Histopathologic Classification of Liver Pathologies

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Benign and Malignant Nodular Hepatocellular



Regenerative Lesions


Dysplastic or Neoplastic Lesions


Benign and Malignant Tumors of the Biliary



Bile Duct Adenoma


Bile Duct Cystadenoma


Biliary Papillomatosis


Bile Duct Carcinoma (Cholangiocarcinoma)


Bile Duct Cystadenocarcinoma


Gallbladder Carcinoma


Benign Non-Epithelial Tumors




Infantile Hemangioendothelioma






Malignant Non-Epithelial Tumors




Malignant Epitheloid Hemangioendothelioma


Undifferentiated (Embryonal) Sarcoma


Rhabdomyosarcoma (Sarcoma Botryoides)


Other Primary Sarcomas


Primary Lymphoma of the Liver




Tumor-like Lesions




Mesenchymal Hamartoma


Biliary Hamartoma


Inflammatory Pseudotumor


Other Tumor-like Lesions: Peliosis Hepatis


Infectious Diseases of the Liver


Liver Abscess


Helminthic Infections


Parenchymal Disease




Transfusional Iron Overload (Hemosiderosis)

2.8.3 Fatty Liver

2.8.4 Wilson's Disease

2.8.5 Primary Sclerosing Cholangitis

2.8.6 Cirrhosis

2.8.7 Primary Biliary Cirrhosis

2.8.8 Secondary Biliary Cirrhosis

2.8.9 Reye's Syndrome

2.8.10 Caroli's Syndrome

2.8.11 Liver Disease in Patients with Cystic Kidneys

2.8.12 Langerhans Cell Histiocytosis

2.8.13 Storage Diseases

2.8.14 Viral Hepatitis

2.8.15 Liver Disease in Congestive Heart Disease

2.9 Vascular Changes

2.9.1 Thrombosis of the Portal Vein

2.9.2 Obstruction of Smaller Portal Branches

2.9.3 Budd-Chiari Syndrome

2.9.4 Veno-Occlusive Disease

2.9.5 Lobular or Segmental Atrophy

2.9.6 Infarction / Ischemia

2.10 HIV-associated Liver Diseases

2.10.1 Kaposi's Sarcoma

2.10.2 Primary Lymphoma of the Liver

2.10.3 Cholangitis

2.10.4 Fungal Infections

2.10.5 Protozoal Infections

2.10.6 Bacterial Infections

2.1 1 Hepatic Trauma

2.1 2 Metastases

2.12.1 Metastases of Colorectal Adenocarcinoma

2.12.2 Metastases of Breast Carcinoma

2.12.3 Carcinoid Metastases

2.1 3 Infiltration of the Liver in Hematologic Diseases

2.13.1 Non-Hodgkin's Lymphoma

2.13.2 Hepatic Hodgkin's Lymphoma

Benign and Malignant Nodular Hepatocellular Lesions

Regenerative Lesions

Generally, a regenerative nodule is a well-circumscribed area of parenchyma showing enlargement as a response to necrosis, altered circulation or other stimuli.

Monoacinar Regenerative Nodule

A monoacinar regenerative nodule is a regenerative nodule limited to one portal tract. Usually, multiple nodules are found involving most of the liver. This is referred to as diffuse nodular hyper-plasia [184].

Diffuse Nodular Hyperplasia without Fibrous Septa (Nodular Regenerative Hyperplasia, NRH)

Diffuse nodular hyperplasia can be subdivided into nodular regenerative hyperplasia in which no fibrous septa can be found, or diffuse nodular hy-perplasia containing fibrous septa or occuring in coexisting cirrhosis.

Nodular hyperplasia is defined by the presence of non-neoplastic nodules that are not limited by fibrous septa (Fig. 1). The cells of the surrounding parenchyma are atrophic (Fig. 2). Nodular hyperplasia is usually a regenerative response occurring after circulatory stress. Portal vein obstruction may be responsible for widespread hepatocellular atrophy and secondary hepatic arterial dilatation (Fig. 3). Increased arterial flow and possible hepa-totropic factors cause hepatocellular hyperplasia and nodule formation.

Monoacinar regenerative nodules may also occur in cases of disturbed circulation, such as hepatic vein obstruction and circulation disorders of the sinusoids. However, the resulting nodules are less uniformly distributed and are accompanied by more congestion and fibrous septa.

The term NRH was originally applied to livers with minimal or no parenchymal fibrosis. NRH can be found in up to 5% of the older population. A higher prevalence occurs in patients with concomitant systemic diseases associated with vascu-lopathy, such as polycythemia, rheumatoid arthritis and polyarteritis nodosa.

