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Liver and intrahepatic bile ducts - Tumor

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Revised: 8 January 2013
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

Benign tumors

Angiomyolipoma (AML)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Mesenchymal tumor arising from perivascular epithelioid cells (PEC)
● Smooth muscle HMB45+ is defining and consistent feature; similar histologically to renal angiomyolipoma but no proven association
● Myoid and vascular components are clonal; adipose tissue component may be reactive
● Other lesions derived from PEC (PEComas) include lymphangioleiomyoma, clear cell (sugar) tumor of lung and rare myomelanocytic tumors
● Approximately 200 cases reported through 2004
● Often misdiagnosed as lipoma, hepatocellular adenoma or carcinoma, sarcoma, other metastatic neoplasms (Am J Surg Pathol 1999;23:34 (review))

Clinical features
=========================================================================

● Liver is #2 site for AML after kidney
● 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
● Similar gene expression profile as hepatic stellate cells and stem cells (Hum Pathol 2005;36:341, Mol Med 2007;13:160)

Radiologic images
=========================================================================



Multiple hypointense lesions

Case reports
=========================================================================

● 46 year old woman with 15+ tumors but without tuberous sclerosis (Mod Pathol 2002;15:167)
● 50 year old man (Hepatobiliary Pancreat Dis Int 2005;4:152)

Gross description
=========================================================================

● Well-circumscribed but not encapsulated, typically solitary masses up to 20 cm (1-36 cm), yellow-gray-white
● Necrosis present in larger tumors, may contain hemorrhage, background liver is normal

Gross images
=========================================================================



Large lobulated tumor with areas containing fat


Multiple lesions


Case report: 50 year old man

Micro description
=========================================================================

● Mature adipose tissue, smooth muscle cells and thick walled blood vessels with loss of elastic lamina
● Spindle cells radiate from walls
● Extramedullary hematopoiesis in 40%; represents hematopoietic function of liver
● Smooth muscle cells are epithelioid or spindled with clear (spider web appearance) or eosinophilic cytoplasm or pleomorphic
● Mast cells common
● Occasional features are cellularity, nuclear pleomorphism with intranuclear inclusions, tumor giant cells
● No/rare mitotic figures
● Most cases have mixed patterns; unusual patterns are angiomatous, inflammatory, lipomatous (70%+ fat), myomatous, oncocytic, pelioid, trabecular
● Inflammatory subtype resembles inflammatory myofibroblastic tumor or follicular dendritic cell tumor (Ann Diagn Pathol 2010;14:240); trabecular variant mimics hepatocellular carcinoma
● Malignant cases recur / metastasize; definite criteria for malignancy not established; features associated with malignancy are: large size (10 cm+), increased mitoses (2-5/hpf), coagulative necrosis, vascular invasion, CD117 weak/negative (Am J Surg Pathol 2008;32:793)

Micro images
=========================================================================


   
Angiomyolipoma


Smooth muscle, vessels, adipose

   
H&E and stains


Case report: 50 year old man - H&E and HMB45

Positive stains
=========================================================================

● Smooth muscle cells: strong - HMB45, MelanA/MART1, microphthalmia transcription factor (50%) and other melanin markers (Arch Pathol Lab Med 2002;126:49), including HBSA5, MART-1, HMB-50, CD63 (NKIC3)
● Variably positive for smooth muscle actin and desmin; S100 (adipose cells); c-kit/CD117 (all cell types, Am J Surg Pathol 2002;26:493 (c-kit staining))

Negative stains
=========================================================================

● Cytokeratin, HepPar1

Electron microscopy description
=========================================================================

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



Benign tumors/conditions

Benign cystic mesothelioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

See similar topic in Small bowel chapter

General
=========================================================================

● Very rare in liver; considered reactive due to its association with abdominal surgery and endometriosis
● Also called multilocular peritoneal inclusion cyst, multifocal peritoneal inclusion cyst, benign muticystic peritoneal mesothelioma
● Arises from undifferentiated mesothelial or submesothelial cells over liver capsule (Arch Pathol Lab Med 2001;125:944)
● Female predominance, may be due to hormonal changes (Am J Surg Pathol 2002;26:1523)
Laboratory: elevated CA 19-9 in serum and cyst fluid

Treatment
=========================================================================

● Excision; indolent, slowly progressive and curable, but may recur

Case reports
=========================================================================

● 51 year old woman (Am J Surg Pathol 2002;26:1523)
● 58 year old man with elevated CA 19-9, multiple benign appearing liver cysts and single cysts in kidney and pancreas (Arch Pathol Lab Med 2001;125:944)

