Liver and intrahepatic bile duct - tumor

3 April 2006, copyright (c) 2004 PathologyOutlines.com, LLC

Home Page

PRINTER FRIENDLY VERSION

Bold and underlined topics are hypertext links and may open a new window

 

Table of contents

Primary references

Benign tumors/conditions: angiomyolipoma, benign cystic mesothelioma, bile duct adenoma, biliary adenofibroma, biliary cystadenoma, biliary cyst, biliary papillomatosis, extramedullary hematopoiesis, fatty change, focal nodular hyperplasia, glomangioma, hemangioma, hemangiomatosis, hepatic vascular malformation with capillary proliferation, hepatocellular adenoma, hereditary hemorrhagic telangiectasia, heterotopia, inflammatory myofibroblastic tumor, intraductal papillary neoplasms, leiomyoma, lipoma, lymphangioma, mesenchymal hamartoma, myelolipoma, nodular regenerative hyperplasia, paraganglioma, perivascular epithelial cell tumor, pseudocyst, pseudolipoma, reactive bile ductule proliferation, solitary fibrous tumor, solitary necrotic nodules

Dysplasia: liver cell dysplasia, borderline nodule, macroregenerative nodule

Hepatocellular carcinoma: general, cytology, variants: clear cell, fibrolamellar, oncocytic, pleomorphic, sarcomatoid, sclerosing, small

Leukemia/lymphoma: leukemia, lymphoma-general, lymphoma-primary, secondary, lymphoma subtypes: Burkitt’s, CLL/SLL, diffuse large B cell, follicular, hepatosplenic alpha-beta, hepatosplenic gamma-delta, Hodgkin’s, lymphoplasmacytic, MALT, nodal CD8+ cytotoxic peripheral T cell, splenic margin zone

Other malignancies: angiosarcoma, biliary cystadenocarcinoma, carcinoid, carcinosarcoma, Castleman’s disease, cholangiocarcinoma, congenital primitive epithelial tumor, epithelial myoepithelial carcinoma, epithelioid hemangioendothelioma, Erdheim-Chester disease, fibrosarcoma, follicular dendritic cell, gastrointestinal stromal tumor, germ cell tumors, hepatoblastoma, infantile hemangioendothelioma, juvenile xanthogranuloma, Kaposi’s sarcoma, Langerhans cell histiocytosis, leiomyosarcoma, liposarcoma, lymphoepithelioma-like carcinoma, malignant fibrous histiocytoma, malignant histiocytosis, mastocytosis, metastases, mixed hepatocellular carcinoma-cholangiocarcinoma, myeloma, neuroendocrine carcinoma, reactive lymphoid hyperplasia, rhabdomyosarcoma, squamous cell carcinoma, undifferentiated sarcoma

Miscellaneous: staging, frozen section, grossing, features to report

 

Go to Liver and intrahepatic bile ducts - Non-tumor

 

Primary references

AJCC Cancer Staging Manual (6th Ed)

American Journal of Surgical Pathology (AJSP), Jan 1999 to Feb 2004

Archives of Pathology and Laboratory Medicine (Archives), Jan 1999 to Apr 2004

Human Pathology, Jan 1999 to Mar 2004

Modern Pathology, Jan 1999 to Mar 2004

Rosai, J:  Ackerman’s Surgical Pathology (8th Ed); Mosby-Year Book, Inc., 1996

Sternberg, S: Diagnostic Surgical Pathology (3rd Ed); Lippincott Williams & Wilkins, 1999

Loyola University textbook

University of Pittsburgh liver textbook, liver transplant page

USCAP short course: Mod Path 2000;13:679

Virtual Hospital

Journal search terms: liver, hepatic

 

Please refer to these primary references for more detailed discussions

 

Benign tumors

Angiomyolipoma (AML)

<100 cases reported; often misdiagnosed

Mesenchymal tumor arising from perivascular epithelioid cells; also lymphangioleiomyomas, clear cell sugar tumors of lung, rare myomelanocytic tumors

Similar histologically to renal angiomyolipoma

Mean age 50 years, range 9-79 years; 80% women

Only 6-10% associated with tuberous sclerosis, these cases are associated with renal AML and may be multiple

Myoid and vascular components are clonal; adipose tissue component may be reactive

Case report of 15+ tumors in 46 year old woman without tuberous sclerosis (Mod Path 2002;15:167)

Gross: well circumscribed, solitary masses up to 20 cm, yellow-gray-white; necrosis present in larger tumors, background liver is normal

Micro: mature adipose tissue, smooth muscle cells and thick walled blood vessels with spindle cells radiating from walls; extramedullary hematopoiesis (40%); smooth muscle cells are epithelioid or spindled with clear or eosinophilic cytoplasm; mast cells common; occasional features are cellularity, nuclear pleomorphism with intranuclear inclusions, tumor giant cells; no/rare mitotic figures; unusual subtypes are oncocytic and trabecular

Positive stains: HMB45, MelanA/MART-1, microphthalmia transcription factor (50%), S100, smooth muscle actin, desmin, c-kit/CD117 (all cell types)

Negative stains: cytokeratin

EM: epithelioid myoid cells have premelanosomes, numerous mitochondria, abundant rough endoplasmic reticulum, glycogen, tight junctions and basal lamina, but no thick filaments

References: AJSP 2002;26:493 (c-kit staining), Archives 2002;126:49 (melanoma markers), AJSP 1999;23:34 (review)

 

Benign cystic mesothelioma

Also called multilocular peritoneal inclusion cyst

Very rare in liver; elsewhere usually young women with local recurrence

Benign, indolent, slowly progressive, curable

Laboratory: elevated CA 19-9 in serum and cyst fluid

Case reports: 58 year old Italian man with elevated CA 19-9, multiple benign appearing liver cysts and single cysts in kidney and pancreas (Archives 2001;125:944), 51 year old woman (AJSP 2002;26:1523)

Treatment: excision, but may recur

Micro: well encapsulated, partially cystic, highly vascular; no cirrhosis; loose cords of tumor cells separated by medium to large vessels with walls of varying thickness; cystic spaces lined by tumor cells, either epithelioid or with hobnail appearance

Positive stains: CK 8/18 (CAM 5.2), calretinin, EMA, vimentin, estrogen receptor

DD: hydatid cyst, biliary cystadenoma, serous cystadenoma, cystic neoplasms

 

Bile duct adenoma

Incidental finding, although often confused with adenocarcinoma

Usually adults > 40 years old, no gender preference

Benign

Much less common than bile duct hamartoma

Gross: well-circumscribed but unencapsulated, firm, gray-white, tan, subcapsular nodules; 85% solitary; usually 5 mm or less but 7% are larger than 1 cm; may have central depression

