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Hepatocellular carcinoma

Hepatocellular carcinoma (HCC, also called hepatoma or liver cancer) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either hepatitis infection (usually hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis). In countries where hepatitis is not endemic, most cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g. the colon. Treatment options of HCC and prognosis are dependent on many factors but especially on tumor size and staging. more...

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In Sub-Saharan Africa and most other Third World countries the commonly accepted prognosis is a median survival of 3 months from diagnosis. This is partially due to late presentation with large tumours, but also the lack of medical expertise and facilities.


The epidemiology of HCC exhibits two main patterns, one in North America and Western Europe and another in Non-Western Countries (regions such as sub-Saharan Africa, central Asia, Southeast Asia, and the Amazon basin).

Non-Western Countries

In some parts of the world, such as Sub-Saharan Africa and Southeast Asia (and especially Taiwan and China) HCC is the most common cancer, generally affecting men more than women, and with an age of onset between late teens and 30's. This variability is in part due to the different patterns of Hepatitis B transmission in different populations - infection at or around birth (as in Taiwan) predispose to earlier cancers than if people are infected later. The time between hepatitis B infection and development into HCC can be years even decades, but from diagnosis of HCC to death the average survival period is only 5.9 months, according to one Chinese study during the 1970-80s, or 3 months (median survival time) in Sub-Saharan Africa according to Manson's textbook of tropical diseases. HCC is one of the deadliest cancers in China. Food infected with Aspergillus flavus (especially peanuts and corns stored during prolonged wet seasons) which produces aflatoxin, poses another risk factor for HCC.

North America and Western Europe

Most malignant tumors of the liver discovered in Western patients are metastases (spread) from tumors elsewhere. In the West, HCC is generally seen as rare cancer, normally of those with pre-existing liver disease. It is often detected by ultrasound screening, and so can be discovered health-care facilities much earlier than in developing regions such as Sub-Saharan Africa.

Diagnosis, screening and monitoring

Hepatocellular carcinoma (HCC) most commonly appears in a patient with chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or with cirrhosis (about 80%). These patients commonly undergo surveillance with ultrasound due to the cost-effectiveness.

In patients with a higher suspicion of HCC (such as rising alpha-fetoprotein levels), the best method of diagnosis involves a CT scan of the abdomen using intravenous contrast agent and three-phase scanning (before contrast administration, immediately after contrast administration, and again after a delay) to increase the ability of the radiologist to detect small or subtle tumors. It is important to optimize the parameters of the CT examination, because the underlying liver disease that most HCC patients have can make the findings more difficult to appreciate.


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Fine-Needle Aspirates of Adenocarcinoma/Metastatic Carcinoma That Resemble Hepatocellular Carcinoma: Correlating Cytologic Features and Performance in
From Archives of Pathology & Laboratory Medicine, 10/1/05 by Renshaw, Andrew A

Context.-The cytologic features of adenocarcinoma/metastatic carcinoma in liver fine-needle aspirates are well described. We review the cytologic findings from 16 aspirates of adenocarcinoma/metastatic carcinoma that were frequently misclassified as hepatocellular carcinomas and compare them with 17 cases that were rarely misclassified.

Objective.-To compare the cytologic features of adenocarcinoma/metastatic carcinoma in fine-needle aspiration specimens of the liver that were frequently misclassified as hepatocellular carcinoma with those of aspirates that were rarely misclassified.

Design.-We reviewed a total of 1712 interpretations from 33 different cases of adenocarcinoma/metastatic carcinoma tumor in liver fine-needle aspiration specimens in the College of American Pathologists Nongynecologic Cytology Program and correlated the cytologic features with performance in the program.

Results.-Overall, cases that were frequently misclassified as hepatocellular carcinoma were misclassified on average 26% of the time (range, 13%-54%), while infrequently misclassified cases were interpreted as hepatocellular carcinoma on average 0.7% of the time (range, 0%-3%). The difference was statistically significant (P

Conclusion.-Cases of adenocarcinoma/metastatic carcinoma with moderate amounts of granular cytoplasm and round nuclei with even chromatin are frequently misclassified as hepatocellular carcinoma. Recognition of this problem, attention to cytologic criteria, and frequent use of immunohistochemical studies and core biopsy may help avoid this pitfall.

(Arch Pathol Lab Med. 2005;129:1217-1221)

The cytologic features of adenocarcinoma/metastatic carcinoma in fine-needle aspiration specimens of the liver are well known1,2 and in general are different than those that have been described for hepatocellular carcinoma.1-14 While it is commonly recognized that some poorly differentiated hepatocellular carcinomas may be difficult to distinguish from adenocarcinoma, difficulty in distinguishing cases of adenocarcinoma/metastatic carcinoma from hepatocellular carcinoma has not been as well described.