Gross description
=========================================================================

● Partially cystic, encapsulated mass with soft-glistening surface

Gross images
=========================================================================



Cyst before and after aspiration

Micro description
=========================================================================

● Well-encapsulated, partially cystic and 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
=========================================================================



Various images and immunostains

Positive stains
=========================================================================

● CK8/18 (CAM 5.2), calretinin, EMA, vimentin and estrogen receptor

Electron microscopy description
=========================================================================

● Desmosomes and microvilli

Differential diagnosis
=========================================================================

Biliary cystadenoma
● Congenital mesothelial cyst: usually neonates (Pediatr Surg Int 2008;24:463)
● Cystic neoplasms
Hydatid cyst
● Serous cystadenoma
● Vascular neoplasms (due to high vascularity)



Benign tumors

Bile duct adenoma / Atypical bile duct adenoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 July 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Benign, but not a true neoplasm
● Incidental finding, although often confused with adenocarcinoma
● Currently regarded as a peribiliary gland hamartoma or a localized reactive ductular proliferation due to previous unknown injury
● Usually adults (age range 1-99 years), no gender preference
● Much less common than bile duct hamartoma/von Meyenburg complex

Gross description
=========================================================================

● Well-circumscribed but unencapsulated, firm, gray-white, tan or yellow, subcapsular round to oval nodules; 85% solitary
● May have central depression
● Usually 5 mm or less but 7% are larger than 1 cm (0.5cm to 1.5cm)
● Larger than von Meyenburg complex and smaller than cholangiocarcioma;

Micro description
=========================================================================

● Compact network of simple noncystic 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
● Rarely clear and oncocytic cells (Histopathology 2006;49:318)
● Variable fibrous stroma
● Center of larger lesions is paucicellular, densely collagenised; nodular lymphoid aggregate at periphery
● Non caseating granulomas, microcalcification, inflammatory cells; normal portal tracts with bile ducts may be present
● 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

Differential diagnosis
=========================================================================

● Adenocarcinoma: atypical cytologic and architectural features
Cholangiocarcioma: larger, infiltrative
von Meyenburg complex: 0.5cm or smaller, less cellular, curvilinear angulated inspissated bile containing ducts, more abundant stroma


Atypical bile duct adenoma, clear cell type

General
=========================================================================

● Rare; ages 25-63 years in 3 cases described (Am J Surg Pathol 2001;25:956)
● Incidental finding
● Cytoplasmic clearing may be due to accumulation of fat, acid mucin, or distended endoplasmic reticulum

Gross description
=========================================================================

● 1 cm, subcapsular

Micro description
=========================================================================

● Bile duct tumor composed almost entirely of small nests and tubules of clear cells infiltrating hepatic parenchyma by involving entrapped normal bile ducts; 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)

Differential diagnosis
=========================================================================

Clear cell cholangiocarcinoma: larger, tubular pattern, desmoplastic stroma, more nuclear atypia increase mitotic activity and elevated Ki-67 labeling index; similar immunostains results
Metastatic renal cell carcinoma
● Well-differentiated adenocarcinoma



Benign tumors

Biliary adenofibroma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 July 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Extremely rare (<25 reported cases) large solid cystic mass
● Age ranges from 21-79 years; no gender predilection
● Monosomy 22 in one case (Cancer Genet Cytogenet 1997;93:183)
● Appears to originate from interlobular or larger bile ducts
● Benign behavior to date, but may be premalignant

Case reports
=========================================================================

● 47 year old woman (Am J Surg Pathol 2003;27:693)
● 79 year old man (Patholog Res Int 2010;2010:504584)

Micro description
=========================================================================

● Microcystic and tubular structures lined by low columnar/cuboidal epithelium
● Luminal eosinophilic material, red blood cells, bile and dense fibrous stroma with spindle cells displaying mild nuclear pleomorphism; no/rare mitotic figures, no stromal invasion

Micro images
=========================================================================


               
Various images

Positive stains
=========================================================================

Epithelium: AE3, CAM5.2, CK7, CK19, CEA, EMA, D10, IF6, p53

Negative stains
=========================================================================

● Alcian blue, vimentin, desmin

Differential diagnosis
=========================================================================

Benign cystic mesothelioma
Biliary cyst
Biliary cystadenoma: larger, multiloculated cysts, mucinous epithelium with ovarian-type of stroma
Bile duct adenoma: incidental, small
von Meyenburg complex: smaller, usually multifocal, but similar staining pattern



