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Cancer of the liver is a devastating disease. By the time the diagnosis is suspected or made, it is often at an advanced stage.
There are many tumors which may mimic the disease.

Liver cell Adenoma
Dysplastic Nodule (Macroregenerative Nodule)
Hepatocellular carcinoma


Histopathological Features and Variants  
Special Stains/Immunohistochemistry/Electron Microscopy  
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Atypical Bile Duct Adenoma, Clear Cell Type A Previously Undescribed Tumor of the Liver

Jorge Albores-Saavedra, M.D.; Mai P. Hoang, M.D.; Linda A. Murakata, M.D.; Prasanna Sinkre, M.D.; Hadi Yaziji, M.D.

From the Division of Anatomic Pathology (J.A.-S., M.P.H., P.S.), University of Texas Southwestern Medical Center, Dallas, Texas; the Department of Hepatic and Gastrointestinal Pathology (L.A.M.), the Armed Forces Institute of Pathology, Washington, DC, and PhenoPath Laboratories (H.Y.), Seattle, Washington, U.S.A.

Am J Surg Pathol 2001;25:956-960 Abstract quote

A variable proportion of bile duct adenomas of the liver are still confused with metastatic well-differentiated adenocarcinoma by surgeons and pathologists.

We present here three examples of previously undescribed primary hepatic bile duct tumors that were composed almost entirely of clear cells that closely mimicked metastatic renal cell carcinoma. They were interpreted as atypical bile duct adenomas and occurred in two males and one female whose ages ranged from 25 to 64 years.

All three tumors were incidental findings and measured from 0.8 to 1.1 cm. The clear neoplastic cells showed mild nuclear atypia and no mitotic activity. They were arranged in tubules and nests that focally infiltrated the hepatic parenchyma. For comparison, a case of clear cell cholangiocarcinoma and 13 conventional bile duct adenomas were examined. The clear cell cholangiocarcinoma was larger (6.0 cm) and had the tubular pattern of conventional cholangiocarcinoma and an abundant desmoplastic stroma. The clear cells of this tumor exhibited greater nuclear atypia and increased mitotic activity. All three atypical bile duct adenomas expressed cytokeratin (CK) 7, p53 protein, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA); they were negative for CK20, vimentin, Hep Par 1, chromogranin, and prostatic specific antigen (PSA) and exhibited less than 10% of Ki-67-positive nuclei. One atypical bile duct adenoma displayed luminal immunoreactivity for villin. With the exception of Ki-67 reactivity, the 13 conventional bile duct adenomas and the clear cell cholangiocarcinoma had essentially a similar immunohistochemical profile as that of the atypical clear cell bile duct adenomas.

The absence of an extrahepatic primary tumor, the histologic features, the immunohistochemical profile, and the fact that all patients are symptom-free 2 months to 18 years after wedge liver biopsy support the interpretation of atypical clear cell bile duct adenoma. The differential diagnosis with clear cell hepatocellular carcinoma and metastatic clear cell carcinomas is discussed.


Undifferentiated (embryonal) sarcoma of the liver in middle-aged adults: smooth muscle differentiation determined by immunohistochemistry and electron microscopy.

Nishio J, Iwasaki H, Sakashita N, Haraoka S, Isayama T, Naito M, Miyayama H, Yamashita Y, Kikuchi M.

Department of Pathology, School of Medicine, Fukuoka University, Fukuoka, Japan.


Hum Pathol 2003 Mar;34(3):246-52 Abstract quote

Undifferentiated (embryonal) sarcoma of the liver (UESL) is a rare pediatric liver malignancy that is extremely uncommon in middle-aged individuals.

We studied 2 cases of UESL in middle-aged adults (1 case in a 49-year-old woman and the other in a 62-year-old man) by histology, immunohistochemistry, and electron microscopy to clarify the cellular characteristics of this peculiar tumor. One tumor showed a mixture of spindle cells, polygonal cells, and multinucleated giant cells within a myxoid matrix and also revealed focal areas of a storiform pattern in a metastatic lesion. The other tumor was composed mainly of anaplastic large cells admixed with few fibrous or spindle-shaped components and many multinucleated giant cells.

In both cases, some tumor cells contained eosinophilic hyaline globules that were diastase resistant and periodic acid-Schiff positive. Immunohistochemically, the tumor cells showed positive staining for smooth muscle markers, such as desmin, alpha-smooth muscle actin, and muscle-specific actin, and also for histiocytic markers, such as alpha-1-antitrypsin, alpha-1-antichymotrypsin, and CD68. Electron microscope examination revealed thin myofilaments with focal densities and intermediate filaments in the cytoplasm of tumor cells.