The College of American Pathologists (CAP) Nongynecologic Cytology Program is a national educational program that includes cases of adenocarcinoma/metastatic carcinoma. We recently noted that the performance of some cases of adenocarcinoma/metastatic carcinoma in the liver was quite poor, and some of these cases were frequently misdiagnosed as hepatocellular carcinoma. To identify causes for this misinterpretation, the cytologie features of individual cases of adenocarcinoma/metastatic carcinoma were reviewed and correlated with their performance in the program.


The CAP Nongynecologic Cytology Program is a quarterly mailed, glass slide quality improvement program. Cytology laboratories of all types participate, with the largest number (approximately 60%) being hospital laboratories. In addition, independent laboratories, federal and government laboratories, university laboratories, and others such as those associated with a group practice or physician's office also are in the participant base.

Slides are submitted by the members of the CAP Nongynecologic Cytology Working Group, which is a subcommittee of the CAP Cytopathology Resource Committee. All types of nongynecologic cytology sites are included in the program. Slides are reviewed by at least 2 experienced cytopathologists from the CAP Cytopathology Resource Committee before acceptance into the program. Each slide must be judged to be of good technical quality and an excellent example of the reference diagnosis. Both reviewers must agree on the exact target diagnosis, and this diagnosis must agree with the submitted diagnosis prior to accepting a slide for circulation.

Liver fine-needle aspirates with a reference diagnosis of adenocarcinoma/metastatic carcinoma were identified, and the performance of individual slides was tabulated. These cases were retrieved and reviewed by 2 of the authors (A.A.R. and T.R.M.) to identify potential cytologie features that could be responsible for the hepatocellular carcinoma responses.

Statistical analysis of categorical data was performed using a 2-tailed Fisher exact test or χ^sup 2^ test, as appropriate. P


A total of 1712 individual interpretations from 33 different cases of adenocarcinoma/metastatic carcinoma tumor in liver fine-needle aspiration specimens were reviewed. Overall, cases that were frequently misclassified as hepatocellular carcinoma were misclassified 26% of the time (range, 13%-54%). cases that were rarely misclassified, on the other hand, were less likely to be classified as hepatocellular carcinoma, recording on average only 0.7% of the time (range, 0%-3%; P

On review, cases that were frequently misclassified most often had moderate amounts of granular cytoplasm (16/ 16 cases) and round nuclei with even chromatin (13/16 cases; Figure 1, a through d). Trabeculae (3/16 cases), bare nuclei (2/16 cases; Figure 2, a and b), and endothelial wrapping (1/16 cases; Figure 3) were rarely present. In contrast, cases that were rarely misclassified had at least some areas with cells showing scant amounts of cytoplasm, which were crowded and overlapped or molded (13/17 cases) and which contained dark hyperchromatic chromatin (13/17 cases; Figure 4, a through c and Figure 5, a and b). These cytoplasmic and nuclear characteristics were statistically significantly different than those seen in cases that were frequently misclassified (P


The CAP Nongynecologic Cytology Program provides a unique opportunity to correlate the cytologie features of individual cases of a particular diagnosis with the interpretive opinions of numerous cytologists with a broad range of backgrounds and in a wide variety of practice settings, which may reflect the performance of a cross section of cytologists nationally. The results of this program are unique, and there are no results available from similar programs of comparable size.

The cytologie features of adenocarcinoma/metastatic carcinoma tumors in aspiration specimens of the liver are well known1,2 and in general are different than those that have been described for hepatocellular carcinoma.1,14 While it is commonly recognized that some poorly differentiated hepatocellular carcinomas may be difficult to distinguish from adenocarcinoma,1,2,5,9,12 difficulty in distinguishing cases of adenocarcinoma/metastatic carcinoma from hepatocellular carcinoma has not been as well described.

On review, it appeared that cases that were more likely to be misclassified had cytologie features distinct from cases that performed well, and consisted of cells with moderate amounts of granular cytoplasm and round nuclei with even chromatin. Such features are also typical of both normal and neoplastic hepatocytes, and it appears that participants may be using these features to suggest a diagnosis of hepatocellular carcinoma, rather than more specific features, such as broad trabeculae, bare nuclei, or endothelial cell wrapping. In support of this conclusion, cases that performed well almost always had areas that lacked this type of cytoplasm, and as a result the cells were crowded together, with either overlapping or nuclear molding. In addition, the nuclear chromatin was more often more dark and granular, a feature that is less common in hepatocytes, either normal or neoplastic.

These results highlight a very important problem in making the distinction between hepatocellular carcinoma and adenocarcinoma. While cases of hepatocellular carcinoma that show specific features, such as cellular trabeculae, are relatively easy to recognize, there are some cases of hepatocellular carcinoma that lack such specific features. In cases such as these, the present study results suggest that participants may rely too greatly on cytologie similarities of the cells with hepatocytes,2 while ignoring more typical features indicative of a nonhepatic origin. Additional educational efforts to increase participants' abilities to recognize subtle distinctions between these 2 tumors may be of benefit. In the context of this program, in which additional clinical history and special studies are not available, participants must rely strongly on fine cytologie details to make these often difficult, but clinically important distinctions. In actual clinical practice, both immunohistochemical studies and use of core needle biopsy would most likely help reduce this type of error. However, honing one's interpretive ability on the basis of cytology alone will ultimately lead to more accurate and cost-effective overall practice.

