14 Clinico-Pathological Classifi cation
Clotilde Della Pina, Erika Rocchi, Andrea Conti, Sara Montagnani, and
Laura Crocetti
C. Della Pina, MD; E. Rocchi, MD; A. Conti, MD;
S. Montagnani, MD; L. Crocetti, MD
Division of Diagnostic and Interventional Radiology, Depart- ment of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Via Roma 67, 56126 Pisa, Italy CONTENTS
14.1 Introduction 203
14.2 Hepatocellular Tumors 203 14.2.1 Hepatocellular Carcinoma 203 14.2.2 Fibrolamellar Carcinoma 204 14.2.3 Hepatoblastoma 204
14.3 Cholangiocellular Tumors 204 14.3.1 Cholangiocellular Carcinoma 204 14.3.2 Cystoadenocarcinoma 205 14.4 Mesenchymal Tumors 205 14.4.1 Angiosarcoma 205
14.4.2 Epithelioid Haemangioendothelioma 205 14.4.3 Lymphoma 206
References 206
14.1 Introduction
Primary malignant tumors of the liver can be classifi ed into three groups according to their origins: those derived from the hepatocytes, those arising from the bile-duct epithelium, and those originating from the mesenchymal tissues of the liver. In this chapter, clinico-pathological features of hepatocellular malig- nancies arising in noncirrhotic liver are discussed, including hepatocellular carcinoma, fi brolamellar carcinoma and hepatoblastoma. Cholangiocellular tumors (cholangiocarcinoma and cystoadenocarci- noma) and tumors that origin from hepatic mes- enchymal tissues (epithelial hemangioendothelioma, angiosarcoma and primary hepatic lymphoma) will also be examined.
14.2
Hepatocellular Tumors 14.2.1
Hepatocellular Carcinoma
Most cases of hepatocellular carcinoma (HCC) can be attributed to chronic hepatitis B (HBV) and/or C (HCV) (Llovet et al. 2003). However, some cases of HCC are not associated with cirrhosis (Nzeako et al.
1996). Nzeako et al. (1996) estimated that 40% of the HCC seen in North America occurs in noncirrhotic livers; they reported that only 10% of those patients had evidence of viral hepatitis or alcoholism. In a more recent study serologic evidence of hepatitis B or C or history of alcohol intake was present in only 36%
of noncirrhotic patients with HCC, the remaining 64% having no evidence of risk factors for cirrhosis or HCC (Brancatelli et al. 2002). These data sup- port the fact that HBV and HCV are associated with carcinogenesis of the HCC arising in noncirrhotic liver, but in most cases the cause of HCC remains uncertain. Recent reports have shown that transpla- cental transmission of HBV and HBV DNA integra- tion into the cellular genomic DNA during fetal life is a possible explanation of HBV-related HCC in young adults without cirrhosis (Sezaki et al. 2004). The suspicion that oral contraceptives might play a role in the genesis of liver cancer has yet to be confi rmed (Smalley et al. 1988).
When the tumor develops in the absence of cir-
rhosis, the course of the disease is generally turbu-
lent. These patients are younger, generally about 40
years old, and with abnormally elevated serum tumor
markers. Patients generally have severe, diffuse ab-
dominal pain; weakness, weight loss, and lack of ap-
petite may also be present. Extrahepatic extension of
HCC is common in noncirrhotic patients (Trevisani
et al. 1995). Noncirrhotic patients with HCC have a
relatively favourable prognosis, with a median sur-
vival of 2.7 years and with 25% of patients surviv-
ing for at least 5 years after resection (Smalley et
al. 1988).
The hepatic mass is commonly a large, lobulated and encapsulated solitary mass; necrosis and hy- pervascularity are prominent features. Vascular and biliary invasion are common. HCC had been reported as well-differentiated in 15% of patients, moderately differentiated in 82%, and poorly-differentiated in 3% of cases (Brancatelli et al. 2002).
14.2.2
Fibrolamellar Carcinoma
Fibrolamellar carcinoma (FLC) is a rare neoplasm of hepatocellular origin, considered as independent entity from HCC (El-Serag and Davila 2004). FLC occurs predominantly in young people of both sex, usually without preexisting liver disease (Craig et al.