Micro: compact network of simple tubular ducts or more complex tortuous arrangement, with small or indistinct lumina; epithelium has abundant cytoplasm and pale nuclei compared to interlobular bile ducts in adjacent liver; variable fibrous stroma, granulomas, calcification, inflammatory cells; usually no cystic change, no cytoplasmic or intraluminal bile, no atypia, no mitotic figures, no angiolymphatic invasion

Positive stains: mucin (intracytoplasmic), CEA, EMA, keratin, PAS highlights basement membrane

DD: cholangiocarcioma, adenocarcinoma

 

Atypical clear cell type

Rare; ages 25-64 years in 3 cases described

Incidental finding

Gross: 1 cm, subcapsular

Micro: bile duct tumor composed almost entirely of small nests and tubules of clear cells infiltrating hepatic parenchyma; small nests surrounded by PAS+ membrane (may represent tubular structures); well defined cytoplasmic borders, mild nuclear hyperchromasia, mild stromal sclerosis; no mitotic activity

Positive stains: CK7, EMA, CEA, p53, mucin (focal)

Negative stains: CK20, vimentin, HepPar1, chromogranin, Ki-67 (<10% positive)

DD: well differentiated adenocarcinoma, metastatic renal cell carcinoma, clear cell cholangiocarcinoma (larger, tubular pattern, desmoplastic stroma, more nuclear atypia and mitotic activity; similar immunostains results)

References: AJSP 2001;25:956

 

Biliary adenofibroma

Extremely rare (< 5 reported cases)

Case report in 47 year old woman, AJSP 2003;27: 693

Appears to originate from interlobular or larger bile ducts

Benign behavior to date, but may be premalignant

Micro: (a) microcystic and tubular structures lined by low columnar/cuboidal epithelium and (b) dense fibrous stroma with spindle cells displaying mild nuclear pleomorphism; no/rare mitotic figures, no stromal invasion

Positive stains: epithelium - AE3, CAM5.2, CK 7, CK9, CEA, EMA, D10, p53

Negative stains: Alcian blue, vimentin, desmin

DD: von Meyenburg complex (smaller, usually multifocal, but similar staining pattern)

 

Biliary cystadenoma

5% of all hepatic solitary cysts

95% occur in women, mean age 45 years (range 2-87 years)

84% are intrahepatic, also in common bile duct (6%), hepatic ducts (4%), cystic duct (4%), gallbladder (2%)

Associated with polycystic liver disease, abnormal hepatobiliary anatomy

Usually slow growing with good prognosis after surgical excision, although 25% have coexisting malignancy

Complications: intracystic hemorrhage, bacterial infection, rupture

Also associated with borderline or malignant lesions

Laboratory: elevated CA 19-9 (in cases with ovarian type stroma) and CEA in cyst fluid and serum

Xray: calcification in 20% (resemble echinococcal cyst)

Treatment: complete excision (rarely has delayed recurrence)

Case reports: tumor arising from left hepatic duct (Archives 2001;125:1507), encased in smooth muscle tumor (AJSP 1999;23:854)

Gross: encapsulated, solitary, mean 15 cm (range 3-28 cm), usually mucinous, multilocular by definition (locules have varied sizes); contains up to several liters of fluid; smooth inner surface with few trabeculations or polypoid cystic projections; rarely contains gallstones; nodules of solid tissue suggests malignancy

Micro: mucinous - lined by single layer of columnar-cuboidal mucinous epithelium with basal nuclei and apical mucin; spindle-cell ovarian type stroma only in women (resembles pancreatic mucinous cystic neoplasms); spindle cells may contain fat and smooth muscle; may have collagenous zone above stroma (resembling collagenous colitis); capsule composed of dense collagen with blood vessels, variable bile ducts; may have squamous or intestinal metaplasia, often neuroendocrine cells; may have dysplastic or borderline foci; may have ulceration with macrophages containing lipofuscin or hemosiderin, cholesterol clefts with foreign body giant cell reaction or calcification; no/rare atypia, no/rare mitotic figures

serous - lined by bland, flat to cuboidal cells with clear, glycogen-rich cytoplasm, no spindle cell stroma; no mucin; may represent hepatic metastasis from pancreatic serous cystadenocarcinoma

Positive stains: epithelial cells - cytokeratin, EMA, CEA; stromal cells - muscle specific actin, vimentin. focal ER and PR

 

Borderline

Tumors with high grade dysplasia with complex architecture

 

Biliary cyst

Micro: lined by cuboidal or biliary type epithelium; rarely squamous lined; thin fibrous wall

 

Biliary papillomatosis

Rare, 50 cases reported

2/3 men, usually ages 40+ years

Multiple papillary adenomas extensively throughout intra- or extrahepatic biliary tract

Often recurs, 25% have malignant transformation, but only rare metastases (to lung)

Associated with Caroli’s disease, choledochal cyst, polyposis coli and ulcerative colitis

Most patients die within 3 years due to cholangitis and hepatic failure

Case report in 66 year old man with cirrhosis due to Hepatitis C and malignant transformation, Archives 2002;126:369

Treatment: difficult to treat because multifocal; liver transplant may be helpful

Gross: inner surface of ducts has velvety papillary growths with masses filling dilated ducts; masses are soft, friable, white-red-tan

Micro: dilated ducts contain multiple papillary tumors composed of fibrovascular cores lined by columnar, pseudostratified, biliary-type cells with numerous cytoplasmic mucin vacuoles; tumor may be solid or cribriform; varying cytologic atypia and mitotic activity; may have associated tubular adenocarcinoma with invasion

 

Extramedullary hematopoiesis

Usually asymptomatic or associated with anemia; rarely presents as a liver mass

Case report of 52 year old woman with 2.5 cm, 5 cm and 7 cm liver masses and normal serum AFP, Archives 2003;127:631

Treatment: radiation or hydroxyurea if symptomatic

Micro: erythroid precursors in sinusoids (resemble lymphocytes), myeloid precursors in portal tracts (resemble mixed portal infiltrate or eosinophils in neonates); also megakaryocytes within sinuses

 

Fatty change

Not neoplastic, but simulates lipomatous tumor

Associated with obesity, diabetes, alcohol abuse, dyslipidemia

Stable or regresses if underlying condition improves

Gross: subcapsular yellow-white foci, often multiple, up to 10 cm

Micro: diffuse or focal steatosis adjacent to unremarkable liver, may have foreign-body type granulomatous inflammation

