Liver and intrahepatic bile duct - tumor
Last revised 23 August 2010
Copyright (c) 2004-2010, PathologyOutlines.com, Inc.
Bold and underlined topics are hypertext links and may open a new window
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
epithelioid 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,
neuroendocrine carcinoma, reactive lymphoid hyperplasia, rhabdomyosarcoma, squamous cell carcinoma, undifferentiated
sarcoma
Miscellaneous:
staging-HCC, staging-intrahepatic
bile duct tumors, 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
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)
MRI image :
multiple
hypointense lesions
Gross: well circumscribed, solitary masses up to 20 cm,
yellow-gray-white; necrosis present in larger tumors, background liver is
normal
Gross
images : multiple
well circumscribed lesions
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
Micro images: H&E
and stains
Micro
images : low
power, epithelioid
tumor and smooth muscle actin
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
Gross
images: cyst
before and after aspiration
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
Micro
images: H&E,
EM, CA 19-9, CEA, CA 125
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: Case of the Week #70, tumor arising from left hepatic duct (Archives 2001;125:1507), encased in smooth muscle tumor (AJSP 1999;23:854), 39 year old woman with abdominal pain (World J Gastroenterol 2006;12:6062)
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
Gross
images: large,
smooth lined cyst
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
Micro
images: image
#1-low power; #2-low
power; #3-high
power; #4-high
power; #5-high
power; #6-high
power; #7-high
power; #8-CA19-9;
#9-progesterone
receptor
Positive
stains: epithelial cells -
cytokeratin, EMA, CEA, CA19-9; stromal cells - muscle specific
actin, vimentin; usually ER and PR (Dig
Dis Sci 2006;51:623)
DD: borderline tumors (have high grade dysplasia and
complex architecture), invasive tumors (put through numerous sections to
exclude)
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
Micro
images: fibrovascular
cores and invasive disease (in case report above)
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
Cytology
images: Diff-Quick
(2), Pap stain
Also called focal fatty change
Focal fatty change first described in 1980 (Gastroenterology 1980;78:247)
Clinical: rare, often incidental finding at autopsy or with
imaging studies
Simulates lipomatous tumor or malignancy
(Przegl Lek 2006;63:695)
Associated with obesity, diabetes, alcohol abuse,
dyslipidemia
Stable or regresses if underlying condition improves
Unknown cause; may be due to focal tissue hypoxia or
local effects of insulin (Pathol Int 2008;58:59)
Case reports: 42 year old woman with possible hepatic adenomas (Case of Week #141)
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
Differential diagnosis:
●
angiomyolipoma (smooth muscle and vascular components present, positive for
melanocytic markers)
●
coelomic fat ectopia (Arch
Pathol Lab Med 1985;109:783)
●
diffuse steatosis (not a focal mass lesion)
●
focal nodular hyperplasia - nodular, but not a fatty tumor; has hepatocyte nodules surrounded by fibrous septa
with large malformed arterial branches
●
hepatic adenoma - neoplastic hepatocytes
●
lipoma - well circumscribed mass, often encapsulated, no trapped hepatocytes
●
myelolipoma - features of lipoma plus adrenal gland elements
● foci
of hepatocellular carcinoma may have fatty change also (AJR Am J Roentgenol 1988;151:717)
Focal nodular hyperplasia (FNH)
Common
(#2 liver tumor after hemangioma)
Mass lesion of young (median age 38 years); some
studies show female predominance
Represents 2-10% of pediatric
hepatic tumors
May be associated with oral
contraceptives (66-95% of cases), hepatic cavernous hemangioma (20%), glycogen
storage disease type Ia, portal hypertension
Tumors associated with oral
contraceptives often have hemorrhage, necrosis, infarction
Usually an incidental finding;
present in 1% of autopsies
May
have abdominal discomfort, pain, anorexia or fatigue (Hepatobiliary Pancreat Dis Int. 2004;3:199)
May represent hyperplastic
response to arterial malformation or other vascular anomaly; is NOT a neoplasm
(Am
J Gastroenterol 2006;101:2341)
Case reports: Case of the Week
#88
Xray: mass with central scar, centrifugal hypervascularity by angiography; CT and MRI are important, but often cannot make a definite preoperative diagnosis (Hepatobiliary Pancreat Dis Int. 2007;6:52)
Treatment: excellent prognosis; adult women should discontinue oral contraceptives, if applicable; surgery if symptomatic, complications, compression of adjacent organs or lesion progression (Eur J Pediatr Surg 2006;16:235)
Gross: well-demarcated,
subcapsular, 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; hemorrhage, necrosis, infarction, bile
staining often seen; larger tumors may have multiple scars; adjacent liver is
normal
Gross images: well circumscribed mass with central stellate scar #1; #2
Micro:
hepatocyte nodules are surrounded by fibrous septa with large malformed
arterial branches not accompanied by interlobular bile ducts or portal veins;
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
Most
tumors (80%) have the 3 classic features of abnormal architecture, bile
ductular proliferation and malformed vessels. Non-classic forms lack
either abnormal architecture or malformed vessels, and are divided into three
types - (a) telangiectatic, (b) mixed hyperplastic and adenomatous or (c)
atypia of large cell (AJSP
1999;23:1441)
Telangiectatic FNH is considered by some to be a variant of hepatocellular adenoma (World J Gastroenterol 2007;13:2649)
Micro images: fibrous
area with blood vessels and bile ductules #1; #2;
#3; associated
with fibrolamellar carcinoma; diagram
of possible pathogenesis
Positive stains: alpha-1-antitrypsin
Negative stains: p53, CD143 (angiotensin I-converting enzyme: reduced expression, AJSP
2004;28:84)
DD:
Osler-Weber-Rendu disease, Budd-Chiari syndrome or cirrhosis (adjacent liver is
not normal), fibrolamellar hepatocellular carcinoma (marked atypia of
hepatocytes), hepatocellular adenoma (encapsulated, monoclonal), peritumoral
hyperplasia (Archives 2000;124:1105)
References: Radiographics 2004;24:3, eMedicine
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
Xray
images: hypervascular
mass
Micro: small to medium branched vessels with stroma
containing small, round regular cells with sharply outlined round/oval nuclei
Micro
images: small
bland tumor cells in vascular network, smooth
muscle actin and CD34
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
Gross images: well circumscribed
lesion #1, #2
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
Micro images: adenoma #1, #2
in 14 year old (figures a-d), ER
and PR
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
Gross images: dilated
and thickened hepatic artery branches
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)
Micro images: dilated
arteries, vein and sinusoids, three
dimensional reconstruction
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% are age one year or less (rarely adults), 60-70%