1980 ). FLC does not appear to be related to previous HBV or HCV infection, and is not associated with elevated alpha-fetoprotein levels. Serum unsaturated vitamin B
12binding capacity and plasma neuroten- sin may be used as tumoral markers (Kwee 1989).
In most patients signs and symptoms are represented by abdominal pain, hepatomegaly or palpable mass in the abdomen. In a recent study, the survival rates were signifi cantly longer in patients with FLC than HCC: the 5-year relative survival rate was 31% for FLC and 6% for HCC (El-Serag and Davila 2004).
The neoplasm usually presents as a large, lobulated and solitary mass with a central fi brous scar that may be calcifi ed (Ichikawa et al. 1999). Microscopically, FLC is characterized by cords of tumor cells sur- rounded by abundant avascular fi brous tissue. Fibrotic lamellae often form a central scar and multiple septa which radiate from the centre of the lesion.
14.2.3
Hepatoblastoma
Hepatoblastoma is the most common hepatic neo- plasm in the paediatric age, comprising approxi- mately 1% of all paediatric cancers (Schnater et al. 2003). The tumor is often detected before 3 years of age, more frequently in males, with a median sur- vival of 1 year (Jung et al. 2001). The neoplasm is frequently combined with congenital disorders and malformations of other organ such as hemihyper- trophy, glycogen storage disease, diaphragmatic and umbilical hernias, and Wilms tumor (Lack et al.
1982; Mann et al. 1990). Presentation is often due to the mass effects accompanied by anorexia, vomiting, fever, and weight loss. The serum α-fetoprotein level
is usually high. Metastases can be found in the ab- dominal lymph nodes, the lungs, and, less commonly, the brain (Begemann et al. 2004). Recent evidence suggests the possible association between prematu- rity and hepatoblastoma (Feusner and Plaschkes 2002).
On macroscopic examination, hepatoblastoma is, in most cases, a solid, solitary and lobulated mass.
Areas of necrosis and calcifi cation are commonly present. Microscopically it can be classifi ed as an epi- thelial or mixed (epithelial-mesenchymal) neoplasm.
Epithelial hepatoblastoma is composed of fetal or embryonal malignant hepatocytes. Mixed hepato- blastoma has epithelial and mesenchymal component as osteoid material or cartilage. The histologic clas- sifi cation has prognostic implications: the epithelial type, particularly fetal histologic type, is associated with improved survival when compared with other histologic patterns (Haas et al. 1989).
14.3
Cholangiocellular Tumors
14.3.1
Cholangiocellular Carcinoma
Cholangiocellular carcinoma or cholangiocarcinoma (CCA) is a primary malignancy arising from the bile duct epithelium. The incidence of CCA among pri- mary liver tumors is around 20% of the cases. It gen- erally occurs during the sixth and seventh decades of life (Okuda et al. 2002). Risk factors are primary scle- rosing cholangitis, congenital anomalies of the biliary tree, hepatolithiasis, infection with Clonorchis sinen- sis, familial polyposis and congenital hepatic fi brosis (Abdel-Rahim 2001; Burak et al. 2004; Kim et al.
2003 ). Some data point to a potential role for chronic liver disease, hepatitis B and C in development of in- trahepatic CCA (Shaib and El-Serag 2004; Liu et al.
2003 ). Peripheral intrahepatic CCA usually presents with non-specifi c symptoms, such as anorexia and weight loss, or can be detected as incidental lesion by ultrasound examination (Kaczynski et al. 1998).
On the other hand perihilar or extrahepatic tumours
present signs and symptoms related to the biliary
obstruction. In most cases serum α-fetoprotein level
is normal whereas a recent study had shown that
serum CA 19-9 could be an effective tumor marker
(Qin et al. 2004).