Benign tumors

Biliary cystadenoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 August 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Less than 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%)
● Single and multiloculated with predilection for right lobe of the liver
● 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, spontaneous rupture, recurrence, malignant transformation
Laboratory: elevated CA 19-9 (in cases with ovarian type stroma) and CEA in cyst fluid and serum

Radiology description
=========================================================================

● Calcification in 20% (resemble echinococcal cyst)

Treatment
=========================================================================

● Complete excision (rarely has delayed recurrence)

Case reports
=========================================================================

● 32 year old woman with tumor arising from left hepatic duct (Arch Pathol Lab Med 2001;125:1507)
● 47 year old woman (Case of the Week #70)
● 59 year old woman with hepatic smooth muscle tumor encasing hepatobiliary cystadenoma (Am J Surg Pathol 1999;23:854)

Gross description
=========================================================================

● Encapsulated, solitary, mean 15 cm (range 3-30 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 description
=========================================================================

● Usually mucinous: lined by single layer of columnar-cuboidal mucinous epithelium with basal nuclei and apical mucin
● 3 types: (a) hepatobiliary cystadenoma with mesenchymal stroma, (b) without mesenchymal stroma, and (c) intraductal polypoid with mesenchymal stroma
● 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; no communication with the bile ducts
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
=========================================================================


           

               
Case of Week

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)

Differential diagnosis
=========================================================================

● Borderline tumor: high grade dysplasia and complex architecture
● Invasive tumor: put through numerous sections to exclude invasion
● Foregut/ciliated cyst: asymptomatic, males, unilocular, present in segment IV, ciliated columnar/cuboidal epithelial lining with subepithelial connective tissue surrounded by a muscle layer



Benign tumors

Biliary cyst


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 July 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Unilocular; single or multiple; when multiple usually a component of adult polycystic kidney disease
● Usually age 40+ years; prevalence increases with age
● No malignant potential
● Subcapsular, not connected to biliary tree

Micro description
=========================================================================

● Lined by cuboidal or biliary type epithelium; rarely squamous lined
● Thin fibrous wall with pigment laden macrophages; adjacent von Meyenberg complexes are present



Benign tumors

Biliary papillomatosis


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Now known as intraductal papillary neoplasm (IPN) (WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010)
● Rare, 50 cases reported
● 2/3 men, usually ages 60+ years in intrahepatic bile ducts, hilar and extrahepatic bile ducts
● Synchronous and dyssynchronous disease can develop in intrahepatic and extrahepatic biliary tree, gallbladder, major pancreatic ducts
● Multiple papillary adenomas extensively throughout intra- or extrahepatic biliary tract
● Often recurs, 25% have malignant transformation, but only rare metastases (to lung)
● Patients may present with recurrent cholangitis and obstructive jaundice
● Associated with Caroli’s disease, choledochal cyst, polyposis coli, hepatolithiasis and ulcerative colitis
● Most patients die within 3 years due to cholangitis and hepatic failure

Case reports
=========================================================================

● 66 year old man with cirrhosis due to Hepatitis C and malignant transformation (Arch Pathol Lab Med 2002;126:369)

Treatment
=========================================================================

● Difficult to treat because multifocal and propensity to grow and spread along the biliary tree
● Liver transplant may be helpful

Gross description
=========================================================================

● Focal (localized), multifocal, or diffuse
● Dilated bile ducts are fusiform or cystic (unilocular or multilocular)
● Inner surface of ducts has velvety finger like papillary growths with masses filling dilated ducts
● Masses are soft, friable, white-red-tan
● 1/3 secrete mucin in the duct lumen, accounting for prior terminology of mucin secreting biliary tumor

Micro description
=========================================================================

● 4 subtypes: pancreatobiliary, intestinal, gastric, oncocytic; based on morphology and mucin expression (Am J Surg Pathol 2004;28:327, Hum Pathol 2009;40:1543)
● 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
● Also classified as IPN-low grade and IPN-high grade based on the highest degree of architectural and cytological atypia
● Identify stromal invasion by thorough sampling

Micro images
=========================================================================



Fibrovascular cores and invasive disease in case report above



Benign tumors

Castleman’s disease


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon lymphoproliferative disorder involving lymph nodes in one region or systemic
● Also called angiofollicular hyperplasia

Micro description
=========================================================================

● Stellate fibrous scar separates 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 are arranged in onion-skin pattern around follicles



Benign tumors

Extramedullary hematopoiesis


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Usually discovered incidentally or associated with anemia
● Rarely presents as liver mass
● Only very few liver nodules of EMH have been described in the literature (Diagn Cytopathol 1997;16:51)