male
8% of pediatric liver tumors
Usually asymptomatic
Serum AFP is usually normal or mildly elevated;
occasionally is markedly elevated
Origin either neoplastic or a developmental anomaly
in bile duct plate formation
Rarely associated with undifferentiated sarcoma (Pediatr
Dev Pathol 2001;4:482)
Adult cases are usually women with abdominal pain,
more prominent fibrosis and a lesser myxoid component than childhood cases,
usually no extramedullary hematopoiesis
Case
reports: Case
of the Week #61, with cytogenetic analysis (Archives 2006;130:1216)
Treatment: excision (curative, but surgery has high mortality
for large masses); liver transplantation may be necessary (J
Clin Pathol 2006;59:542)
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 sized, contain mucoid or pink
fluid with adjacent solid, pink-white areas; may have satellite nodules;
usually no necrosis, hemorrhage or calcification
Gross
images: fluid
filled cysts
Micro: branching bile
ducts without atypia in a loose, myxoid stroma with myofibroblast-like cells,
dilated vessels and lymphatics; may resemble breast fibroadenoma at low power;
also normal appearing hepatocytes, thick walled veins, variable collagen; bile
ducts may have mesenchymal collars 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
Micro images: image #1; #2; #3; #4; #5
Positive
stains: CK7, vimentin, smooth muscle
actin, desmin, actin
Negative
stains: CK20
Molecular: interstitial deletion near 19q13.4 (Cancer
Genet Cytogenet 2004;153:60)
Molecular images: figures 3 and 4
EM: myofibroblastic features
DD: bile
duct adenoma (no hepatocyte islands) or cystadenoma (adults), bile duct
hamartoma (usually multiple with fibrous background), infantile
hemangioendothelioma (more vascular), embryonal sarcoma (marked cellularity and
atypical cells)
References: Hum
Path 2002;33:893 (immunostains in adult tumors), Archives 2006;130:1567
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
Micro
images: H&E
and reticulin stain
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
Gross/micro
images: mineralized
nodule composed of cells with homogenized basophilic material
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
Gross/micro
images: H&E
and CD34
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
Micro
images: intact
cell plate architecture
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)
Hepatocellular carcinoma (continued)
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
Gross images: green tumor,
with satellite
nodules #1, #2; involvement
of inferior vena cava and other large vessels
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
Micro images: smaller tumor cells
infiltrate normal hepatocytes, thick cords without
lobules, vascular
invasion, liver
tumor and vascular invasion in lung, acinar
(pseudoalveolar) pattern resembling cholangiocarcinoma, solid
pattern with loss of cell plate architecture (reticulin stain), H&E
and HepPar1, pCEA,
AFP,
H&E
and CD10, adenocarcinoma
staining with MOC31, pCEA and CD10, MOC31
in hepatocellular carcinoma vs. cholangiocarcinoma, pCEA
in hepatocellular carcinoma vs. cholangiocarcinoma, post
radiofrequency ablation #1, #2
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
Micro
images: tumor
cells with clear cytoplasm, with
central focus of typical hepatocellular carcinoma, with
cirrhosis and hemochromatosis, CEA
and Mallory bodies, HepPar1
Renal cell carcinoma - tumor
cells with clear cytoplasm, EMA,
LeuM1, pan-keratin
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
Fewer than 10% of all cases of HCC, but 35% of all cases in patients younger than 50 years
Similar symptoms as classic
HCC; rarely associated with gynecomastia and Budd-Chiari syndrome
Not associated with hepatitis B
virus, cirrhosis or metabolic abnormalities; pathogenesis unknown
5 year survival is 60-75%, better than classic
hepatocellular carcinoma (Cancer
2006;106:1331)
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: aggressive surgery (Am J Gastroenterol 2009;104:2617); early detection of relapse combined with multimodality therapy has been recommended (Eur J Surg Oncol 2009;35:617).
Case reports: 14 year old girl with tumor developing 5 years after hepatocellular
adenoma (Archives 2004;128:222), 18 year old
man (Case of Week #161), 27 year old woman with
central HCC within fibrolamellar HCC (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,
sheets 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 (Adv Anat Pathol 2007;14:217); vascular invasion and necrosis
common; fibrotic tissue coalesces into central scar; remaining liver is
unremarkable; radiologic calcification corresponds to necrosis with foreign
body type reaction; other possible features include focal nuclear pleomorphism,
conventional hepatocellular carcinoma; trabecular, adenoid or pelioid patterns
Micro images: fibrolamellar
carcinoma in 14 year old (figures e-h)
Case of Week #161: #1; #2; #3; pale
bodies; trichrome; CK7; CK20; HepPar; Ki67; pCEA; vimentin
Cytology: discohesive cells with inconspicuous strands of collagen; may contain
bile
Positive stains: HepPar and CK7 (Am J Clin Pathol 2005;124:512); also fibrinogen
(pale bodies), copper, copper-binding protein, bile, alpha-1-antitrypsin,
polyclonal CEA, CAM 5.2 (CK 8/18)
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; overall show fewer
chromosomal abnormalities than classic HCC, and tumors with no cytogenetic
changes appear to behave less aggressively (Mod
Pathol 2009;22:134)
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 (glandular, mucin+), adenosquamous
carcinoma with sclerosis, metastatic carcinoma with sclerotic stroma, paraganglioma
(may have nesting pattern at biopsy,
round nuclei without atypia, vascular stroma but typically no dense fibrosis,
positive for neuroendocrine markers, Am J Surg Pathol
2002;26:945), other neuroendocrine tumors
References: eMedicine
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
Gross images: well
circumscribed tumor
Micro images: classic
fibrolamellar foci and clear cell foci, antimitochondrial
antibody stain
EM images: distended
membrane bound vesicles represent dilated mitochondria
Oncocytic variant of
hepatocellular carcinoma
Oncocytes are present in fibrolamellar variant and
occasionally in classic hepatocellular carcinoma
Rarely these cells predominate without fibrous stroma
of fibrolamellar variant
Cytoplasm is intensely eosinophilic with coarse
granules
Pleomorphic (giant cell)
variant of hepatocellular carcinoma
<1% of all hepatocellular carcinomas, although 15%
have some tumor giant cells
Multinucleated tumor giant cells predominate, marked
loss of cell cohesion
Sarcomatoid variant of hepatocellular
carcinoma
Also called spindle cell, pseudosarcomatous
1-9% of all hepatocellular carcinomas have prominent
sarcomatoid pattern
Mean 62 years old, range 46-84 years, usually men
Metastases common, often to lung and lymph nodes
Most patients die of disease
Micro: diffuse collection of spindle cells resembling
fibrosarcoma or malignant fibrous histiocytoma; classic hepatocellular
carcinoma is also present; may have pleomorphic and osteoclast-like giant cells
Positive
stains: cytokeratin (60%), alpha