According to the site of origin, CCA can be classi- fi ed into: 1) peripheral CCA, which arises from intra- hepatic bile ducts; 2) hilar CCA (Klatskin’s tumor), which originates from one of the hepatic ducts or from the bifurcation of both hepatic ducts; 3) clas- sical bile-duct carcinoma from the extrahepatic bile ducts (Nakeeb et al. 1996). However, this classifi ca- tion scheme is controversial because the differentia- tion between peripheral and hilar forms is sometimes diffi cult: peripheral CCA can spread into the hepatic hilum, and hilar CCA can infi ltrate intrahepatic bile ducts (Yamasaki 2003). The Liver Cancer Study Group of Japan (1997) has proposed a new classifi - cation based on macroscopic appearance and growth characteristics. Among all CCA, the peripheral CCA represents 20%, hilar CCA 60% and bile-duct carci- noma 20% of cases.
Macroscopically CCA is a grayish-white, fi rm and fi brous mass because of its large amount of fi brous stroma. Characteristically this tumor has a large cen- tral core of fi brotic tissue, due to the desmoplastic reaction induced by the neoplastic cells. CCA differs from HCC since it is poorly vascularised, and the in- vasion of the portal tree is an infrequent complica- tion. Hilar and bile-duct CCA grow into the walls of the bile ducts with invasion of the lumen, so obstruc- tive jaundice and dilatation of the biliary tree are early signs. In the bile ducts, CCA presents papillary growth and periductal infi ltration. Microscopically CCA represent an adenocarcinoma with its tubular or acinar-glandular structures. The neoplastic cells induce a variable desmoplastic reaction.
14.3.2 Cystoadenocarcinoma
This rare neoplasm is seen predominantly in females in the middle age. It arises from a cystoadenoma or a congenital biliary cyst (Devaney et al. 1994).
When present, the symptoms are due to the growing abdominal mass. Most of the lesions are intrahepatic, less than 10% are extrahepatic, arising in the extrahe- patic biliary ducts. Connections to the biliary tree may be seen, but are uncommon.
From a macroscopic point of view, cystadenocar- cinoma is a large cystic mass containing bile-stained mucus and divided by internal septa. The neoplasm originates from the mucinous-secreting epithelium of the biliary ducts. Microscopically cystoadenocar- cinoma shows similar features to those of mucinous cystic tumors of pancreas and ovary. The neoplastic tissue consists in epithelial cells arranged in papil- lary structures circumscribed by an abundant mes-
enchymal stroma, that can bear some resemblance to ovarian stroma (Gourley et al. 1992). Biliary cysta- denocarcinoma with ovarian stroma is documen ted only in women developing from a pre-existing biliary cystadenoma and has a good prognosis. In contrast cystadenocarcinoma without ovarian stroma is seen both in men and women and is not associated with a pre-existing cystadenoma (Devaney et al. 1994).
14.4
Mesenchymal Tumors 14.4.1
Angiosarcoma
Angiosarcoma is a very rare neoplasm, but it is the most common hepatic tumor of mesenchymal ori- gin. It displays a predilection for males and gener- ally occurs during the sixth and seventh decade of life. Angiosarcoma has been associated to the ex- posure to a variety of chemical agents (inorganic arsenic, vynil chloridre) and radiation (radium, tho- rium oxide [Thorotrast]) (Ito et al. 1988;Kojiro et al. 1985). Association with hemochromatosis, von Reckinghausen’s disease, and alcoholic cirrhosis have also been noted (Locker et al. 1979). Primary hepatic angiosarcoma is highly aggressive and, therefore, symptoms and signs are those of a rapidly progres- sive disease. The patient complains of pain, anemia, fever of unknown origin, weight loss, and abdominal mass (Molina and Hernandez 2003). The median survival after diagnosis is only 6 months (Molina and Hernandez 2003 ). This tumor metastasize early, par- ticularly to lung and spleen (Buetow et al. 1994).
Macroscopically, angiosarcoma presents often multifocal growth pattern, with nodules ranging from few millimeters to several centimeters. Angiosarcoma may also appear as solitary, not encapsulated, large mass with large cystic areas fi lled with blood debris.
Microscopically the neoplastic tissue is characterised by malignant endothelial cells that line dilated sinu- soidal spaces. As the tumor grows, the dilated sinu- soids become cavernous cavities with poorly defi ned borders (Ito et al. 1988).