 

Focal nodular hyperplasia (FNH)

Spontaneous mass lesion of young (median age 38 years) women (80-90%), excellent prognosis

7-15% occur in children; FNH represents 2-10% of pediatric hepatic tumors

May be associated with oral contraceptives (use reported in 66-95% of cases), hepatic cavernous hemangioma (20%), glycogen storage disease type Ia, portal hypertension

Tumors associated with oral contraceptive use often have hemorrhage, necrosis, infarction

Usually incidental finding; present in 1% of autopsies

May represent hyperplastic response to arterial malformation or other vascular anomaly; NOT a neoplasm

Xray: mass with central scar, centrifugal hypervascularity by angiography

Treatment: excision unnecessary if confident of diagnosis but follow up is suggested; discontinue oral contraceptives

Gross: well-demarcated, poorly encapsulated, light brown to yellow, lighter than surrounding liver; bulging nodule, 70-80% solitary, up to 5 cm; ; rarely > 10 cm; has central gray-white stellate scar (unless < 1 cm) from which fibrous septa radiate to periphery and create multiple smaller nodules; pedunculated, hemorrhage, necrosis, infarction, bile staining often seen; larger tumors may have multiple scars; adjacent liver is normal

Micro: hepatocyte nodules surrounded by fibrous septa with large malformed arterial branches but no interlobular bile ducts or portal veins (i.e. no portal tracts); septal margins have foci of intense lymphocytic infiltrates and marked bile duct proliferation with histologic changes of chronic cholestasis (Mallory’s hyaline, bile pigment, copper deposits, pseudoxanthomatous change), variable neutrophilic infiltration; ductules appear to arise from limiting plate; central scar contains central fibrous body with tortuous large vessels with fibromuscular hyperplasia and luminal narrowing; hepatic plates are 1-2 cells thick, similar to surrounding liver, but may be larger and paler with fat or glycogen; no atypia, no mitotic figures; telangiectatic variant has multiple dilated vascular channels in center of mass

Positive stains: alpha-1-antitrypsin

Negative stains: p53, CD143 (angiotensin I-converting enzyme: reduced expression)

DD: nodules in patients with Osler-Weber-Rendu disease, Budd-Chiari syndrome, cirrhosis (but adjacent liver is not normal), fibrolamellar hepatocellular carcinoma (gross bile staining), biliary cirrhosis, hepatocellular adenoma (encapsulated), peritumoral hyperplasia (Archives 2000;124:1105)

References: AJSP 2004;28:84 (CD143), AJSP 1999;23:1441 (review)

 

Multiple focal nodular hyperplasia syndrome

Multiple FNH lesions plus one other lesion: either hepatic hemangioma, arterial dysplasia, Klippel-Trenaunay-Weber syndrome, brain telangiectasia, berry aneurysm, astrocytoma or meningioma

Micro: often telangiectatic variant with multiple dilated vascular channels in center of mass

 

Glomangioma

Rare, <10 cases reported

Type of glomus tumor (neoplasm of glomus apparatus) with prominent vascular structures

Case report in 57 year old man with flank pain and 3 cm liver mass, Archives 2004;128:e46

Micro: small to medium branched vessels with stroma containing small, round regular cells with sharply outlined round/oval nuclei

Positive stains: vimentin, smooth muscle actin, CD34, calponin (focal)

Negative stains: desmin, S100, chromogranin, CD117

 

Hemangioma

Most common primary hepatic tumor

Usually an incidental finding, found in 1% of routine autopsies and 20% of autopsies with extensive investigation

More common in adults than children, 75% in women, who are more likely symptomatic

10% enlarge with follow-up, may be related to pregnancy or oral contraceptives

Associated with multiple focal nodular hyperplasia syndrome

Giant cavernous hemangiomas (> 4-10 cm) only rarely rupture

Fibrotic tumors may be precursor of solitary necrotic nodules

Solitary capillary hemangiomas are extremely rare

Treatment: excision or observation (may involute)

Gross: solitary (70-90%), usually 2-4 cm, although tumors up to 20 cm are overrepresented in studies of excisions; soft, red-purple, well circumscribed; subcapsular or deep; collapse when sectioned as blood oozes out

Micro: variably sized vascular spaces lined by flat endothelial cells and myxoid or fibrous stroma; large fibrous septa may trap bile ducts; variable thrombosis, calcification, phleboliths; increased fibrosis with age of lesion may obliterate lumen

Positive stains: elastin and trichrome may expose vessels in old fibrous lesions

DD: peliosis hepatis (no fibrous septa), hereditary hemorrhagic telangiectasia (aberrant portal vessels, dilated vascular channels within portal tracts), hemangiomatosis, infantile hemangioendothelioma (atypia present, although not necessarily everywhere)

 

Hemangiomatosis

Also called diffuse hemangiomatosis

Rare disease of adults

May also affect lung and bone

Gross: nodules may replace entire liver

Micro: numerous small, poorly circumscribed, hemangiomatosis nodules in portal tracts, may become sclerosed

 

Hepatic vascular malformation with capillary proliferation

Usually symptomatic at birth

Congenital vascular malformation

Does not regress spontaneously

Symptoms: abdominal mass or distention, cardiomegaly, congestive heart failure, anemia, thrombocytopenia, DIC, fever, jaundice, elevated serum AFP

Treatment: lobectomy; good outcome

Gross: single large mass, mean 8 cm, range 5-11 cm; central infarction and hemorrhage is common

Micro: outer dilated vessels lined by flattened endothelium and loose myxoid stroma; central infarction and hemorrhage

DD: infantile hemangioendothelioma (GLUT1+, Hum Path 2004;35:200)

 

Hepatocellular adenoma

Also called liver cell adenoma

Arises in normal or nearly normal liver in patients with abnormal hormonal or metabolic condition

95% women, usually child-bearing age (very rare in children), history of 5+ years of oral contraceptives in 85% (occasionally regress after discontinuation); also associated with anabolic steroids (in men), anti-estrogens, Klinefelter’s syndrome or other abnormal secretion of sex steroids

Also associated with glycogen storage disease types Ia and III, Fanconi’s anemia, familial adenomatous polyposis, familial diabetes mellitus, Hurler’s disease or tyrosinemia; also spontaneous

2-4% of hepatic tumors in children

Subcapsular tumors may rupture, particularly during pregnancy

Benign, but may contain hepatocellular carcinoma or cause severe hemorrhage

10% or lower risk of hepatocellular carcinoma if not resected; definite risk in young men with glycogen storage disease type Ia