fetoprotein; variable HHF-35, smooth muscle actin, desmin, CD68, S100
DD: collision tumors, carcinomas
with foci of spindle shaped epithelial cells
Sclerosing
variant of hepatocellular carcinoma
Also called scirrhous
May not be a distinct histopathologic entity
1-2% of all hepatocellular carcinoma
Associated with hypercalcemia
and hypophosphatemia but not with bone metastases
Gross:
single, large, gray-white, firm, circumscribed mass, often with serrated border;
often satellite nodules; more diffuse fibrosis than fibrolamellar variant, no
radiating fibrous bands, no central scar, usually no cirrhosis
Micro:
fibrous septa separate trabecular cell plates but no lamellar fibrosis; cell
plates 3 or more cells thick; tumor cells may have pseudoglandular (acinar)
features compared to fibrolamellar variant, tumor cells are smaller, lack
vesicular nuclei and prominent nucleoli, have less abundant and granular
cytoplasm; no apparent endothelial sinusoidal cells
Positive stains: AFP
Negative stains: mucin
DD:
cholangiocarcinoma (resemblance when neoplastic cells are arranged as narrow
tubular structures resembling bile ductules), metastatic carcinoma of pancreas
(usually less dense sclerosis), fibrolamellar variant (see gross/micro above
for differences), epithelioid hemangioendothelioma (CD34+, factor VIII+,
mucin-), post-chemoradiation therapy
Small hepatocellular carcinoma
Defined as tumors less than 2 cm
Detected by screening of patients with chronic liver
disease
May have normal serum AFP
Gross: may not be identifiable or nodules that bulge from
cut surface; gray, white, green or yellow; no necrosis; may be within
borderline nodule (nodule within nodule); usually distinct fibrous capsule or
fibrous septa; may have indistinct borders
Micro: usually well differentiated morphology with
trabeculae 2-3 cells thick; nuclear density is 2x normal, has mild but definite
nuclear atypia (hyperchromasia, irregular nuclear borders); enlarging nodules have
less differentiated foci centrally; 40% have fatty or clear cell change, often
with Mallory bodies; may invade stroma or portal tract; vascular invasion rare
Micro
images: associated
with Hepatitis C #1, #2
Leukemia/lymphoma
Gross: usually hepatomegaly, but no discrete nodules except
for SLL/CLL
Acute T cell leukemia/lymphoma
Micro:
pleomorphic lymphocytes
Acute myeloid leukemia
Case report of erythroleukemia (AML-M6) in newborn
with hepatic failure, Archives
2003;127:1362
Micro
images: erythroleukemic
blasts
Positive stains: myeloperoxidase, Leder stain
Chronic lymphoblastic leukemia
Liver involvement common
Micro: periportal
infiltrate of monomorphic small lymphocytes with minimal cytoplasm
Chronic myelogenous leukemia
Liver involvement common
Micro: sinusoidal
infiltrate of various myeloid precursors
Hairy cell leukemia
Associated with pancytopenia
Micro:
clear cytoplasm, round/reniform nuclei, appear as “beads on a string” along
sinusoids; may have angiomatous spaces
Positive stains: TRAP
Large granular lymphocyte leukemia
Associated with leukemia and
neutropenia
Peripheral smear shows large
granular lymphocytes
Micro:
round lymphocytes with abundant pale cytoplasm
Uniform expansion of portal tracts by sheets of
lymphocytes with little piecemeal necrosis or interface hepatitis suggests
lymphoma
Large lymphoid cells suggests lymphoma
Occasional small lymphocytes in portal tracts
probably does NOT represent lymphoma
Granulomatous component often present
Rare; ~ 100 cases reported
Definition: clinical disease due mainly to liver involvement,
without systemic disease or distal lymphadenopathy
75% men, median 55 years but
all ages
Symptoms:
abdominal pain and hepatomegaly
Associated with
immunocompromise or may be incidental finding in cirrhotic liver
Subtype usually diffuse large B
cell lymphoma
Two year survival of 66%; poor
survival if cirrhosis or immunocompromised
Case report in 49 year old
white man, Archives
2001;125:695
Gross:
large mass or multiple masses (30-35%) resembling carcinoma; may contain
hemorrhagic and necrotic areas
Micro:
may have diffuse sinusoidal infiltration
DD:
primary or metastatic carcinoma, primary biliary cirrhosis, granulomas,
inflammatory myofibroblastic tumor, venous outflow obstruction, hepatitis
(polymorphic infiltrates with minimal atypia), EBV or CMV (need serology or
stains to confirm)
Usually disseminated with incidental involvement
found during staging or at autopsy
Rarely hepatosplenic T cell
lymphoma, disseminated disease and incipient hepatic failure
Associated with splenic
involvement
Lymphoma
subtypes
Case report arising post-transplant, AJSP
2003;27:818
Chronic lymphocytic leukemia / small
lymphocytic lymphoma (CLL/SLL)
Micro
images: CLL/SLL
Case report of intravascular lymphomatosis affecting
liver, omentum, bone marrow, Archives
1999;123:952
Gross: bulky tan-white mass
Micro
images: associated
with Hepatitis C
Gross: diffuse pattern of miliary nodules
Hepatosplenic alpha beta T cell
lymphoma
Less common than gamma delta variant
Associated with thrombocytopenia, anemia,
hepatosplenomegaly, B symptoms, but usually no lymphadenopathy
Mean 36 years old, but wide range; female
preponderance
Aggressive clinical course leading to death
Appears to be clinical variant of gamma-delta T cell
lymphoma
Case reports: S100+ lymphoma in 20 year old woman (Archives
2003;127:e119), 12 year old boy
with hepatosplenomegaly, anemia and thrombocytopenia (AJSP
2001;25:970), 20 year old man
with hepatosplenomegaly, mild anemia and thrombocytopenia (AJSP
2000;24:1027), 19 year old boy with jaundice, splenomegaly, anemia,
thrombocytopenia (AJSP
2000;24:459)
Micro: sinusoidal lymphoid infiltrate within liver, splenic
red pulp, bone marrow of small-medium sized atypical lymphoid cells with
scant/moderate cytoplasm, round/oval nuclei, slightly dispersed chromatin, indistinct
nucleoli; marked periportal infiltrates in CD57+ cases
Micro
images: H&E,
CD45RO, S100
Positive
stains: CD2, CD3, CD8 (61%), CD16
(44%), CD45RO, CD57 (40%), TIA1, reticulin, T cell receptor alpha-beta chains
Negative
stains: CD4, CD5
Cytogenetics: isochromosome 7q
References: AJSP
2001;25:285
Hepatosplenic gamma-delta T cell
lymphoma
Rare, < 100 cases reported
Usually young or middle aged men with massive
hepatosplenomegaly and elevated liver function tests, no significant nodal
involvement, pancytopenia, B symptoms (fever, night sweats, weight loss) and
aggressive clinical course (median survival 8 months)
Often occurs after solid organ transplantation, but
reduction in immunosuppression does not affect clinical course
Case
reports: 45 year old man with
leukemic disease 5 years after renal transplant, Hum
Path 2002;33:253
Micro: sinusoidal lymphoid infiltrate of liver, spleen and
bone marrow by medium sized lymphocytes with condensed chromatin and rim of
eosinophilic cytoplasm
Positive
stains: CD2, CD3, CD7, CD16 (50%),
CD43, CD45RO, CD56, TIA1, reticulin, T cell receptor gamma-delta chains
Negative
stains: CD4, CD5, CD8, CD57, T cell
receptor alpha-beta chain, EBV
Molecular: isochromosome 7q (i7q10 in 2/3), trisomy 8, Y-
Gross: either diffuse miliary nodules or bulky, tan-white masses
Micro: atypical mononuclear cells with prominent nucleoli