Our studies suggest that UESL exhibits at least a partial smooth muscle phenotype in middle-aged adults, and this specific differentiation may be more common in this age group than in children. Tumor cells of UESL with smooth muscle differentiation in middle-aged adults show phenotypic diversity comparable to those of malignant fibrous histiocytoma with myofibroblastic differentiation.



A Comparison of CD10 to pCEA, MOC-31, and Hepatocyte for the Distinction of Malignant Tumors in the Liver

Carl Morrison, M.D., D.V.M., William Marsh, Jr, M.D. and Wendy L. Frankel, M.D.
Department of Pathology, The Ohio State University, College of Medicine, Columbus, Ohio

Modern Pathology 2002;15:1279-1287 Abstract quote

The distinction of hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) and cholangiocarcinoma (CC) in some cases requires the use of immunohistochemistry. CD10 has recently been suggested as a useful stain for HCC.

We directly compared CD10 with other immunohistochemical markers, Hepatocyte, pCEA, and MOC31, that have previously shown to be useful for the distinction between tumors in the liver to help define the current panel of stains that most readily distinguishes HCC from CC and MA. One hundred previously well-characterized tumors in the liver were evaluated and included 25 HCC, 15 CC, and 60 MAs (15 each from breast, esophageal/gastric, pancreatic, and colorectal origin).

Tumors were immunostained with the commercially available antibodies Hepatocyte, pCEA, MOC31, and CD10. CD10 stained 13 of 25 HCC and was rarely positive in MA and CC (3/75). Hepatocyte stained 24 of 25 HCC and was negative in all 75 MA and CC. pCEA stained 24 of 25 HCC and 71 of 75 MA and CC with the proper pattern of immunoreactivity, but the pattern of staining was difficult to interpret in several cases. MOC31 stained 1 of 25 HCC and 65 of 75 MA and CC. Hepatocyte was the most sensitive and specific single marker for HCC. CD10 is not a useful addition or substitution to the panel of Hepatocyte, MOC31, and pCEA.

The combination of Hepatocyte, MOC31, and pCEA correctly classified 99 of 100 tumors in this study and is our proposed panel of immunostains for the initial workup of malignant tumors in the liver.

Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.

Lau SK, Prakash S, Geller SA, Alsabeh R.

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Hum Pathol 2002;33:1175-1181 Abstract quote

Distinguishing hepatocellular carcinoma (HCC) from cholangiocarcinoma (CC) and metastatic adenocarcinoma (MA) involving the liver can be problematic, often requiring the use of immunohistochemistry to facilitate diagnosis. Hep Par 1, a monoclonal antibody with expression confined primarily to benign and malignant hepatocytes, has recently become commercially available.

We evaluated Hep Par 1 along with other immunohistochemical markers used to differentiate HCC, CC, and MA, including AE1/AE3, CAM 5.2, B72.3, monoclonal carcinoembryonic antigen (mCEA), polyclonal CEA (pCEA), alpha-fetoprotein (AFP), factor XIIIa, inhibin, CD10, villin, MOC-31, cytokeratin (CK) 7, CK 19, and CK 20, to determine the markers most useful in differentiating these entities. Forty-two cases of HCC, 9 cases of CC, and 56 cases of MA (24 colon, 15 pancreas, 8 ovary, 5 breast, and 4 stomach) were studied. Hep Par 1 was sensitive and specific for HCC, with 38 of 42 (90%) cases staining positively, whereas reactivity was observed in only 8 of 56 (14%) MAs and 0 of 9 CCs.

Though limited somewhat by poor sensitivity, a bile canalicular pattern of staining with pCEA, CD10, and villin was specific for HCC and was not observed in the other tumors. Lack of mCEA and MOC-31 immunoreactivity was also characteristic of HCCs. CK 19 positivity favored CC over HCC, but was not useful in differentiating CC from MA.

Expression of AFP, although observed in only about one third of the cases, favored HCC over CC and MA. CK 7 and CK 20 were also useful in this differential diagnosis, particularly when dealing with MA of colonic origin. AE1/AE3, CAM 5.2, B72.3, inhibin, and factor XIIIa were noncontributory in differentiating these entities.


With cirrhosis Macroregenerative nodule (low-grade dysplastic nodule)
Borderline (high-grade dysplastic nodule)
Hepatocellular carcinoma
Without cirrhosis Multiacinar regenerative nodule
Focal nodular hyperplasia
Fibrolamellar heptocellular carcinoma
Hepatocellular carcinoma
Mimics cirrhosis clinically Nodular regenerative hyperplasia
Partial nodular transformation
In children without cirrhosis Hepatoblastoma
Mesenchymal hamartoma
Diagnosis of focal nodular hyperplasia of the liver by needle biopsy.