Must sample generously to rule out coexisting hepatocellular carcinoma

May contain hepatic progenitor cells, AJSP 2001;25:1388

Laboratory: normal liver function tests, may have elevated alpha fetoprotein

Hepatocellular adenomatosis: 10+ tumors

Treatment: excision

Case reports: tumor in 9 year old girl with later fibrolamellar carcinoma (Archives 2004;128:222)

Gross: solitary (70%, anabolic steroid related more often multiple), pale, yellow-tan (different from surrounding liver), frequently bile-stained nodules, often subcapsular, 10-30 cm, sharply demarcated or encapsulated; usually right lobe, may be pedunculated (10%); may have hemorrhagic, necrotic or infarcted foci; usually no fibrous septa or central scar; adjacent liver is noncirrhotic

Micro: sheets and cords 1-3 cells thick of normal appearing hepatocytes with variable glycogen; no/rare mitotic figures; no portal tracts, no central veins or connection with biliary system but see prominent “free floating” arterial vessels and draining veins throughout the tumor; intact reticulin framework; pseudoglands may be present; may have cytoplasmic globules (PAS+, diastase resistant, alpha-1-antitrypsin+, AFP-), 10% have multinucleation, but no atypia, no prominent nucleoli, no intranuclear vacuoles, no/rare mitotic figures, no angiolymphatic invasion, no/rare extramedullary hematopoiesis, no epithelioid granulomas, no decreased reticulin framework; degenerative changes include dilated sinusoids, blood filled (pelioid) spaces, myxoid stroma, focal necrosis, infarction, hematoma; rarely contains abundant fat, oncocytic changes, Mallory’s hyaline, granulomatous inflammation

Positive stains: ER, PR

Negative stains: p53

DD: hepatocellular carcinoma (mitotic activity, atypia, trabecular growth, cell plates > 2 cells thick, vascular invasion, infiltrative, often different clinical features), focal nodular hyperplasia (central stellate scar and radiating fibrous septa)

References: Hum Path 2002;33:852 (childhood tumors with beta catenin abnormalities)

 

Atypical hepatocellular adenoma

Androgen related tumors that regress with androgen withdrawal

Only rarely metastasize

Micro: marked pleomorphism with prominent nucleoli and extensive pseudoglands, resembling hepatocellular carcinoma, but no trabecular pattern, low N/C ratio, no vascular invasion

DD: hepatocellular carcinoma (elevated serum AFP, cirrhosis, vascular invasion, high N/C ratio, trabecular pattern), focal nodular hyperplasia (central scar), hepatoblastoma (elevated serum AFP, age < 3 years, no metabolic disease, light and dark cytoplasmic pattern, small cell size)

 

Pigmented liver cell adenoma

Black pigment present

Case reports in 2 men without Dubin-Johnson syndrome, AJSP 2000;24:1429

Micro: pigment granules are larger and darker than lipofuscin; no portal tracts, bile ducts or ductules within the tumor

Positive stains: Masson-Fontana (for melanin and Dubin-Johnson pigment)

DD: well differentiated hepatocellular carcinoma

 

Hereditary hemorrhagic telangiectasia

Also called Osler-Weber-Rendu syndrome

Autosomal dominant; systemic fibrovascular dysplasia; prevalence of 10-20 per 100,000 population

Caused by HHT1 (encodes endoglin on #9, expressed in central vein endothelium of normal liver) and HHT2 (encodes activin receptor-like kinase 1 / ALK1 on #12)

Hemorrhage, telangiectasia and arteriovenous malformations of vessels in skin, mucous membranes, lung, liver (up to 33%), CNS

Usually asymptomatic

May have hepatic vascular shunts that may cause high output congestive heart failure, portovenous shunts that cause hepatic encephalopathy or arterioportal shunts that cause portal hypertension

Case reports: 56 year old woman with pulmonary hypertension and intractable pulmonary bleeding (due to pulmonary capillary hemangiomatosis) and GI bleeding, Hum Path 2004;35:266

Gross: telangiectatic lesions throughout the liver

Micro: focal sinusoidal ectasia, abnormal direct communications between hepatic arterial branches and ectatic sinusoids (AV shunts), frequent and large communications between portal and central veins through ectatic sinusoids (portovenous shunts)

References: Archives 2001;125:1219

 

Heterotopia

Usually from pancreas, adrenal gland or spleen

Pancreas: 4% of autopsies, usually within large and medium sized portal tracts; acinar cells but no islets

Adrenal gland rests: rare, may be confused with renal cell carcinoma or other clear cell carcinomas

Heterotopic liver is not connected to main liver; is found in gallbladder, spleen, pancreas, umbilicus, adrenal gland, small intestine, lesser omentum, lung

 

Inflammatory myofibroblastic tumor

Also called inflammatory pseudotumor

Uncommon

Mean 37 years but all ages, 75% male

Associated with occlusive phlebitis and chronic cholangitis

Rarely associated with sarcoma or follicular dendritic cell tumor

In extrapulmonary tumors, recurs locally in 25%; 8% metastasize

Symptoms: fever, upper abdominal pain

Treatment: excision, occasionally regresses spontaneously

Gross: well circumscribed, solitary (70%), 1-25 cm, variegated cut surface, may extend into vena cava or soft tissue

Micro: plasma cells, lymphocytes, neutrophils, macrophages, mast cells and myofibroblast-like spindled cells in varying amounts, in whorled, fibrotic stroma; occasional myxoid areas, minimal vascular component; minimal pleomorphism, no/rare mitotic activity; rarely is highly cellular or has mitotic activity (often in children)

Positive stains: vimentin (>90%), smooth muscle actin (80%), muscle specific actin (80%), desmin (40%), CD68 (40%), pankeratin (30%), p53 (30%), ALK1

Negative stains: S100, CD21, myoglobin

DD: sclerosing hemangioma, leiomyoma, solitary fibrous tumor, follicular dendritic cell tumors (CD21+, CD35+), Hodgkin’s lymphoma (stromal cells CD15+, CD30+), organizing abscess, postoperative spindle cell nodule, spindle cell carcinoma or sarcoma

 

Intraductal papillary neoplasms of biliary tract

Uncommon

Solitary or may spread along biliary tree to cystic duct or duodenal papilla

May resemble intrapapillary mucinous neoplasms of pancreas as both arise within a dilated duct system and demonstrate predominantly intraductal growth

Risk factor for cholangiocarcinoma, biliary obstruction, recurring ascending cholangitis