Hyperplasia The Liver
Fig. 1. Cut surface of a nodular regenerative hyperplasia (NRH)
Regenerative Liver Cells
Fig. 2. Nodular regenerative hyperplasia demonstrating a nonneoplastic nodule with hyperplastic liver cells surrounded by at-rophic parenchyma
Fig. 3. Histology of diffuse nodular regenerative hyperplasia with demonstration of multiple nodules (arrows) surrounded by atrophy in adjacent liver tissue caused by Budd-Chiari syndrome
Budd Chiari Syndrome Pathology

Fig. 4 . Nodular regenerative hyperplasia with a diffuse micro-nodular pattern

Clinical symptoms, which aid the diagnosis in affected patients, include esophageal varices, splenomegaly, moderate increased alkaline phos-phatase and ascites [118,176].

Diffuse Nodular Hyperplasia with Fibrous Septa or in Cirrhosis

As described above, this lesion corresponds to nodular regenerative hyperplasia with concomitant fibrous septa, or which is superimposed on a previous hepatic cirrhosis [177,184].

Fig. 4 . Nodular regenerative hyperplasia with a diffuse micro-nodular pattern

Multiacinar Regenerative Nodule

A regenerative nodule involving more than one solitary portal tract is called a multiacinar regenerative nodule. Normally, it presents in livers with pre-existing pathology such as cirrhosis, or in cases of severe disease of the portal veins, hepatic veins, or sinusoids. Usually, multiple nodules occur within the liver and these can correspond to cirrhotic nodules if they are surrounded by fibrous septa. If larger than most cirrhotic nodules of the same liver or measuring at least 5 mm in diameter, multiacinar regenerative nodules are also called large regenerative nodules or macroregenerative nodules [172] (Fig. 4).

Cirrhotic Nodule (Monoacinar Cirrhotic Nodule/ Multiacinar Cirrhotic Nodule)

Generally, a cirrhotic nodule is defined as a regenerative nodule in which hepatocytes are partially or completely surrounded by fibrous septa. It can be subdivided according to its expansion. Thus, a monoacinar cirrhotic nodule contains no more than one terminal portal tract, whereas a multiaci-nar cirrhotic nodule is composed of two or more portal tracts. However, this definition is not in accordance with the classifications micronodule and macronodule that exist in cirrhosis. This is usually defined by size with a division point at 3 mm in diameter [14].

Lobar or Segmental Hyperplasia

Lobar or segmental hyperplasia is defined as the enlargement of an entire lobe or the major part of a lobe in one or several liver segments, while other parts of the liver show atrophy, necrosis or fibrosis. This pathologic pattern has also been described as atrophy-hypertrophy complex [71].

Lobar or segmental hyperplasia may occur in Budd-Chiari syndrome or in primary sclerosing cholangitis involving the hepatic veins or bile ducts. It introduces both a hyperplasia and an atrophy or fibrosis into the liver parenchyma. As hyperplasia typically arises in regions with increased blood flow in Budd-Chiari syndrome, the caudate lobe often presents as hyperplastic because the drainage of this part of the liver is usually independent of the main hepatic veins. Normally lobar or segmental hyperplasia measures at least several centimeters in diameter but consists of histologically normal liver cells [164].

Focal Nodular Hyperplasia (FNH)

Focal nodular hyperplasia is defined as a nodule that consists of benign-appearing hepatocytes which are accompanied by fibrous stroma and which may contain ductules that form a characteristic central stellate scar. It usually occurs in an otherwise histologically normal or nearly normal liver.

Similar to adenoma (, FNH is predominantly found in female patients. Although oral contraception does not seem to be causal, continuous enlargement of lesions has been reported concomitant with the taking of birth-control pills and during pregnancy [182].

Multiple FNH occur in 10-20% of all cases while an association with hemangioma occurs in 5-10% of cases [78,107].

Macroscopically, FNH shows septations and, in classical cases, a central scar. However, in up to 30% of all cases a central scar is not present. In contrast to fibrolamellar carcinoma (, the

Fig. 5. Focal nodular hyperplasia consists of liver nodules which are separated by fibrous septa (arrows). Bile ducts, sometimes numerous, are always present at the interface between liver nodules and septa.

Kupffer Cell Hyperplasia

Fig. 6. Histology of focal nodular hyperplasia demonstrating Kupffer cells (arrows)

Fig. 5. Focal nodular hyperplasia consists of liver nodules which are separated by fibrous septa (arrows). Bile ducts, sometimes numerous, are always present at the interface between liver nodules and septa.

Fig. 6. Histology of focal nodular hyperplasia demonstrating Kupffer cells (arrows)

scar is not a true one, but rather congeries of blood vessels and bile ducts and sometimes a focal area of cirrhosis.An elevated fat- and glycogen-content can often be demonstrated. FNH is thought to derive from an initial regional vascular arteriovenous (AV) malformation which undergoes consecutive localized overgrowth of all liver constituents. Thus, histologically, FNH consists of abnormally arranged normal liver cells (Fig. 5). In contrast to adenoma, small bile ductules that do not communicate with larger bile ducts are found. Kupffer cells are also present although their function is frequently deficient (Fig. 6).