present in portal tracts, background of polymorphous inflammatory infiltrate;
Reed-Sternberg cells are rare; may see vanishing bile duct syndrome with
ductule proliferation
Positive
stains: CD15, CD30
DD: abscess, inflammatory myofibroblastic tumor,
dendritic cell tumor (CD21+, CD35+)
Also called Waldenstrom’s macroglobulinemia
Case report (with other sites) at AJSP
2003;27:1104
Micro: portal tracts and sinusoids markedly expanded by
small, plasmacytoid lymphocytes
Mucosal associated lymphoid tissue
(MALT) lymphoma
Rare, < 20 cases reported
Usually no underlying liver
disease
Treatment: local excision; tumor is indolent
Case reports: 57 year old woman with primary biliary cirrhosis (Archives
2000;124:604), 69 year old woman as
incidental finding (Archives
1999;123:716)
Gross
images: tan
subcapsular nodule
Micro
images: atypical
lymphocytes entrapping islands of hepatocytes, entrapping
bile ducts, CD20
Nodal CD8+ cytotoxic
peripheral T cell lymphoma
Most peripheral T cell lymphomas are CD4+; CD8+ tumors
are rare
Associated with disseminated intravascular
coagulation and hemophagocytic syndrome
Poor prognosis
Sites: lymph node (all), liver, bone marrow, CNS
Micro: medium sized cleaved-like cells
Micro
images: large
cells and small cleaved cells, CD8,
perforin,
granzyme
B, TIA1
Positive
stains: CD3, CD8, perforin, TIA1,
granzyme B
References:
Mod
Path 2002;15:1131
Splenic marginal zone lymphoma
Liver is often involved, AJSP
2000;24:1581
Micro: diffuse infiltration of portal spaces by
medium-sized, monocytoid B cells and smaller centrocyte-like cells; occasional
sinusoidal infiltration by small lymphocytes
Other
malignancies
Rare
(10-30 annual cases in US), but most common hepatic primary sarcoma in adults
(2% of all primary liver tumors)
75%
men, usually age 50+ years; rare in children
Nonoperative biopsy may cause severe bleeding and death
Causes:
25-42% associated with exposure to vinyl chloride, arsenic, Thorotrast (thorium
dioxide) or androgen steroids; rarely associated with copper sulfate,
estrogenic steroids, phenelzine, radiotherapy, chemotherapy, hereditary
hemochromatosis; cases with known cause usually have latent period of 20-35
years, are accompanied by fibrosis or cirrhosis, have precursor conditions of
hypertrophy and atypia of hepatocytes and sinusoidal lining cells, but are
histologically similar to idiopathic cases
Patients
with exposure to vinyl chloride or Thorotrast may have synchronous
cholangiocarcinoma or hepatocellular carcinoma
Thorotrast’s alpha particle emissions can be detected by
autoradiography
Most patients die within 6 months from hepatic failure,
intraabdominal bleeding; metastasizes widely, often to lung, except for vinyl
chloride cases which usually lack distant metastases
Case
report of 71 year old man with metastatic hepatic epithelioid angiosarcoma, Archives
2001;125:968
Gross:
multicentric, involves right and left lobes; diffusely infiltrative,
hemorrhagic and gray-white solid nodules with blood filled cavities;
Thorotrast-associated tumors have subcapsular hepatic and splenic deposits of
yellow chalky material
Micro: tumor
composed of infiltrative, freely anastomosing vascular channels; tumor cells
grow along sinusoids adjacent to hepatic cords; tumor cells have abundant, pale
eosinophilic cytoplasm, poorly defined cell borders, are usually pleomorphic
with hyperchromatic nuclei, but may be only mildly atypical; also variably
prominent nucleoli, blood filled cavities present are lined by tumor cells that
may be papillary; 75% have vascular invasion of portal or hepatic vein
branches; frequent mitotic activity; also epithelioid cells with abundant
cytoplasm and prominent nucleoli, bizarre tumor giant cells, fibrosarcoma-like
spindle cells, cholestatic hepatocellular rosettes with bile plugs, tumor cell
phagocytic activity, extramedullary hematopoiesis; childhood cases may have
kaposiform areas of spindle cells with PAS+ intracytoplasmic globules; no
prominent myxoid areas
Thorotrast exposed patients
have brown-gray refractile but not birefringent granules of Thorotrast free or
within macrophages; also precursor stage with endothelial hypertrophy and
hyperplasia
Micro images: FNA
and H&E, FNA,
AE1/AE3, pleomorphic epithelial cells in sinusoidal pattern, CD31
Positive stains: CD34, CD31, factor VIII related antigen, Ulex europaeus lectin type 1
(may not be present in poorly vasoformative areas)
Negative stains: keratin (but positive in 12-35%)
EM: Weibel-Palade
bodies
Molecular: 50% of vinyl chloride associated cases have A:T to T:A transversion in
p53
DD: reactive disorders (lack atypical endothelial lining
cells), hepatocellular carcinoma (atypical hepatocytes, normal endothelial
cells), Kaposi’s sarcoma (HIV+, have extrahepatic nodules, portal distribution,
lack angiosarcomatous foci), peliosis hepatis, epithelioid hemangioendothelioma
(less atypia, less mitotic activity, less necrosis)
<100 cases reported
Usually ages 50+ years; equal gender frequency
Usually mucinous, often associated with cystadenoma
Tumors more indolent in women with ovarian-like
stroma, more aggressive in men
May be associated with intraductal oncocytic
papillary neoplasm
May have intraabdominal dissemination as terminal
event
Cysts represent dilated intrahepatic bile ducts
invaded by tumor cells with a colloid carcinoma like pattern, like IPMN of
pancreas
Case
reports: 43 year old woman with
tumor exhibiting oncocytic differentiation (Archives
2004;128:e25), 71 year old man
with multiple tumors resembling oncocytes (Mod
Path 2001;14:1304)
Survival: 50% at 4 years, better prognosis if spindle-cell
stroma
MRI images
: multiple
cysts and solid lesion
Gross: 5-20 cm cysts, may have blood tinged fluid, solid
areas, large papillary masses
Gross
images : multiple
cysts and solid lesion
Micro: papillary or tubulopapillary neoplasm of malignant
cells lining fibrovascular cores that project into cystic cavities; epithelium
is columnar or cuboidal with stratification, loss of polarity, nuclear
pleomorphism, prominent nucleoli and mitotic activity; women may have
ovarian-like stroma; extensive stromal and hepatic parenchymal invasion; woman
also have features of cystadenoma; rarely adenosquamous, hepatoid,
oncocyte-like features; malignant diagnosis is based on stromal invasion
Micro
images: oncocytic
tumor, papillary
oncocytic tumor within fibrous cyst wall
Positive
stains: CK7, AE1/AE3, HepPar1,
variable CEA and C19-9
Negative
stains: CK20, mucin, AFP,
calretinin, CD31, chromogranin
EM: numerous mitochondria
DD: metastases from pancreas, ovary, appendix
Usually represents metastasis from GI tumor (small
intestinal tumors may be very small)
Rarely associated with
Zollinger-Ellison syndrome, VIP production
Indolent low-grade clinical
course with prolonged survival, but recurs or metastasizes more frequently than
appendiceal carcinoids
Treatment: surgical resection
Micro:
nested, trabecular or microacinar architecture; composed of small, uniform
tumor cells with granular chromatin and round nuclei
Gross/micro images: A/B:
liver metastases from lung primary
References: Archives
2003;127:1200 (childhood tumors)
Case report in 84 year old man of adenocarcinoma and