Often are carcinomas

Micro: papillary fronds with fine vascular cores; epithelial cells are either biliary type or have gastric or intestinal differentiation with goblet cells and Paneth cells; production of extracellular intraductal mucin less common than pancreatic IPMNs

Borderline tumors: mild to moderate nuclear atypia and nuclear pseudostratification limited to basal 2/3 of the epithelium

Carcinomas: severe cytological atypia, loss of nuclear polarity or architectural cribriforming / papillary fusion is present

Negative stains: p53, CK20

Molecular: Kras activating mutations (29%), 18q- (31%) but no loss of DPC4

References: Hum Path 2003;34:902, Hum Path 2002;33:503 (stains)

 

Leiomyoma

Solitary nodule that may resemble metastatic well differentiated leiomyosarcoma

May be associated with HIV, EBV

 

Lipoma

Rare, usually incidental finding

Gross: solitary, 1-20 cm

Micro: mature fat or brown fat (hibernoma)

DD: angiomyolipoma, focal fatty change

 

Lymphangioma

Very rare

May actually represent mesenchymal hamartoma

 

Mesenchymal hamartoma

Formerly called cavernous lymphangioadenomatoid tumor, cystic hamartoma, benign mesenchymoma

75% age 1 or less (rarely adults), 60-70% male

8% of pediatric liver tumors

Benign with excellent prognosis, although intraoperative and postoperative deaths may occur with very large masses

Origin either neoplastic or a developmental anomaly in bile duct plate formation

Rarely associated with undifferentiated sarcoma

Usually normal or slightly elevated serum AFP

Adult cases are usually women with abdominal pain, more prominent fibrous and lesser myxoid component than childhood cases, usually no extramedullary hematopoiesis

Treatment: excision (curative, but surgery has high mortality)

Gross: well circumscribed, solitary, 5-23 cm, 20% pedunculated, myxoid mass with fluid filled cysts; may be multiloculated; becomes fibrotic with age; cysts are variable size, contain mucoid or pink fluid with adjacent solid, pink-white areas; may have satellite nodules; usually no necrosis, hemorrhage or calcification

Micro: irregular but bland bile ducts in myxoid stroma with variable collagen resembling breast fibroadenoma at low power; also bland hepatocytes, thick walled veins, bile ducts may have mesenchymal collar and are often cystically dilated; usually extramedullary hematopoiesis (90%); often pools of fluid; no tumor giant cells; adult cases have densely hyalinized or fibrotic stroma and only focal myxoid areas

Positive stains: vimentin, smooth muscle actin, desmin, actin, CK7,

Negative stains: CK20

Molecular: 19q translocation

EM: myofibroblastic features

DD: lymphangioma, vascular malformation, infantile hemangioendothelioma, biliary cystadenoma (adults)

References: Hum Path 2002;33:893 (adult cases)

 

Myelolipoma

Resembles adrenal tumor

Micro: fat and bone marrow hematopoietic cells

 

Nodular regenerative hyperplasia

Nodular hyperplasia diffusely affecting entire liver

Associated with no/minimal fibrous septa

Incidental finding at autopsy in 1-3%; present in 5% of elderly

Develops at all ages, but usually symptomatic at age 40+

Associated with portal hypertension, connective tissue disease (rheumatoid arthritis, polyarteritis nodosa), myeloproliferative or lymphoproliferative disorders, vascular disorders, chemotherapy or immunosuppressive drugs

May be due to moderate to severe sclerosis of small portal veins, causing heterogeneous blood flow, variable ischemia and reactive hepatocyte hyperplasia

Laboratory findings: mildly elevated alkaline phosphatase, normal alpha fetoprotein

Gross: heavy liver in patients with myeloproliferative disorders, otherwise normal; finely granular capsule, parenchyma has multiple tan-white nodules, 0.1 to 1 cm, separated by congested parenchyma; large nodules may exhibit hemorrhage or necrosis; may resemble metastatic carcinoma or cirrhosis

Micro: (a) diffuse nodules of hyperplastic hepatocytes with central, single portal tract but with different orientation at low power; (b) regions of internodular hepatocyte atrophy, usually centrilobular, associated with areas of hepatocyte regeneration (plump hepatocytes with pale cytoplasm), sinusoidal congestion / dilation and compression of central veins making them difficult to identify; (c) no/minimal fibrosis; hepatocyte plates are usually 2-3 cells thick compared to thin plates in atrophic areas; hepatocytes may have clear / vacuolated cytoplasm, cholestasis associated with pseudoglandular spaces, variable large cell change; no lipofuscin in atrophic hepatocytes; no/rare extramedullary hematopoiesis, no/minimal inflammation

On biopsy, apparent lack of central veins and presence of curvilinear areas of congestion are suggestive

Positive stains: reticulin highlights nodular architecture and hepatocyte atrophy, trichrome highlights the compressed central veins

DD: cirrhosis, primary biliary cirrhosis, focal nodular hyperplasia (central scar), other noncirrhotic portal hypertension, incidental focus of nodular hyperplasia, hepatocellular adenoma

References: Archives 2004;128:49 (association with thioguanine therapy)

 

Partial nodular transformation

Very rare, focal form of nodular regenerative hyperplasia

Portal hypertension usually prominent

Micro: nonfibrotic nodules in liver near porta hepatis; regenerating hepatocytes with thickened cell plates compressing adjacent single cell plates (highlighted with reticulin stain); normal portal tracts

 

Paraganglioma

Very rare; case report confined to liver in 46 year old man, AJSP 2002;26:945

Benign

Treatment: excision

Gross: firm, pale gray nodule with variable fibrosis and thin fibrous capsule, large (~ 10 cm); no cirrhosis

Micro: polygonal eosinophilic tumor cells, round nuclei, indistinct nucleoli, arranged in small nests (“zellballen”) or trabeculae in vascular stroma; no pleomorphism, no mitotic figures

Positive stains: chromogranin A, synaptophysin, neuron-specific enolase, insulin like growth factor II (IGF-II); sustentacular cells are S100+

Negative stains: albumin mRNA, keratin, CD10, vimentin, smooth muscle actin

Molecular: insulin like growth factor II by ISH

DD: fibrolamellar hepatocellular carcinoma

 

Perivascular epithelioid cell tumor (PEComa)

Case report of tumor in ligamentum teres hepatis with benign behavior in 13 year old Japanese girl, AJSP 2000;24:1295

Related tumors include angiomyolipoma, clear cell sugar tumor of lung, lymphangioleiomyomatosis

Gross: well defined, 9 cm, tan-white homogenous cut surface, no hemorrhage, no necrosis

