN can be further classified as low-grade and highly malignant lesions.
The distinction between low-grade DN and general regenerative nodules is more difficult.
High grade DN has many features suggestive of precancerous lesions or cancer. Sometimes atypical hyperplastic nodules, either diffuse or confined subnodules, are difficult to distinguish from obvious HCC, and some authors refer to these nodules as adventitial lesions, which are also included in the classification of high grade DN. In addition, some highly DN contain extremely obvious areas of HCC, and such lesions are referred to as highly DN with HCC or carcinoma in situ.
3.HCC Early stage HCC can form two types: extended type and non-extended type. Extended type has no envelope on the surface, does not invade, and is highly differentiated. This type of lesion may be an early stage of hepatocellular carcinoma development (whether it exists in DN or not). The non-extended type often has an envelope on the surface, contains hypodifferentiated areas, is often associated with local invasion, and is a later stage of tumor development. The difficulties in the diagnosis of HCC in the setting of cirrhosis are mainly related to the specimen. If too few or too small biopsy specimens are taken from the mass, or if the diagnosis is made by fine needle aspiration, it is difficult to determine whether the normal-appearing hepatocytes represent highly differentiated HCC or nearby regenerative nodules, when observation of the vasculature is important.
Another factor that makes the diagnosis of HCC difficult is the size of the lesion, especially when the lesion is less than 2.0 cm. If there is some degree of heterogeneity within the biopsy specimen from the above lesion, but the degree of structural or cellular heterogeneity does not reach cancer, then the possibility of a high degree of DN must be considered, and it is best to express the above features clearly in the diagnostic description to draw clinical attention to the fact that any such lesion is at great risk of progressing to HCC, and the patient should undergo further imaging. If the lesion is larger than 2 cm, then the diagnosis of HCC is more likely, and further deeper examination of the biopsy specimen can often reveal definite features of HCC.