chondrosarcoma, Archives
2000;124:888
Gross
images: gray
white tumor with necrosis
Micro
images: tubular
structures and chondrosarcoma
Also called angiofollicular hyperplasia
Micro: stellate fibrous scar separating small nodules of
disorganized large and clear hepatocytes; scar contains hyperplastic follicles
with germinal centers, separated by sheets of plasma cells and vessels; small
lymphocytes arranged in onion-skin pattern around follicles
Cholangiocarcinoma
(intrahepatic)
Also called bile duct carcinoma
10% of primary liver cancers
Adenocarcinoma arising from
intrahepatic bile duct epithelial cells
High prevalence in southeast
and eastern Asia, including Korea
10-20% are associated with chronic bile stasis or cholangitis due to autosomal dominant polycystic
disease, congenitally dilated hepatic ducts (Caroli’s disease), congenital
hepatic fibrosis, infection by liver flukes Clonorchis sinensis or Opisthorchis
viverrini, Thorotrast, anabolic steroids, intrahepatic lithiasis (5-10% of
these patients), primary sclerosing cholangitis (7-42% of these patients) or
choledochal cysts
Rarely associated with neoplastic transformation of von Meyenburg complexes, AJSP
2000;24:1131
Not associated with cirrhosis
Diagnosis of exclusion (must
rule out metastatic adenocarcinoma)
Usually age 60+ years; no
gender preference; but mean age 40 years in those with primary sclerosing
cholangitis or chronic inflammatory bowel disease
Klatskin tumor [American internist]: hilar tumor arising at confluence of left and
right hepatic ducts
Laboratory: normal AFP, occasional hypercalcemia
Poor prognosis; death usually
within 6 months; 5 year survival in resectable cases is 30%
50-75% metastasize to regional
lymph nodes, lungs, vertebrae, adrenals, brain, elsewhere at autopsy
50% are metastatic to
perihilar, peripancreatic and para-aortic nodes
Poor prognostic factors: lymphatic
or intrahepatic metastases, AJSP
1999;23:892
Reduced keratin 903 expression
may be a favorable prognostic factor, Mod
Path 2002;15:1181
Case reports: 61 year old woman with history of Caroli’s disease (Archives
2002;126:717), 55 year old with
synchronous small cholangiocarcinoma and small hepatocellular carcinoma arising
in 2 different dysplastic nodules in an explant cirrhotic liver (Mod
Path 2002;15:1096)
Gross: solitary,
7-10 cm, multinodular or diffuse small nodules < 1 cm; gray-white and firm;
often hepatomegaly and satellite nodules; no peripheral hyperemic zone seen in
metastatic disease; rarely cirrhosis; rarely bile stained, although may see
bile in periphery; may invade portal vein
Gross images: subcapsular
tumor
Micro: moderate
to well differentiated adenocarcinoma with glandular and tubular structures,
mucin production and dense desmoplasia; epithelial cells are anaplastic,
cuboidal to columnar with eosinophilic cytoplasm and round central nuclei,
tumor cells are heterogeneous even within the same gland but resemble bile duct
cells, not hepatocytes; spread along hepatic plates, duct walls, via nerves
(81% perineural), but not sinusoidal; stroma may be circumferential around
glands; associated with neutrophils; variable vascular invasion; no bile
production
Patterns: signet ring, adenosquamous,
osteoclast giant cell, sarcomatous, colloid, mucoepidermoid, rhabdoid, clear
cell, lymphoepithelioma-like
Cytology:
abundant, finely granular cytoplasm
Micro images: cholangiocarcinoma
#1, #2
arising in Caroli’s disease, #3
associated with multiple von Meyenburg complexes; pseudoalveolar
hepatocellular carcinoma vs. cholangiocarcinoma, CK7,
keratin 903, HepPar1, Alcian blue, MOC31
in hepatocellular carcinoma vs. cholangiocarcinoma, pCEA
in hepatocellular carcinoma vs. cholangiocarcinoma
Positive stains: mucin (almost always), CEA (cytoplasmic and luminal, not canalicular),
CAM 5.2, AE1-AE3, keratin 903 (74%), CK7 (90-96%), CK19 (84%), CK20 (30-70%,
more often positive in non-peripheral tumors), EMA, amylase, PTH-related
peptide, p53 (10-94%), PCNA, MOC31, BerEP4
Negative stains: AFP
Molecular: Kras mutations
DD:
metastatic adenocarcinoma from pancreas, extrahepatic biliary tree, breast,
colon (CK7-/CK20+ [strong]) or gallbladder (must exclude based on clinical and
radiographic findings); hepatocellular carcinoma with ductular differentiation,
epithelioid hemangioendothelioma (vascular markers+, mucin-), benign bile duct
proliferations (smaller, no atypia, incidental)
References: AJSP
2000;24:870 (CK stains)
Intraductal cholangiocarcinoma
Gross: pink-white papillary excrescences within dilated
ducts
Micro:
papillary and flattened epithelium; noninvasive by definition, although may
have capacity to invade through duct wall; resemble villous adenomas with
fibrovascular cores lined by columnar, mucinous epithelium and flat epithelium;
“carcinoma” implies high grade dysplastic features
DD:
intraductal lesions without high grade dysplasia - intraductal adenoma, biliary
papillomatosis, adenomatosis, borderline tumor
Lymphoepithelioma-like cholangiocarcinoma
Rare,
<10 cases reported
Men
and women ages 41-67 years
EBV
related
May
have better prognosis than ordinary cholangiocarcinoma
Gross:
3-12 cm, yellow-white, firm; may have tumor satellites; no cirrhosis
Micro: syncytial
pattern of undifferentiated epithelial cells and glands in lymphocyte-plasma
cell rich stroma (note: presence of glands differentiates this from
lymphoepithelioma-like carcinoma); may have granulomatous reaction
Micro images : neoplastic
glands with dense lymphoplasmacytic infiltrates, focal
granulomatous reaction, CK19,
EBER
Positive stains: CK7, CK19, AE1-AE3, EBER-1 (in situ hybridization)
Negative stains: CK20, CEA
DD:
metastatic lymphoepithelioma-like carcinoma from other sites
References:
AJSP
2001;25:516, Mod
Path 2001;14:527
Congenital primitive epithelial tumor
Case report with focal rhabdoid features, Hum
Path 2000;31:259
Epithelial myoepithelial carcinoma
Case report in 67 year old man; incidental finding;
unclear if primary or metastases from oral lesion 50 years prior, AJSP
1999;23:349
Epithelioid hemangioendothelioma
Malignant endothelium derived neoplasm with intermediate
clinical course between hemangioma and angiosarcoma, but unpredictable
Mean age 47 years, but occurs at any age, 60% women
No predisposing factors
FNA not recommended as even small biopsies can be
misleading
50% have extrahepatic involvement at diagnosis, which
does not preclude long survival
Often misdiagnosed
Symptoms: abdominal pain, weight loss, hepatic venous outflow
obstruction; 40% are asymptomatic
Xray: calcifications in 20%; peripheral nodules with
capsular retraction by CT scan
Prognostic
factors: high cellularity is
unfavorable, but histology is otherwise of no value
Indolent and slow growing; 5 year survival 43%;
metastases to lung, spleen, abdominal lymph nodes, omentum, peritoneum
Case
reports: 83 year old man with
incidental tumor (Archives
2002;126:225), presence of t(1;3)(p36.3;q25) (AJSP
2001;25:684), with multiple
focal nodular hyperplasias (Archives
1999;123:846)
Treatment: resection, liver transplantation
Gross: multiple (80%), tan-gray, firm, circumscribed,
focally confluent nodules 1-12 cm with infiltrative borders that may involve