Makhlouf HR, Abdul-Al HM, Goodman ZD.

Division of Hepatic Pathology, Department of Hepatic and Gastrointestinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.

Hum Pathol. 2005 Nov;36(11):1210-6. Abstract quote  

Focal nodular hyperplasia (FNH) of the liver can be a difficult diagnosis to establish in limited diagnostic samples such as a needle-core tissue biopsy, especially for pathologists with limited experience with the lesion.

To characterize the features that can be used to make the diagnosis, we reviewed and analyzed the clinicopathologic features of 100 consecutive cases submitted for consultation in which we were confident of the diagnosis of FNH in needle biopsy material. A diagnosis of FNH was correctly made by the contributing pathologist in 24 of the 100 referred cases. Most of the patients (81%) were women of childbearing age with a mean age of 36.75 +/- 9.82 years. Most of the patients (70%) were asymptomatic at diagnosis.

The most consistent diagnostic histological feature of FNH in needle biopsy was the presence of ductular reaction with varied intensity at the junction of the fibrous septa with the hepatocellular component, which was present in all 100 cases. Thick abnormal arteries were seen in all but 2 cases (n = 98). Features of chronic cholestasis with cholate stasis and accumulation of copper (demonstrable by the rhodanine stain) and copper-binding protein (demonstrable with the Victoria blue stain) were nearly as common (n = 94). A confident diagnosis of FNH can be made with a needle biopsy, especially if the biopsy is known to come from a mass, and the lesion contains characteristic fibrosis with ductules at the interface between hepatocytes and the fibrous region, prominent arteries, and benign hepatocytes with features of chronic cholestasis.
Histologic scoring of liver biopsy in focal nodular hyperplasia with atypical presentation.

Fabre A, Audet P, Vilgrain V, Nguyen BN, Valla D, Belghiti J, Degott C.

Service d'Anatomie Pathologique, Hopital Beaujon, Clichy, France.

Hepatology. 2002 Feb;35(2):414-20. Abstract quote  

The contribution of radio-guided transcutaneous biopsy in the diagnosis of focal nodular hyperplasia (FNH) of the liver was compared with the findings on surgical specimens to assess its contribution in clinical and radiologic atypical cases.

This retrospective study involved 30 patients with atypical tumors on imaging who underwent liver biopsy and then surgery. All surgical specimens were diagnosed as FNH, either classical (n = 18) or nonclassical (n = 12). Imaging data were reviewed according to 4 radiologic criteria on magnetic resonance imaging (MRI) and/or computed tomography (CT) scan (hypervascularity, homogeneity, nonencapsulation, and presence of a central scar), and classified depending on the number of criteria found (group I, 4 of 4; group II, 3 of 4; group III, 2 or fewer).

Histologic assessment of ultrasound (US)-guided liver biopsy recorded major diagnostic features (fibrous bands, thick-walled vessels, reactive ductules, and nodularity) and minor features (sinusoidal dilatation and perisinusoidal fibrosis). "Definite FNH" (3 or 4 major features) was diagnosed in 14 biopsies, "possible FNH" (2 major and 1 or 2 minor features) in 7 cases, and "negative for FNH" (2 or fewer major features without minor features) in 9 cases. The diagnosis of FNH on biopsy was reached in 14 cases (58.3%) in patients with 2 or fewer imaging criteria (group III; n = 24). Biopsies with a diagnosis of "possible FNH" corresponded to a large proportion of telangiectatic-type FNH on the specimen.

In conclusion, liver biopsy does not appear to be necessary in cases in which imaging is typical. However, the absence of radiologic diagnostic criteria in FNH does not preclude a positive diagnosis on liver needle biopsy. Using the proposed histologic scoring system, surgical management may be avoided in these cases.
TUMOR Liver Cells Bile Ducts Large Vessels Connective Tissue Mitoses Reticulin stain
Adenoma Normal or slightly larger or smaller, may have glycogen and fat Not present Present May be present None Normal or slightly decreased, sinusoidal staining, may show double cell plates
Focal nodular hyperplasia Normal, no small or large cell change Present in scar Present Scar None Normal pattern, sinusoidal staining, may show double cell plates
Nodular regenerative hyperplasia Normal or slightly compressed, suggesting foci of small cell change Present in portal zones Not present Not present None Normal with regenerative foic (thicker cell plates) compressing single cell plates
Fibrolamellar HCC Larger than normal polygonal to spindle shapes, pale bodies, enlarged nuclei, abundant eosinophilic granular cytoplasm Not present Not typical, variable Lamellar fibrosis Rare Not used for diagnosis, variable pattern

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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
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DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Basic Principles of Disease
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Commonly Used Terms
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Diagnostic Process
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Last Updated December 5, 2005

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