FNH is currently divided into a classic and a non-classic type. The classic type presents with an abnormal nodular architecture, malformed vessels, and cholangiocellular proliferation. The non-classic type can be further subdivided into a) teleangiectatic FNH, b) FNH with cytologic atypia and c) mixed hyperplastic and adenomatous FNH

The gross appearance of classic FNH consists of nodules surrounded by fibrous septations in a radiating appearance originating from the central scar. On histologic examination there is nodular hyperplastic parenchyma and often moderately thickened hepatic plates with normal hepatocytes. The central scar consists of fibrous tissue, cholangiocellular proliferation with surrounding inflammation and malformed vessels of different calibres. In contrast to adenoma, the blood flows centrifugally from anomalous central arteries in FNH.

Non-classic FNH typically does not show a central scar formation, its appearance is variable, and often resembles adenoma. The teleangiectatic type presents with atrophic hepatic plates separated by dilated sinusoids. Short fibrous septa and bile-duct proliferation is always found in teleangiectatic FNH.

FNH with cytologic atypia typically exhibit the appearance of classic FNH, but contain areas of cell dysplasia.

Mixed hyperplastic and adenomatous FNH presents features of the teleangiectatic type as well as a resemblance to adenoma.

A so-called FNH syndrome is present if more than two FNH co-exist with intracerebral vascular malformations, meningioma or astrocytoma. If any of the associated lesions are found in the presence of a solitary FNH, the syndrome is probably present with incomplete expression. Since the risk of rupture is quite low and patients usually do not present relevant symptoms (90% of all FNH are discovered by chance), surgical intervention is not mandatory [88].

Focal Nodular Hyperplasia, Solid Type

The solid type of FNH occurs most commonly. Solitary lesions are observed in two thirds of individuals, while two or more lesions may be present in the remaining one third of individuals.

On cut sections most solid FNH have a central fibrous stalk region (Figs. 7,8). However, this is often absent in lesions smaller than 1 cm in diameter. The stalk region contains an artery that typically is larger than expected considering its localization. Degenerative changes such as post-throm-botic arterial fibrosis and cholestasis may be observed in larger lesions.

Nodular Focal Hyperplasia Histology
Fig. 7. Focal nodular hyperplasia with characteristic central fibrous region (arrow) and radiating fibrous cords

Fig. 8. Histology of a central stellate scar in FNH demonstrating thick-walled vessels (arrow) of a large arterial malformation surrounded by fibrous tissue

Focal Nodular Hyperplasia, Telangiectatic Type

This type of FNH shows multiple dilated blood spaces near the center of the lesion, so that large lesions may resemble hemangioma or peliosis. Compared with solid FNH, the arteries in the central region are small and numerous. The teleangiectat-ic type of FNH is usually observed in cases of multiple FNH syndrome.

Dysplastic or Neoplastic Lesions

Hepatocellular Adenoma

Liver cell adenoma has an incidence of 1/1,000,000 and is mainly found in women of child-bearing age [65].

In contrast to the situation with FNH, oral contraceptives seem to lead to an increased incidence of hepatocellular adenoma [16]. Moreover, both lesion size and complication rate seem to correlate positively with the duration of oral contraception [26]. Some authors have noted tumor regression after discontinuation of oral contraceptives [43].

Androgen therapy, familial insulin-dependent diabetes, Fanconi anemia and some glycogen storage diseases tend to predispose subjects to adenoma [61].

If subjects have more than ten hepatic adeno mas the condition is referred to as liver adeno-matosis. This entity is independent of gender or hormone therapy and seems to be associated with an elevated complication rate.

Adenomas are unencapsulated tumors of light brown or yellow colour in gross specimen, with compressed adjacent liver tissue that may mimic capsule formation.

Biopsy of adenoma reveals enlarged and glycogen-rich hepatocytes, sometimes surrounded by a capsule (Fig. 9). Portal tracts and bile ducts are characteristically absent and, in contrast to FNH, there is a substantially increased risk of spontaneous bleeding [121] (Fig. 10). He-patocytes are normal in appearance, but the typical acinar architecture is missing. Mitoses are often absent.

The missing bile ducts enable the differential diagnosis of adenoma from FNH on hepatobiliary sequence scintigraphy. Around 80% of patients with liver cell adenoma complain of abdominal symptoms, which are typically caused by compression, intratumoral bleeding or even rupture and hemoperitoneum [154].

Patients with liver cell adenoma should undergo resection to avoid these complications, and female patients should discontinue oral contraception. Some authors report individual cases of malignancy developing in liver cell adenoma, however, as yet, there is no valid proof of malignant transformation [60].

On rare occasions it may be impossible to distinguish adenoma from well-differentiated hepa-tocellular carcinoma (HCC) on biopsy.

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