14.4.2
Epithelioid Haemangioendothelioma
Epithelioid haemangioendothelioma (EHE) is a rare
malignant hepatic tumor of vascular origin that oc-
curs generally in young females. This neoplasm has a lower grade of malignancy than angiosarcoma, but is however progressive: overall metastasis rate is 45% with preferential involvement of lungs and bones (Lauffer et al. 1996). The clinical signs and symptoms of patients with EHE are non-specifi c; the tumor is usually discovered incidentally, although symptoms like weakness, weight loss, and jaundice can occur. The 5-years survival of 55% for EHE is signifi cantly better than for other hepatic malignan- cies (Lauffer et al. 1996).
Macroscopically, EHE presents as multiple nodules or large intrahepatic mass, the latter being the natu- ral evolution of multiple confl uent nodules (Miller et al. 1992). EHE characteristically has a fi brotic hypo- vascular central area and a peripheral hyperemic rim.
At the outer edge of these tumors there is often a nar- row avascular zone where hepatic sinusoids and small vessels are infi ltrated by advancing tumor (Miller et al. 1992). The hepatic capsule overlying an EHE is frequently retracted inward, probably due to fi brosis induced by the tumor. The neoplastic tissue is com- posed of epithelioid cells that proliferate into the si- nusoids and central hepatic veins.
14.4.3 Lymphoma
Lymphoma is considered to be a primary neoplasm of the liver when the tumor is limited to hepatic paren- chyma. Primary lymphoma of the liver is extremely rare, and is more common among immunocompro- mised patients. It typically occurs during the fi fth dec- ade of life and has a male predominance (Avlonitis and Linos 1999;Harris et al. 1987;Siskin et al.
1995). Some studies have highlighted the association between hepatic lymphoma, arising in the post-trans- plant time or in patients with AIDS, and the infec- tion with Epstein-Barr virus (Nalesnik et al. 1988).
It has also been suggested that HCV plays a role in the pathogenesis of lymphoma (Bronowicki et al.
2003;Kim et al. 2000). Abdominal pain or discomfort, weight loss and fever are the most frequent present- ing symptoms (Avlonitis and Linos 1999;Ryan et al. 1988). Serum tumor markers are usually normal but serum lactic dehydrogenase activity may be in- creased (Scoazec et al. 1991). Follow-up studies show that hepatic lymphoma had a relatively favora- ble prognosis when early detection of the disease was possible (Ohsawa et al. 1992;Scoazec et al. 1991).
Macroscopically, the liver may be occupied by soli- tary mass, multiple masses or a diffuse lesion without
nodule formation (Ohsawa et al. 1992). Hodgkin’s disease occurs more often as miliary lesions than masses. According to the WF classifi cation, most cases of primary lymphoma of the liver are of intermediate or high grade. Diffuse large cell lymphoma is the most commonly encountered histological subtype and most of cases are B-cell lymphoma. In both Hodgkin and non-Hodgkin’s lymphoma, initial involvement is seen in the portal areas, because here the majority of the lymphatic tissue of the liver is found.
References
Abdel-Rahim AY (2001) Parasitic infections and hepatic neo- plasia. Dig Dis 19:288-291
Avlonitis VS, Linos D (1999) Primary hepatic lymphoma: a review. Eur J Surg 165:725-729
Begemann M, Trippett TM, Lis E, et al (2004) Brain metastases in hepatoblastoma. Pediatr Neurol 30:295-297
Brancatelli G, Federle MP, Grazioli L, et al (2002) Hepatocellu- lar carcinoma in noncirrhotic liver: CT, clinical, and patho- logic fi ndings in 39 U.S. residents. Radiology 222:89-94 Bronowicki JP, Bineau C, Feugier P, et al (2003) Primary lym-
phoma of the liver: clinical-pathological features and rela- tionship with HCV infection in French patients. Hepatol- ogy 37:781-787
Buetow PC, Buck JL, Ros PR, et al (1994) Malignant vas- cular tumors of the liver: radiologic-pathologic correlation.