Case reports
=========================================================================

● 52 year old woman with 2.5 cm, 5 cm and 7 cm liver masses and normal serum AFP (Arch Pathol Lab Med 2003;127:631)

Treatment
=========================================================================

● Radiation or hydroxyurea if symptomatic

Micro description
=========================================================================

● Erythroid precursors in sinusoids (resemble lymphocytes), myeloid precursors in portal tracts (resemble mixed portal infiltrate or eosinophils in neonates)
● Also megakaryocytes within sinuses

Micro images
=========================================================================



Contributed by Dr. Deepali Jain


H&E and CD68

Cytology images
=========================================================================



Diff-Quick (2), Pap stain

Differential diagnosis
=========================================================================

● Abscess/infections
● Lymphoproliferative disorder
● Prominent megakaryocytic component may suggest atypical or malignant diagnosis



Benign tumors

Fatty change


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 6 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called focal fatty change
● Focal fatty change first described in 1980 (Gastroenterology 1980;78:247)

Clinical description
=========================================================================

● Rare, often incidental finding at autopsy or misinterpreted on imaging as neoplastic growth
● Ill-defined, single or multiple
● Simulates lipomatous tumor or malignancy (Przegl Lek 2006;63:695)
● Associated with obesity, diabetes, alcohol abuse, dyslipidemia, malnutrition, steroids, chemotherapeutic agents, AIDS
● Hepatic enzymes may be normal or mildly abnormal
● 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)
● Treatment directed against underlying disorder

Case reports
=========================================================================

● 42 year old woman with possible hepatic adenomas (Case of Week #141)

Gross description
=========================================================================

● Subcapsular, unencapsulate, yellow-white foci, often multiple, up to 10 cm

Gross images
=========================================================================


   
Various images

Micro description
=========================================================================

● Diffuse or focal steatosis adjacent to unremarkable liver, no compression of perinodular liver tissue
● Prominent blood vessels within and at the margin of the nodule
● May have foreign-body type granulomatous inflammation

Micro images
=========================================================================


       
Various images

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)



Benign tumors

Focal nodular hyperplasia (FNH)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 7 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Common benign mass with an indolent course (#2 liver tumor after hemangioma); no known malignant potential
● Usually an incidental finding; present in 1% of autopsies
● Median age 38 years; F:M ratio varies from 8-12:1
● Represents 2-10% of pediatric hepatic tumors; never reported in elderly
● 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
● May have abdominal discomfort, pain, anorexia or fatigue (Hepatobiliary Pancreat Dis Int. 2004;3:199)
● Telangiectatic FNH are monoclonal and more closely resemble hepatic adenomas than classical FNH

Etiology
=========================================================================

● May represent hyperplastic response to preexisting arterial malformation or other vascular anomaly; is NOT a neoplasm (Am J Gastroenterol 2006;101:2341)


Diagram of possible pathogenesis

Case reports
=========================================================================

● 13 month old girl (Case of the Week #88)

Radiology decription
=========================================================================

● 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 description
=========================================================================

● Well demarcated, nonencapsulated, subcapsular, light brown to yellow (lighter than surrounding liver)
● Bulging nodule, 70-80% solitary, up to 5 cm; rarely > 10 cm
● 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

Micro description
=========================================================================

● Most tumors (80%) have 3 classic features: abnormal architecture, bile ductular proliferation, malformed vessels
● Hepatocyte nodules are surrounded by fibrous septa with large malformed arterial branches not accompanied by interlobular bile ducts or portal veins
● Typically void of any formal portal triads
● 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
● Non-classic forms lack either abnormal architecture or malformed vessels, and are devoid of central scar
● 3 types: (a) telangiectatic, (b) mixed hyperplastic and adenomatous, (c) atypia of large cell (Am J Surg Pathol 1999;23:1441)
● Telangiectatic variant: multiple dilated vascular channels in center of mass; considered by some to be a variant of hepatic adenoma (World J Gastroenterol 2007;13:2649)
● Mixed hyperplastic and adenomatous: contain regions resembling telangiectatic and hepatic adenoma
● Atypia of large cell: atypical hepatocytes with enlarged hyperchromatic nuclei with irregular contours frequently demonstrating cytoplasmic–nuclear inclusions

Micro images
=========================================================================


       
Fibrous area with blood vessels and bile ductules


Associated with fibrolamellar carcinoma

Positive stains
=========================================================================

● Alpha-1-antitrypsin

Negative stains
=========================================================================