Micro: nests or sheets of polygonal or oval cells with clear/finely granular cytoplasm, moderate nuclear atypia; well developed capillary network, occasional perivascular hyalinization of sinusoidal vessels; no mitotic figures, no invasive growth

Positive stains: HMB45, MelanA/Mart1, PAS+ diastase sensitive, smooth muscle actin

Negative stains: cytokeratin, desmin, EMA, S100, CD34, CD68, CD99, ER, PR

EM: numerous degenerated mitochondria, glycogen, thin filaments with focal densities, subplasmalemmal densities

 

Pseudocyst

By definition, no true epithelial lining

Causes: trauma, ischemia, pancreatitis

Gross: may be large, contain blood or bile; may become secondarily infected

Micro: fibrous lining, may contain hemosiderin, bile

 

Pseudolipoma

Also called pseudolipoma of Glisson’s capsule, coelomic fat ectopia

Rare, embedded in cavity on liver surface

Represents trapped appendix epiploica, often related to prior surgery

Case report in 69 year old man with incidental finding, Archives 2003;127:503

Gross: smooth, hard nodule of fat necrosis, calcification, ossification

Micro: thick fibrous capsule surrounding mature fat cells with degenerative changes including calcification

 

Reactive bile ductule proliferation

Associated with cirrhosis, biliary tract disorders, atrophy and focal nodular hyperplasia

Micro: periductular neutrophils common; no angulated structures, usually no dense fibrosis (except with atrophy), variable bile

DD: adenocarcinoma (particularly confusing after chemotherapy, has more severe atypia with irregular nuclear membranes, prominent nucleoli, hyperchromasia, increased N/C ratio, desmoplasia, infiltrative cells)

 

Solitary fibrous tumor

Also called localized fibrous tumor

Rare; may arise from beneath liver capsule

Case report of 66 year old Italian man, Archives 2003;127:e255

Associated with hypoglycemia

Treatment: complete surgical resection with long term follow up

Gross: well circumscribed, often 15 cm or more, with bulging, solid, gray-white cut surface

Micro: spindle cells without atypia mixed with hyalinized collagen; mild atypia; rare mitotic figures; no necrosis

Positive stains: CD34, bcl2, vimentin

Negative stains: cytokeratin, EMA, CD117, S100, smooth muscle actin, desmin, chromogranin, synaptophysin

 

Solitary necrotic nodules

May represented sclerosed hemangiomas, prior infection, trauma, bile duct hamartomas

Gross: 0.2 to 2.5 cm, single or multiple, below anterior border of liver

Micro: hyalinized fibroelastic capsule surrounds necrotic core; variable calcification

 

 

Dysplasia

Liver cell dysplasia

Apparent precursor lesion of hepatocellular carcinoma

Micro: large cells with abundant cytoplasm and relatively normal nuclear/cytoplasmic ratio or small cells with minimal basophilic cytoplasm and increased N/C ratio; both have enlarged, pleomorphic nuclei, clumped chromatin, thick nuclear membranes, prominent nucleoli

 

Borderline nodule

Also called macroregenerative nodule type II, atypical macroregenerative nodule, atypical adenomatous hyperplasia, grade 1 hepatocellular carcinoma

Much less common than macroregenerative nodule

Present in 5-15% of cirrhotic livers or livers with mild scarring

Considered a precursor to hepatocellular carcinoma; usually increase in size over time and don’t regress

66% risk of hepatocellular carcinoma in liver explants, 100% risk at autopsy

Biopsy may be best described as “uncertain malignant potential” because cannot exclude hepatocellular carcinoma without a complete resection

Treatment: ablation or resection should be strongly considered

Gross: frequently multiple, coexists with macroregenerative nodule (which they grossly resemble), usually less than 2 cm

Micro: either dysplastic features in subpopulation of cells 1 mm or more or normal histology with evidence of clonality; may be low grade or high grade; dysplastic features include small cell change (small size, reduced and more basophilic cytoplasm) or large cell change in more than random cells; may have pseudoglands, moderate nuclear pleomorphism, rare mitotic figures, rare hepatic plates 3 cells wide; no uniformly prominent nucleoli; often conspicuous intranodular arteries, portal tracts may be abnormal

Positive stains: sinusoids positive for factor VIII and CD34

DD: dysplastic focus (less than 1 mm), hepatocellular carcinoma (denser nuclei per unit area excluding atrophic areas [2 x density of extranodular hepatocytes], irregular nuclear contour, invasion of stroma or portal tracts, mitotic figures, pseudoglands)

 

Macroregenerative nodule

Also called macrogenerative nodule type I, large regenerative nodule, adenomatous hyperplasia, hepatocellular pseudotumor, low grade dysplastic nodule

May be clonal

Usually ages 40+, 2/3 male

May be due to disturbance in local blood flow

Often static; 25% regress after radiographic follow up

15-20% risk of hepatocellular carcinoma in liver explants, 41% risk at autopsy

Treatment: close follow up (more frequent than in cirrhosis patients)

Gross: usually multiple, 0.5 to 1.5 cm, occasionally up to 5 cm; well circumscribed by thin rim of fibrous tissue, but similar in color and texture to surrounding liver, may be pale or bile stained; found in 15-50% of cirrhotic livers, rarely in acute liver injury or precirrhotic livers

Micro: hepatocytes resemble those in remaining liver and may reflect disease process there (bile pigment, pseudoglands), liver cell plates 1-2 cells thick (with reticulin stain), reduced and scattered portal tracts with variable structural distortion (prominent bile ductules, absent interlobular bile ducts); may have architectural and cytologic atypia

 

 

Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma-general

Also called liver cell carcinoma, hepatoma (misleading since implies benign)

85% of hepatic malignancies (30% in children); major cause of cancer death worldwide (20-40% in China, Japan, sub-Saharan African), although not in North America

Primary carcinomas are rare in North America, but more common in countries bordering Mediterranean Sea endemic for viral hepatitis; highest rates in Korea, Taiwan, southeast China, Mozambique; 250,000 worldwide cases annually

Higher rates in blacks vs. whites (4:1)

Most are age 60+ years with cirrhosis or ages 20-40 years without cirrhosis, occasionally are second tumors in Wilm’s tumor patients

Risk factors/causes: hepatitis B virus (HBV) (infant carriers have 200x risk), cirrhosis (85% in West with HCC have cirrhosis, 3% with cirrhosis develop HCC annually), hepatitis C virus (HCV), alcohol abuse, aflatoxins, genetic variation (all act synergistically), small cell change but probably not large cell change, Thorotrast exposure, androgenic steroids, tyrosinemia