Radiographics 14:153-l 66
Burak K, Angulo P, Pasha TM, et al (2004) Incidence and risk factors for cholangiocarcinoma in primary sclerosing chol- angitis. Am J Gastroenterol 99:523-526
Craig JR, Peters RL, Edmondson HA, et al (1980) Fibrolamellar carcinoma of the liver: a tumor of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46:372-379
Dean PJ, Haggitt RC, O’Hara CJ (1985) Malignant epitheli- oid hemangioendothelioma of the liver in young women:
relationship to oral contraceptive use. Am J Surg Pathol 9:695-704
Devaney K, Goodman ZD, Ishak KG (1994) Hepatobiliary cyst- adenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients. Am J Surg Pathol 18:1078-1091
El-Serag HB, Davila JA (2004) Is fi brolamellar carcinoma dif- ferent from hepatocellular carcinoma? A US population- based study. Hepatology 39:798-803
Feusner J, Plaschkes J (2002) Hepatoblastoma and low birth weight: a trend or chance observation? Med Pediatr Oncol 39:508-509
Gourley WK, Kumar D, Bouton MS, et al (1992) Cystadenoma and cystadenocarcinoma with mesenchymal stroma of the liver. Immunohistochemical analysis. Arch Pathol Lab Med 116:1047-1050
Haas JE, Muczynski KA, Krailo M, et al (1989) Histopathology and prognosis in childhood hepatoblastoma and hepato- carcinoma. Cancer 64:1082-1095
Harris KM, Schwartz ML, Slasky BS, et al (1987) Post-trans-
plantation cyclosporine-induced lymphoproliferative dis- orders: clinical and radiologic manifestations. Radiology 162:697-700
Ichikawa T, Federle MP, Grazioli L, et al (1999) Fibrolamellar hepatocellular carcinoma: imaging and pathologic fi ndings in 31 recent cases. Radiology 213:352-361
Ishak KG, Sesterhenn IA, Goodman ZD, et al (1984) Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol 15:839-852 Ito Y, Kojiro M, Nakashima T, et al (1988) Pathomorphologic
characteristics of 102 cases of Thorotrast-related hepatocel- lular carcinoma, cholangiocarcinoma, and hepatic angiosar- coma. Cancer 62:1153-1162
Jung SE, Kim KH, Kim MY, et al (2001) Clinical characteris- tics and prognosis of patients with hepatoblastoma. World J Surg 25:126-130
Kaczynski J, Hansson G, Wallerstedt S (1998) Incidence, etio- logic aspects and clinicopatholgic features in intrahepatic cholangiocarcinoma. A study of 51 cases from a low-ende- micity area. Acta Oncol 37:77-83
Kelleher MB, Iwatsuki S, Sheahan DG (1989) Epithelioid hemangioendothelioma of the liver. Clinicopathological correlation of 10 cases treated by orthotopic liver trans- plantation. Am J Surg Pathol 13:999-1008
Kim JH, Kim HY, Kang I, et al (2000) A case of primary hepatic lymphoma with hepatitis C liver cirrhosis. Am J Gastroen- terol 95:2377-2380
Kim YT, Byun JS, Kim J, et al (2003) Factors predicting concur- rent cholangiocarcinomas associated with hepatolithiasis.
Hepatogastroenterology 50:8-12
Kojiro M, Nakashima T, Ito Y, et al (1985) Thorium dioxide- related angiosarcoma of the liver. Pathomorphic study of 29 autopsy cases. Arch Pathol Lab Med 109:853-857 Kwee HG (1989) Fibrolamellar hepatocellular carcinoma. Am
Fam Physician 40:175-177
Lack EE, Neave C, Vawter GF (1982) Hepatoblastoma. A clinical and pathologic study of 54 cases. Am J Surg Pathol 6:693- 705
Lauffer JM, Zimmermann A, Krahenbuhl L, et al (1996) Epi- thelioid hemangioendothelioma of the liver. A rare hepatic tumor. Cancer 78:2318-2327
Liu XF, Zou SQ, Qin FZ (2003) Pathogenesis of cholangiocarci- noma in the porta hepatic and infection of hepatitis virus.