venous structures as intravascular proliferations or fibrothrombotic
occlusions; remaining liver is normal
Gross
images: mottled
tumor with cavernous hemangioma
Micro: zonal pattern; periphery shows sinusoidal
proliferation with tufting of tumor cells within portal vein branches; midzone has sinusoidal obliteration with
atrophic hepatocyte plates and increased myxochondroid and sclerotic stroma;
perivenular stroma is paucicellular and often calcified; variable inflammatory
infiltrate; epithelioid and fibromyxoid tumor cells have focal intracytoplasmic
vacuoles containing red blood cells embedded in fibromyxoid matrix; epithelioid
cells are rounded with eosinophilic cytoplasm, mild to moderately atypical
nuclei with prominent nucleoli, rare/no mitotic figures; extramedullary
hematopoiesis; may have myxoid areas; often has infiltrative margins; adjacent
liver usually normal
Micro
images: microvascular
channels and intracytoplasmic vacuoles, intracytoplasmic
vacuoles and projection into vein
Micro
images : epithelioid
and spindle cells in fibromyxoid stroma
Positive
stains: factor VIII related antigen
and CD34 for vacuoles, CD31, trichrome and elastic stains accentuate
obliteration of hepatic venules and hepatic vein branches, NSE, smooth muscle
actin (25%), 15% positive for cytokeratin (also trapped hepatocytes and bile
ductules)
Negative
stains: AE1/AE3 (cytokeratin), CK7,
CK20, alpha fetoprotein, bile, CEA, HepPar1, mucin
EM: Weibel-Palade bodies, intermediate filaments
Cytogenetics: t(1;3)(p36.3;q25), ? involving PAX7 gene at 1p36.3
and MLF1 gene at 3q25
DD: signet ring adenocarcinoma, scirrhous cholangiocarcinoma,
sclerotic hepatocellular carcinoma, sclerosed hemangioma (well circumscribed,
no venous invasion, no atypia), leiomyosarcoma, chondrosarcoma, metastatic
tumor from lung or elsewhere, angiosarcoma (different stroma, more atypia)
Very rare
(<100 cases described), xanthogranulomatous systemic histiocytosis
Unknown
etiology and pathogenesis
Usually adults, ages 30-70
years
Usually symmetric
osteosclerosis of long bones and axial skeleton involvement
50% have extraskeletal
lesions of retroperitoneum, lung, kidney, brain, heart, retro-orbital space
Case report in 32 year old
Hispanic man of liver involvement, Archives
2003;127:e337
Death in 60% of cases due to respiratory and heart
failure
Treatment: oral steroids, chemotherapy or radiotherapy in
severe cases
Micro: diffuse infiltration of large, foamy histiocytes,
lymphocytic aggregates, fibrosis; rare Touton-like giant cells
Micro images: CT
scan, H&E, CD68, EM
Positive stains: CD68
Negative stains: CD1a, S100
EM: no Birbeck granules
<50 cases reported
Usually solitary masses in men age 40+ years
20% associated with cirrhosis, 20% associated with
hypoglycemia
May appear post-transplant
Follicular dendritic cell tumors
<10 cases reported in liver; < 100 cases
reported at all sites, usually in lymph nodes
Usually women, mean age 40 years, range 19-61 years
Often weight loss and fever
Indolent behavior; may recur without causing death
Gross: solitary, fleshy, often > 10 cm with focal
hemorrhage and necrosis
Gross
images : well
circumscribed tumor with hemorrhage and necrosis
Micro: well demarcated from surrounding liver; syncytial
growth of spindle or ovoid tumor cells in background of lymphocytes and plasma
cells; tumor cells have vesicular nuclei, distinct nucleoli, variable nuclear
atypia with some cells resembling Reed-Sternberg cells; focal spindle cell
fascicles; occasional vessels with fibrinoid deposits
Micro
images : spindle
cells, plasma cells and lymphocytes, fascicles
and whorls of spindle cells, CD21,
EBER
in situ hybridization
Positive
stains: CD21/CD35 (best), CD23,
CNA.42, EBV-LMP1 (focal/weak), EBV (in situ hybridization)
Negative
stains: ALK1, CD30
DD: inflammatory pseudotumor
References:
AJSP
2001;25:721 (inflammatory pseudotumor variant), Mod
Path 2001;14:354
Gastrointestinal stromal tumor (GIST)
Malignant tumors often metastasize to liver
Case report of malignant primary liver GIST in 79
year old woman, Archives
2003;127:1606
Gross: firm, homogenous, tan-brown with necrosis; may have
satellite nodules
Gross
images: large
tumor with necrotic center
Micro: spindle cells arranged in short fascicles; variable
mitotic figures
Micro
images: H&E,
CD117
Positive
stains: CD117, vimentin, variable
CD34
Negative
stains: keratin, CD31, desmin,
smooth muscle actin, S100
Teratomas
Uncommon, usually females < 1 year old
Gross: large, cystic, calcified tumors
Micro: derivatives of all 3 cell layers; cyst lined by
ectoderm with skin appendages or endoderm
DD: hepatoblastoma
Most common primary liver tumor in children (50% of
liver malignancies in children)
90% occur by age 5 years, 70% by age 2 years; 2/3
male, prevalence of 1 per 120,000 (1 per million children under age 15 years)
Associated with hemihypertrophy
(Beckwith-Wiedemann syndrome), Wilm’s tumor, glycogen storage disease, familial
colonic polyposis (APC gene, 500x risk); not associated with cirrhosis
Symptoms:
variable virilization due to hCG production by multinucleated giant cells
Laboratory: elevated serum AFP in 75%
Note:
diagnosis difficult on needle biopsy; must sample generously
Metastases to regional lymph
nodes, lung, brain, adrenal glands, bone marrow
Associated with adenomatoid
transformation of Bowman’s capsular epithelium in kidney
Treatment: preoperative chemotherapy and surgery; resect lung metastases; liver
transplant if unresectable
Long term survival now 60-70%,
with most recurrences detected within 3 years
Prognostic factors: stage, age, sex; histologic pattern not prognostic except that small
cell/undifferentiated and macrotrabecular patterns have worse prognosis;
increase mitotic activity may confer poorer prognosis; presence of osteoid may
confer favorable prognosis
Gross: tan-green,
70% solitary, well circumscribed, variable hemorrhage and cysts; mean 10 cm
(range 3-20 cm), often partially
encapsulated; may be calcified
in prominent mesenchymal component
Micro: epithelial
and mesenchymal elements in varying proportions and at variable stages of
differentiation; pseudocapsule, canaliculi with bile formation, cords 2-3 cells
thick with alternating light and dark pattern due to glycogen and fat; cells
smaller than normal hepatocytes; extramedullary hematopoiesis common in fetal
and embryonal subtypes; usually no pleomorphism, no intranuclear inclusions, no
hyaline globules, rare/no tumor giant cells, no mitotic figures, no associated
cirrhosis; rare rhabdoid cells
Epithelial type (56%)
Fetal pattern (31%): tumor cells in trabeculae 2-3
cells thick (resembling fetal liver), separated by sinusoids lined by CD34+
endothelial cells; tumor cells are same size or smaller than in non-neoplastic
liver; distinct cell membranes, uniform, polyhedral, slightly higher
nuclear/cytoplasmic ratio, inconspicuous nucleoli, may contain bile; minimal
pleomorphism, no/rare mitotic figures; have “dark” and “light” foci related to
amount of glycogen and fat; extramedullary hematopoiesis common; no portal
tracts, bile ducts or ductules; reduced reticulin
Embryonal pattern (19%): sheets, ribbons, rosettes, papillary patterns or