Hepatitis B virus: HBV DNA is integrated into host cell genome, inducing genomic instability; HBV contains 4 open reading frames; HBV X protein may disrupt normal growth control by transcriptional activation of insulin like growth factor II, receptors for insulin-like growth factor I; HBV X binds to p53; HBV vaccination may dramatically reduce HCC incidence

Aflatoxins: aflatoxin B1, a metabolite of the fungus Aspergillus flavus, is a potent carcinogen in some areas endemic for HCC; is activated by hepatocytes, products intercalate into DNA to form mutagenic adducts with guanosine; in sub-Saharan Africa and China, patients have mutation in hepatic enzymes that normally detoxify aflatoxin

Cirrhosis: major risk factor, caused by HCV, alcoholism, primary hemochromatosis, hereditary tyrosinemia (40% develop HCC even with dietary control); due to stimulation of hepatocellular division in background of ongoing necrosis and inflammation

Symptoms: abdominal pain, ascites, hepatomegaly, obstructive jaundice; also systemic manifestations

Laboratory: elevated serum AFP (70% sensitive), reduced sensitivity in alcohol-related cirrhosis (65%), tumors arising in noncirrhotic liver (33%), tumors 2 cm or less (25%)

Screening: recommended to use ultrasound and serum AFP in patients with chronic liver disease; leads to diagnosis of tumors 2 cm or less, may not reduce deaths

Other causes of elevated serum AFP: yolk sac tumors of gonads, cirrhosis, massive liver necrosis, chronic hepatitis, normal pregnancy, fetal distress or death, fetal neural tube defects, hepatoblastoma, hepatoid adenocarcinoma

5 year survival: 10% normally to 50% in tumors 5 cm or less with resection; death usually within 1 year from cachexia, GI bleed, liver failure, rupture of tumor (10%)

Metastases: initially within liver, distant metastases late to lungs, bone, adrenal gland or porta hepatis lymph nodes

Favorable prognosis factors: low stage, encapsulation, single lesion, tumor size < 5 cm, fibrolamellar variant, no cirrhosis (independent of fibrolamellar subtype), no vascular invasion, negative surgical margins; another study: low nuclear grade (grade 1 of 3) regardless of vascular invasion or intermediate nuclear grade (2 of 3) without microscopic vascular invasion

Poor prognostic factors: microscopic vascular invasion, high nuclear grade (grade 3 of 3)

Factors that are not prognostic: age, gender, HBV status

Classification: either small (< 2 cm) or advanced (2 cm or more)

Treatment: resection, transplantation (if solitary tumor 5 cm or less or multiple nodules 3 cm or less), radiofrequency ablation (causes ongoing necrosis, Mod Path 2002;15:110)

Case reports: 48 year old man with lymphangitis carcinomatosis in lung (Archives 2003;127:e11), development of HCC and focal hepatic glycogenosis after 6 years of azathioprine therapy (Hum Path 2000;31:874)

Gross: unifocal, multifocal or diffusely infiltrative soft tumor, paler than normal tissue, may be green due to bile; extensive intrahepatic metastases are common; snakelike masses of tumor may involve the portal vein (35-80%), hepatic vein (20%) or inferior vena cava (similar to renal cell carcinoma); hemorrhage and necrosis are common; occasionally tumor is pedunculated; liver usually cirrhotic, often enlarged

Micro: patterns are trabecular (most common) with 4+ cells surrounded by layer of flattened endothelial cells, solid (compact), pseudoglandular (acinar with proteinaceous material or bile in lumina, may resemble thyroid follicles), pelioid, giant cell, sarcomatoid and clear cell patterns; sinusoidal vessels surrounding tumor cells is important diagnostic feature; scanty stroma, from well differentiated to bizarre (often within same tumor); cells are polygonal with distinct cell membranes, higher N/C ratio than normal, abundant granular eosinophilic cytoplasm, round nuclei with coarse chromatin and thickened nuclear membrane, may have prominent nucleoli; also intranuclear pseudoinclusions, Mallory’s hyaline (2-25%), bile (5-33%) and bile canaliculi, vascular invasion and portal vein thrombosis are common, mitotic figures are common; minimal desmoplasia; occasionally fibrous variants (see below), vascular lakes (pelioid pattern), abundant fat, no central veins

Well differentiated: thin plates (1-3 hepatocytes thick), cells smaller than normal, abnormal reticulin network; minimal nuclear atypia, nuclear density 2x normal liver; commonly fatty change and pseudoglands; may resemble hepatocyte adenoma; common pattern for small hepatocellular carcinoma

Moderately differentiated: trabecular pattern with 4+ cells thick; larger tumor cells than well differentiated HCC with more eosinophilic cytoplasm, distinct nucleoli, pseudoglands, bile, tumor giant cells; most common pattern in advanced HCC

Poorly differentiated: Large tumor cells with hyperchromatic nuclei in compact growth pattern with rare trabeculae or bile; prominent pleomorphism, may have spindle cell or small cell areas; may not appear to be hepatocellular

Positive stains: HepPar1 (80-90%, cytoplasmic and granular), polyclonal CEA in canalicular pattern (50-90%, in better differentiated tumors), AFP (15-70%, not in small tumors), alpha-1-antitrypsin (55-93%), CEA-Gold 5 (76%), albumin mRNA ISH, CD10 (52%), transferrin, copper (7-41%), CAM 5.2 (CK 8/18), Fas, Fas ligand

Note: polyclonal CEA in canalicular pattern is specific for hepatocellular carcinoma, probably due to cross reactivity to biliary glycoprotein I present in bile canaliculi of normal liver and hepatocellular neoplasms; only 50-90% sensitive for hepatocellular carcinoma; monoclonal CEA is usually negative

Negative stains: AE1-AE3, CK7 (80%), CK13, CK19 (>90%), CK20, keratin 903 (>90%), EMA, monoclonal CEA (present in 0-10%), CD15, mucin (mucicarmine), MOC31, BerEP4

Recommended panel: p-CEA or CEA-Gold 5 or (less recommended) CD10, HepPar-1, mucicarmine or MOC31

Note: must differentiate trapped normal hepatocytes from tumor cells when interpreting stains

Molecular: 50-92% hyperploid or aneuploid

EM: numerous mitochondria, microbodies, abundant glycogen; intracytoplasmic bile products (bile canaliculi, peroxisomes)

