Liver and intrahepatic bile duct - tumor
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Table of contents
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
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
University of Pittsburgh liver textbook, liver transplant page
USCAP short course: Mod Path 2000;13:679
Journal search terms: liver, hepatic
Please refer to these primary references for more detailed discussions
Benign tumors
<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)
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
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
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)
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
Micro: lined by cuboidal or biliary type epithelium; rarely squamous lined; thin fibrous wall
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
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
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
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
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)
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)
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
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)
Solitary nodule that may resemble metastatic well differentiated leiomyosarcoma
May be associated with HIV, EBV
Rare, usually incidental finding
Gross: solitary, 1-20 cm
Micro: mature fat or brown fat (hibernoma)
DD: angiomyolipoma, focal fatty change
Very rare
May actually represent 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)
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
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
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
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)
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
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
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)
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)
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