trabeculae of variable thickness with immature appearance, discohesive small
cells with poorly defined cell borders, basophilic cytoplasm, high N/C ratio,
prominent nucleoli, coarse chromatin, increased mitotic figures; extramedullary
hematopoiesis, necrosis and vascular lakes are common; no fat, glycogen or bile
Macrotrabecular pattern (3%): frequent trabeculae > 10 cells thick throughout the
tumor, variable cytologic features
Small cell undifferentiated pattern (3%): discohesive sheets of small
uniform cells with minimal cytoplasm, indistinct cell borders, oval
hyperchromatic nuclei, variable prominent nucleoli and increased mitotic
figures; resembles small cell carcinoma at other sites; may have mucoid stroma,
hyalinized septae; tumor cells are keratin+, bile-
Mixed epithelial mesenchymal
type (44%):
mixture of fetal/epithelial and mesenchymal cell types; teratoid (34%) or not
(10%); mesenchymal component has spindle-oval cells with minimal cytoplasm,
frequent osteoid, fibrous septa, myxoid zones, hemorrhage and necrosis; teratoid
features are keratinized squamous epithelium, intestinal epithelial, skeletal
muscle, mature bone and cartilage, melanin and neuroectodermal structures
Micro images: small
cell pattern: H&E and stains
Positive stains: alpha fetoprotein, CK 8/18 (fetal, epithelial subtypes), CK 19
(embryonal subtypes), chromogranin (fetal, epithelial subtypes, usually focal),
EMA, polyclonal CEA (canalicular pattern), vimentin, hCG (variable), HepPar1,
occasional HMB45 and melanin
Negative stains: CD45/LCA, desmin, neurofilament
Molecular: gain of Xq in 60%, gain of Xp in 43%, also trisomy 2q (2q+), trisomy 20, 1p-,
2q-, 4q-, 4q+; fetal type usually diploid, embryonal often aneuploid, Hum
Path 2003;34:864
EM:
immature hepatocytes
DD: metastatic
tumors (more common than hepatoblastoma, but primary should be present and
tumor cells don’t resemble hepatocytes), including metastatic Wilms’ tumor,
sarcoma, yolk sac tumor (rare yolk sac cells may be present in hepatoblastoma),
teratoma, neuroblastoma, lymphoma and rhabdomyosarcoma; hepatocellular
carcinoma (resembles macrotrabecular variant of hepatoblastoma, children > 5
years old, larger more pleomorphic tumor cells, no extramedullary
hematopoiesis)
References: Mod
Path 2003;16:930
Staging of hepatoblastoma according to Children’s Cancer Study Group
Stage I - completely resected
Stage II - microscopic residual
disease only
Stage III - gross residual
disease or positive lymph nodes or spilled tumor
Stage IV - metastases
Note:
can also stage using TNM
staging below
Infantile hemangioendothelioma
Also called hepatic infantile hemangioma
Most common hepatic mesenchymal tumor in childhood
20% of all pediatric hepatic tumors
90% are less than 6 months old at diagnosis, slight
female predominance
10-40% have coexisting cutaneous cavernous
hemangiomas
50% are incidental findings at autopsy
Symptoms: hepatic mass (48%), high output cardiac failure due
to shunting through tumor (15%); also Kasabach-Merritt syndrome (bleeding
diathesis due to platelet sequestration and severe thrombocytopenia); may be
asymptomatic
Laboratory: normal AFP
70% survival, as tumors often involve and almost
always have benign behavior; tumors often involute after 6-8 months; deaths
usually within 1 month of diagnosis due to congestive heart failure, platelet
consumption leading to bleeding diathesis or massive hemoperitoneum
Xray: multiple small nodules
Poor
prognostic factors: congestive heart
failure, jaundice, multiple nodules, lack of cavernous differentiation
Treatment: resection if solitary, otherwise steroids, radiation
therapy, embolization, transplantation
Case report in 56 year old woman, Archives
2001;125:931
Gross: solitary or multiple, mean 4 cm (range 0.1 to 15
cm), circumscribed but not encapsulated; white-red-tan, soft, spongy; larger
nodules may have hemorrhagic or calcified areas
Micro: well demarcated or infiltrative (35%)
Pure type 1 change: 80%, orderly proliferation of small, capillary-like
vascular spaces, relatively bloodless, may be dilated (particularly centrally),
slightly irregular; lined by bland or plump endothelial cells that may occlude
the lumen; vascular channels separated by variable connective tissue; may have interspersed
small bile ducts; extramedullary hematopoiesis in 60%, often in vascular
lumina; often trapped hepatocytes at periphery; large lesions show thrombosis,
fibrosis, myxoid change, calcification; no/rare mitotic figures, no malignant
spindle cell component
Type 2 change: equivalent to angiosarcoma with irregular branching vascular structures
lined by pleomorphic, hyperchromatic endothelial cells, frequent mitotic
activity
Micro
images: bland
cells with small/medium nuclei and nucleoli, Factor VIII related antigen
Positive
stains: factor VIII related antigen,
CD31, CD34, GLUT1 (Hum
Path 2004;35:200)
DD: angiosarcoma (adequate sampling is important; has
solid sarcomatous areas, vascular and sinusoidal permeation, marked pleomorphism),
mesenchymal hamartoma (vessels lack irregular thin walls, primitive mesenchymal
stroma present), hepatic vascular malformation, hemangioma (lacks peripheral
small vascular proliferation)
Histiocytic disorder, usually through age 19 years
Usually solitary cutaneous lesion, but rarely involves
liver and may cause hepatic failure
Micro: spindle cells mixed with mononuclear cells or
forming short fascicles; diffuse giant cell transformation; may have Touton
giant cells
Positive
stains: vimentin, CD68, factor XIIIa
Negative
stains: S100, CD1a
References: AJSP
2003;27:579
Almost always associated with HIV infection
Present in liver in 12-25% of fatal cases of KS
elsewhere in body
Gross: hemorrhagic, multifocal spongy nodules, 5-7 cm
Micro: spindle cells with hyaline globules and vasoformative
channels with extravasated red blood cells; lesions centered on portal tracts
Positive
stains: CD31, CD34
DD: bacillary peliosis hepatis
Formerly called histiocytosis X
Causes 15% of sclerosing cholangitis in children,
usually affects intrahepatic bile ducts
May affect liver only; also lymph nodes and skin
Micro: Langerhans cells may surround bile ducts and infiltrate
sinusoids in nodules or diffusely; associated with cirrhosis, sclerosing
cholangitis, eosinophils, lymphocytes, plasma cells and neutrophils
Positive
stains: S100, CD1a
References: Mod
Path 1999;12:370
Tumors either primary in liver or arise in ligamentum
teres or inferior vena cava
Also associated with HIV, post-transplantation in
children, Budd-Chiari syndrome
Usually causes death within 2 years
Case
reports: EBV associated leiomyosarcoma
post-cardiac transplant in 26 year old man (AJSP
2000;24:614), multifocal
leiomyosarcoma involving liver, thyroid and lung in a child with congenital
immunodeficiency disease (AJSP
1999;23:473)
DD: epithelioid hemangioendothelioma
Rare, < 10 cases reported
Develop in non-cirrhotic liver
Contraindication for liver transplantation
Case report of myxoid liposarcoma in 54 year old
African American woman, Archives
2001;125:410
Gross: large tumor with yellow-tan, fleshy mass, focal
hemorrhage and necrosis, satellite tumor nodules; noncirrhotic remaining liver
Micro: myxoid - myxoid stroma with