Hepatobiliary Pancreat Dis Int 2:285-289
Liver Cancer Study Group of Japan (1997) Intrahepatic cholan- giocarcinoma, macroscopic typing. In: Okamoto E (ed) Clas- sifi cation of primary liver cancer. Kanehara, Tokyo, pp 6-7 Llovet JM, Borroughs A, Bruix J (2003) Hepatocellular carci-
noma. Lancet 362:1907-1917
Locker GY, Doroshow JH, Swelling LA, et al (1979) The clini- cal features of hepatic angiosarcoma: a report of four cases and a review of the English literature. Medicine 58:48-63 Mann JR, Kasthuri N, Raafat F (1990) Malignant hepatic
tumours in children: incidence, clinical features and aeti- ology. Paediatr Perinat Epidemiol 4:276-289
Miller WJ, Dood GD III, Federle MP, et al (1992) Epithelioid
hemangioendothelioma of the liver: imaging fi ndings with pathologic correlation. AJR Am J Roentgenol 159:53-57 Molina E, Hernandez A (2003) Clinical manifestations of pri-
mary hepatic angiosarcoma. Dig Dis Sci 48:677-682 Nakeeb A, Pitt HA, Sohn TA, et al (1996) Cholangiocarcinoma.
A spectrum of intrahepatic, perihilar, and distal tumors.
Ann Surg 224:463-473
Nalesnik MA, Jatfe R, Starzl TE, et al (1988) The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppres- sion. Am J Pathol 133:173-192
Nzeako UC, Goodman ZD, Ishak KG (1996) Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-his- topathologic study of 804 North American patients. Am J Clin Pathol 105:65-75
Ohsawa M, Aozasa K, Horiuchi K, et al (1992) Malignant lym- phoma of the liver. Report of fi ve cases and review of the literature. Dig Dis Sci 37:1105-1109
Okuda K, Nakanuma Y, Miyazaki M (2002) Cholangiocarci- noma: recent progress. Part 1: epidemiology and etiology. J Gastroenterol Hepatol 17:1049-1055
Qin XL, Wang ZR, Shi JS, et al (2004) Utility of serum CA 19-9 in diagnosis of cholangiocarcinoma: in comparison with CEA. World J Gastroenterol 10:427-432
Radin DR, Craig JR, Colletti PM, et al (1988) Hepatic epitheli- oid hemangioendothelioma. Radiology 169:145-148 Ryan J, Straus DJ, Lange C, et al (1988) Primary lymphoma of
the liver. Cancer 61:370-375
Sanders LM, Botet JF, Straus DJ, et al (1989) CT of primary lymphoma of the liver. AJR Am J Roentgenol 152:973-976 Schnater JM, Kohler SE, Lamers WH, et al (2003) Where do we stand with hepatoblastoma? A review. Cancer 98:668-678 Scoazec JY, Degott C, Brousse N, et al (1991) Non-Hodgkin’s
lymphoma presenting as a primary tumor of the liver: pre- sentation, diagnosis and outcome in eight patients. Hepa- tology 13:870-875
Sezaki H, Kobayashi M, Hosaka T (2004) Hepatocellular car- cinoma in noncirrhotic young adult patients with chronic hepatitis B viral infection. J Gastroenterol 39:550-556 Shaib Y, El-Serag HB (2004) The epidemiology of cholangio-
carcinoma. Semin Liver Dis 24:115-125
Siskin GP, Haller JO, Miller S, et al (1995) AIDS-related lym- phoma: radiologic features in pediatric patients. Radiology 196:63-66
Smalley SR, Moertel CG, Hilton JF, et al (1988) Hepatoma in the noncirrhotic liver. Cancer 62:1414-1424
Trevisani F, D’Intino PE, Caraceni P, et al (1995) Etiologic factors and clinical presentation of hepatocellular carci- noma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer 75:2220-2232
Weiss SW, Enzinger FM (1982) Epithelioid hemangioendothe- lioma: a vascular tumor often mistaken for a carcinoma.
Cancer 50:970-981
Yamasaki S (2003) Intrahepatic cholangiocarcinoma: macro- scopic type and stage classifi cation. J Hepatobiliary Pan- creat Surg 10:288-291