In conclusion, in the CAP Comparison Program in Nongynecologic Cytology, a surprisingly large number of cases of adenocarcinoma/metastatic carcinoma are being misclassified as hepatocellular carcinoma based on the presence of moderately abundant granular cytoplasm and round nuclei with even chromatin, features that mimic hepatocellular differentiation. Such cytologie kinship with hepatocytes should not be interpreted as sufficient for a diagnosis of hepatocellular carcinoma. Awareness of this cytologie overlap, increased educational efforts to improve participants' abilities to make this distinction, liberal use of cell blocks and core needle biopsies as well as histochemistry and immunohistochemistry (mucicarmine, HepPar, CDlO, carcinoembryonic antigen, CK20, and 34βE12), and use of additional clinical or laboratory information (such as serum α-fetoprotein) should improve cytologie practice when faced with this important differential diagnosis on fine-needle aspiration biopsy.


1. Cibas ES, Ducatman BS. Cytology: Diagnostic Principles and Clinical Correlates. 2nd ed. New York, NY: Saunders; 2003.

2. DeMay RM. The Art and Science of Cytopathology. Chicago, III: American Society of Clinical Pathologists; 1996.

3. Bottles K, Cohen MB. An approach to fine-needle aspiration biopsy diagnosis of hepatic masses. Diagn Cytopathol. 1991;7:204-210.

4. Chen MB, Haber MM, Holly EA, Ahn DK, Bottles K. Cytologie criteria to distinguish hepatocellular carcinoma from nonneoplastic liver. Am I CUn Pathol. 1991;95:125-130.

5. Das DK. Cytodiagnosis of hepatocellular carcinoma in fine-needle aspirates of the liver: its differentiation from reactive hepatocytes and metastatic adenocarcinoma. Diagn Cytopathol. 1999;21:37u-377.

6. de Boer WB, Segal A, Frost FA, Sterrett CF. Cytodiagnosis of well differentiated hepatocellular carcinoma: can indeterminate diagnoses be reduced? Cancer. 1999;87:270-277.

7. Pedio G, Landolt U, Zobeli L, Gut D. Fine needle aspiration of the liver: significance of hepatocytic naked nuclei in the diagnosis of hepatocellular carcinoma. Acta Cytol. 1988)32:437-442.

8. Sharifi S, Hayek J, Khettry U, Nassser I. lmmunocytochemical staining of Kupffer and endothelial cells in fine needle aspiration cytology of hepatocellular carcinoma. Acta Cytol. 2000;44:7-12.

9. Wee A, Nilsson B, Chan-Wilde C, Yap I. Fine needle aspiration biopsy of hepatocellular carcinoma: some unusual features. Acts Cytol. 1991;35:661-670.

10. Longchampt E, Patriarche C, Fabre M. Accuracy of cytology vs. microbiopsy for the diagnosis of well-differentiated hepatocellular carcinoma and macroregenerative nodule: definition of standardized criteria from a study of 100 cases. Acta Cytol. 2000;44:515-523.

11. Pitman MB, Szyfelbein WM. Significance of endothelium in the fine-needle aspiration biopsy diagnosis of hepatocellular carcinoma. Diagn Cytopathol. 1995;12:208-214.

12. SoIe M, Calvert X, CuberesT. Value and limitations of cytologie criteria for the diagnosis of hepatocellular carcinoma by fine needle aspiration biopsy. Acta Cytol. 1993;37:309-316.

13. Kung IT, Chan SK, Fung KH. Fine-needle aspiration in hepatocellular carcinoma: combined cytologie and histologie approach. Cancer. 1991;67:673-680.

14. Perez-Cuillermo M, Masgrau NA, Garcia-Solano ], Sola-Perez ), de Agustin y de Agustin P. Cytologie aspect of fibrolamellar hepatocellular carcinoma in fineneedle aspirates. Diagn Cytopathol. 1999;21:180-187.

Andrew A. Renshaw, MD; Jennifer HaJa, CT(ASCP); David C. Wilbur, MD; Theodore R. Miller, MD; for the Cytology Committee, College of American Pathologists

Accepted for publication June 6, 2005.

From the Department of Pathology, Baptist Hospital of Miami, Miami, FIa (Dr Renshaw); College of American Pathologists, Northfield, III (Ms HaJa); Department of Pathology, Massachusetts General Hospital, Boston (Dr Wilbur); and Department of Pathology, University of California Medical Center, San Francisco (Dr Miller).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Andrew Renshaw, MD, Department of Pathology, Baptist Hospital of Miami, 8900 N Kendall Dr, Miami, FL 33156 (e-mail:

Copyright College of American Pathologists Oct 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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