DD: metastatic hepatoid adenocarcinoma from stomach or lung (CK19+, CK20+, CK7-, HepPar1 negative, no cirrhosis), neuroendocrine tumors from pancreas or small bowel (similar trabecular pattern but smaller cells, inconspicuous nucleoli, stippled chromatin, no cirrhosis), poorly differentiated metastatic adenocarcinoma or cholangiocarcinoma (desmoplastic stroma, mucin+), renal cell carcinoma (RCC+, HepPar1-, biopsy may be from renal mass), melanoma, angiosarcoma, epithelioid angiomyolipoma (spindle cell component, thick walled vessels, HMB45+, actin+, CK-), adenoma or macroregenerative nodule (no trabecular growth pattern, different clinical history, minimal atypia; difficulties usually relate to limited sampling)

References: Mod Path 2003;16:137 (HepPar1), AJSP 2002;26:978 (HepPar1), AJSP 2002;26:25 (prognostic indicators), Hum Path 2002;33:1175 (stains), Mod Path 2002;15:1279 (stains), AJSP 2001;25:1297 (CD10), Archives 1999;123:524 (histologic prognostic factors), Mod Path 2000;13:773 (stains)

 

Cytology

90% sensitive and specific

Cell blocks helpful for obtaining stains (reticulin-no framework)

False positives due to regenerative nodules

False negatives in well differentiated tumors

Note: tumor may track along needle path

Diagnostic features: polygonal cells with central nuclei, malignant cells separated by sinusoidal epithelial cells, bile, increased nuclear to cytoplasmic ratio, trabecular pattern, atypical naked nuclei

Micro: highly cellular, polygonal tumor cells with abundant eosinophilic cytoplasm, central hyperchromatic nuclei or variable prominent nucleoli; increased nuclear to cytoplasmic ratio; often naked tumor cell nuclei; aggregates may appear trabecular (branching sinusoids lined by elongated epithelial cells with adjacent polygonal tumor cells or polygonal tumor cells with adjacent endothelial cells); tumor cells may be arranged in rosettes or acini (pseudoglandular pattern); also tumor giant cells and malignant spindle cells; variable bile, hyaline globules, Mallory’s hyaline and cytoplasmic vacuolation

DD: reactive hepatocytes (finely granular chromatin), focal nodular hyperplasia, hepatic adenoma

References: Archives 2002;126:670 (misinterpreting normal)

 

Clear cell variant of hepatocellular carcinoma

Predominant appearance in 5-16% of cases, but some clear cells present in 20-40% of cases

Tumor cells have prominent clear cytoplasm due to cytoplasmic fat or glycogen

May need to hunt for typical hepatocellular carcinoma to rule out metastatic tumor

May have bland nuclear features

Elevated serum AFP in 92%

Similar prognosis to classic tumor

Laboratory: elevated serum AFP; may have hypoglycemia or hypercholesterolemia

Micro: trabecular, pseudoacinar, solid or mixed patterns of large number of neoplastic hepatocytes with abundant clear cytoplasm (glycogen or lipid) and round nuclei; may have intracytoplasmic bile (5-33%); usually no intratumoral fibrosis except in areas of hemorrhage and necrosis

Positive stains: polyclonal CEA (canalicular pattern, 63%), HepPar1 (82-97%), ISH for albumin mRNA (93%), ubiquitin (for Mallory bodies)

Negative stains: EMA and LeuM1 (positive in clear cell renal cell carcinoma)

DD: metastatic renal, adrenal or ovarian carcinoma

References: AJSP 2000;24:177 (stains), Mod Path 2000;13:874 (stains)

 

Fibrolamellar variant of hepatocellular carcinoma

Young adults 20-40 years, but 30-40% in patients are less than 20 years old, no gender preference

1-5% of all hepatocellular carcinoma

Not associated with hepatitis B virus, cirrhosis or metabolic abnormalities; pathogenesis unknown

Better prognosis than classic HCC; 5 years survival is 60%

Similar symptoms as classic HCC; rarely associated with gynecomastia and Budd-Chiari syndrome

Metastasizes to abdominal lymph nodes, peritoneum, lung

Xray: central scar (similar to focal nodular hyperplasia); often calcified (uncommon with FNH)

Laboratory: serum alpha fetoprotein elevated in only 10% vs. 60% of classic HCC

Treatment: can often resect primary or isolated metastases; liver transplant if non-resectable

Case reports: tumor in 14 year old girl developing 5 years after hepatocellular adenoma (Archives 2004;128:222), central HCC within fibrolamellar HCC of 27 year old woman (Hum Path 2002;33:765)

Gross: single (75%), large (mean 13 cm), hard, scirrhous, well-circumscribed, bulging, white-brown tumor with fibrous bands throughout and central stellate scar; most cases involve left lobe, but may involve both lobes; variable bile staining, hemorrhage and necrosis

Micro: nests or cords of well differentiated oncocytic cells in background of dense, acellular collagen bundles that may contain small, thick-walled vessels; cells are large and polygonal with well defined cell borders, abundant granular and eosinophilic cytoplasm, often pale bodies (ground glass cells) or PAS+ hyaline globules, vesicular nuclei, prominent nucleoli; vascular invasion and necrosis common; radiologic calcification corresponds to necrosis with foreign body type reaction; other possible features include focal nuclear pleomorphism, lack of fibrosis, conventional hepatocellular carcinoma; trabecular and adenoid or pelioid patterns; no/rare necrosis, no/rare mitotic figures; liver unremarkable

Cytology: discohesive cells with inconspicuous strands of collagen; may contain bile

Positive stains: fibrinogen (pale bodies), copper, copper-binding protein, bile, alpha-1-antitrypsin, polyclonal CEA, CAM 5.2 (CK 8/18), CK7

Negative stains: mucin (if present, call combined hepatocellular carcinoma-cholangiocarcinoma), alpha fetoprotein

EM: numerous mitochondria; pale bodies contain fibrinogen and are associated with intracytoplasmic luminal/bile canaliculi or accumulation of rough endoplasmic reticulum; may have dense core neuroendocrine-like granules but are not neuroendocrine

Molecular: often diploid

DD: focal nodular hyperplasia (usually 5 cm or less, fibrous stroma contain bile ductules and inflammatory cells, no bile staining grossly, no hepatocyte atypia), sclerosing variant of hepatocellular carcinoma (no oncocytes, smaller tumor cells, pseudoglandular pattern common), cholangiocarcinoma, adenosquamous carcinoma with sclerosis, metastatic carcinoma with sclerotic stroma, neuroendocrine tumors

 

Clear cell variant of fibrolamellar carcinoma

Case report in 59 year old woman, Archives 2001;125:1235

Clear cells apparently due to ballooning and rarefactive changes of mitochondria