plexiform vessels; numerous lipoblasts with granular cytoplasm, nuclei indented
by fat vacuoles; some spindled cells, some anaplastic cells
Micro
images: myxoid
liposarcoma and lipoblasts
Positive
stains: vimentin, alpha smooth
muscle actin (focal)
Negative
stains: S100, keratin, HMB45, CD34
EM images: intracellular
lipid indents nucleus
Lymphoepithelioma-like carcinoma
Rare
Better prognosis than
hepatocellular carcinoma
Usually but not always
EBV+
Case reports: 61 year old, EBV- man
(AJSP 2001;25:1464), 64 year old Korean man with cirrhosis, EBV- (Archives 1999;123:441)
Micro: cords and trabeculae of large polygonal
epithelial cells with marked lymphocytic infiltrate; blurred border at tumor
margin; otherwise normal liver
Positive stains: keratin (CK19), EMA
Negative stains: vimentin, AFP, CEA,
CK20, HMB45, CD30
Malignant fibrous histiocytoma
< 20 cases reported
Usually causes death within 1
year
DD:
sarcomatoid hepatocellular carcinoma (cirrhosis present), cholangiocarcinoma
Micro: large cells with multilobed nuclei, abundant
eosinophilic cytoplasm, erythrophagocytosis
Positive
stains: CD68, MAC387
40-60% of cases have hepatic involvement
Associated with obliterative portal venopathy,
venoocclusive disease, nodular regenerative hyperplasia, cirrhosis
Micro: round or spindled, degranulated mast cells in portal
tracts and sinusoids; may be subtle; usually also portal fibrosis, 50% have
extramedullary hematopoiesis
Positive
stains: tryptase, Leder stain
In U.S. in non-cirrhotic liver, 98% of hepatic
malignancies are due to metastases vs. only 23% in cirrhotic liver
Direct extension is common from tumors of
gallbladder, extrahepatic bile ducts, pancreas, stomach
Primaries in adults often from breast, lung, colon and pancreas; in children
from neuroblastoma, Wilm’s tumor, rhabdomyosarcoma
Unknown primary with hepatic
metastasis is often from pancreas, stomach, lung
Metastatic nodules tend to
outgrow their blood supply and produce central necrosis and umbilication
Symptoms often of abdominal
pain, ascites and jaundice; portal hypertension less common
Survival usually less than 1
year, longer if metastatic neuroendocrine carcinomas, neuroblastoma, some cases
with metastatic colon carcinoma and resection of hepatic metastases
Should compare metastatic tumor
to prior malignancies
Case reports: female adnexal tumor of probable wolffian origin (Archives
2000;124:431)
Gross:
90% are multiple, variable size, may replace entire liver, locally elevate the
capsule or not be visible on external surface; often hemorrhage and necrosis;
extensive hemorrhage suggests choriocarcinoma, angiosarcoma or thyroid
carcinoma; cannot determine malignancy based on gross appearance only
Gross images: multiple metastases
Micro:
sinusoidal dilation, cholestasis, portal lymphocytic infiltrate, tumor
Metastatic carcinomatous cirrhosis
Metastatic carcinoma to liver,
often from breast, that incites an extensive fibrotic reaction simulating
cirrhosis
Case report in 38 year old
woman with infiltrating ductal carcinoma of breast, Archives
2001;125:1084
Xray
images: metastatic
carcinoma, marked
hepatic contour irregularity consistent with macronodular cirrhosis
Gross images: macronodular
cirrhosis
Breast carcinoma metastatic to liver
Post-treatment metastases produce coarsely lobulated
appearance known as hepar lobatum, associated with syphilis
Estrogen receptor 35% sensitive and highly specific;
progesterone receptor neither sensitive nor specific, Archives
2003;127:1591
Micro images: metastatic
breast carcinoma #1, #2, H&E,
ER, PR
Carcinoid tumor metastatic to liver
Chronic lymphocytic leukemia / small lymphocytic lymphoma
Colon carcinoma metastatic to liver
Resection of metastases may improve long term
survival
Case
report: Motilin positive rectal
polyp with bone and liver metastases, AJSP
1999;23:838
Gross:
large umbilicated nodules with extensive necrosis and fibrosis, variable
calcification
Gross images: colonic
adenocarcinoma metastases #1, #2
Micro: tubular, papillary or cribriform patterns of columnar
cells with basophilic cytoplasm and elongated nuclei, extensive necrosis
Hepatoid adenocarcinoma metastatic to liver
Positive stains: AFP, CK8, CK19, CK20
Negative stains: CK7, HepPar1
References: AJSP
2003;27:1302
Melanoma metastatic to liver
Micro: may replace hepatic cords and
grow in trabecular pattern with endothelial lining
Pancreaticobiliary metastases to liver
Micro: atypical angulated glands with desmoplasia
Squamous cell carcinoma metastatic to liver
Case report with primary tumor in large intestine, Archives
2001;125:1251
Gross: soft nodules due to necrosis and keratinization
Micro
images: FNA,
H&E, synaptophysin
Mixed
hepatocellular carcinoma-cholangiocarcinoma
Less than 5% of primary hepatic carcinomas
May be hepatocellular carcinomas with focal ductal
differentiation
Micro: intimate admixture of tumor cells with features of
unequivocal hepatocellular carcinoma and cholangiocarcinoma (cuboidal/columnar
cells with amphophilic cytoplasm, inconspicuous nucleoli, gland formation,
mucin); may have sarcomatoid component or cirrhosis
Transitional
subtype
Defined as having primarily features intermediate
between hepatocellular carcinoma and cholangiocarcinoma
Aggressive, with 5 year survival of 18% overall, 24%
after resection (worse than pure hepatocellular carcinoma at the institution
studied)
Laboratory: serum alpha-fetoprotein usually normal, usually
negative for Hepatitis B and C serum markers
Gross: 3-16 cm, solitary or multiple tumor nodules; pale-tan
to bile stained, variably fibrotic, hemorrhagic or necrotic
Micro: usually no distinct hepatocellular or
cholangiocarcinoma-like areas; transitional areas have glands, sheets or nests
of hepatoid cells; usually no cirrhosis; areas with “antler-like” morphology in
33% (irregular thin branching columns of hepatoid cells separated by broad
desmoplastic stromal bands), rarely papillary
Positive
stains: albumin mRNA by ISH (96%),
cytokeratin, EMA, mucicarmine in glandular areas
DD: collision tumor (if tumors are separate),
undifferentiated carcinoma (features suggestive but not diagnostic of both
tumor types, may represent metastatic disease), hepatocellular carcinoma with
pseudoglandular spaces but not true glands
References: AJSP
2002;26:989
Micro: resembles poorly differentiated
carcinomas with cellular pleomorphism, nuclear atypia, hyperchromasia, frequent
mitotic figures
Gross/micro images: C/D:
H&E and chromogranin
Positive stains: chromogranin, synaptophysin
EM: dense core granules
References: Archives
2003;127:1200 (childhood tumors)
Rare, usually incidental finding
No associated systemic manifestations
May be immune mediated
Resection is curative
Case report of 69 year old white woman with stage I
renal cell carcinoma and hepatic mass, Archives
2001;125:577
Gross: well circumscribed, tan, nonencapsulated, solitary
rubbery nodule
Micro: prominent lymphoid follicles with germinal centers,
tingible-body macrophages and polymorphic small lymphocytes
Positive
stains: CD20
Negative
stains: bcl2; no light chain
restriction
DD: autoimmune hepatitis, primary biliary cirrhosis,
chronic hepatitis B or C infection, Castleman’s disease
References: AJSP
1999;23:302