● p53, CD143 (angiotensin I-converting enzyme: reduced expression, Am J Surg Pathol 2004;28:84)

Differential diagnosis
=========================================================================

● 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 (Arch Pathol Lab Med 2000;124:1105)

Additional references
=========================================================================

Radiographics 2004;24:3, eMedicine


Multiple focal nodular hyperplasia syndrome

General
=========================================================================

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

Micro description
=========================================================================

● Often telangiectatic variant with multiple dilated vascular channels in center of mass



Benign tumors

Glomangioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 July 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, <25 cases reported
● Glomus tumor (neoplasm of glomus apparatus) with prominent vascular structures

Case reports
=========================================================================

● 57 year old man with flank pain and 3 cm liver mass (Arch Pathol Lab Med 2004;128:e46)

Radiology images
=========================================================================



Hypervascular mass

Gross description
=========================================================================

● Well-defined encapsulated tumor mass with dark-red soft cut surface

Micro description
=========================================================================

● Small to medium branched vessels with stroma containing small, round regular cells with sharply outlined round/oval nuclei; low mitotic activity

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

Differential diagnosis
=========================================================================

Angiosarcoma: infiltrative, cellular atypia
Hemangioendothelioma: intracytoplasmic lumina
Hemangiopericytoma: staghorn vessels



Benign tumors

Hemangioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 July 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Soft tissue chapter

General
=========================================================================

● 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
● No known risk of malignant transformation
● Associated with multiple focal nodular hyperplasia syndrome
● Fibrotic tumors may be precursor of solitary necrotic nodules
● Capillary: solitary capillary hemangiomas are extremely rare
● Cavernous: giant cavernous hemangiomas (> 4-10 cm) rarely rupture and require resection

Treatment
=========================================================================

● Excision or observation (may involute)

Gross description
=========================================================================

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

Micro description
=========================================================================

● 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
● Border may be irregular
● May see cavernous hemangioma-like vessels (HLV) in adjacent liver

Micro images
=========================================================================


   
Cavernous hemangioma: contributed by Dr. Deepali Jain

Positive stains
=========================================================================

● Elastin and trichrome may expose vessels in old fibrous lesions

Differential diagnosis
=========================================================================

Hemangiomatosis
Hereditary hemorrhagic telangiectasia: aberrant portal vessels, dilated vascular channels within portal tracts
Infantile hemangioendothelioma: atypia present, although not necessarily everywhere
Peliosis hepatis: no fibrous septa



Benign tumors

Hemangiomatosis


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 July 2012, last major update July 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called diffuse hemangiomatosis
● Usually neonates, rare in adults
● May also affect lung and bone
● Associated with hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease), giant cavernous hemngioma and systemic hemangiomatosis

Gross description
=========================================================================

● Nodules may replace entire liver

Micro description
=========================================================================

● Numerous, small, ill-defined, poorly circumscribed, hemangiomatosis nodules in portal tracts with alternating normal parenchyma; may become sclerosed



Benign tumors

Hepatic vascular malformation with capillary proliferation


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 19 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Congenital vascular malformation; usually symptomatic at birth
● 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

Case reports
=========================================================================

● 3 month old girl (Gastroenterology 2011;140:1883)

Gross description
=========================================================================

● Single large mass, mean 8 cm, range 5-11 cm
● Central infarction and hemorrhage is common

Micro description
=========================================================================

● Outer dilated vessels lined by flattened endothelium and loose myxoid stroma
● Central infarction and hemorrhage; bile duct entrapment

Micro images
=========================================================================



Low magnification

Differential diagnosis
=========================================================================

● Infantile hemangioendothelioma: presents after birth; proliferating multifocal lesion followed by spontaneous involution typically composed of only small vessels without central regression; GLUT1+ (Hum Pathol 2004;35:200)



Benign tumors

Hepatocellular adenoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 19 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 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, thalassemia, familial adenomatous polyposis, familial diabetes mellitus, Hurler’s disease, galactosemia 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
● Risk of malignancy is not related to number of adenomas but to size and pathological subtype (lower risk for steatotic subtype)
● May contain hepatic progenitor cells (Am J Surg Pathol 2001;25:1388)

Laboratory
=========================================================================

● Normal liver function tests, may have elevated alpha fetoprotein
Hepatocellular adenomatosis: 10+ tumors, both in man and woman, genetic mutation of HNF1α no association with oral contraceptives

Treatment
=========================================================================

● Excision

Case reports
=========================================================================

● 9 year old girl with hepatic adenoma and subsequent fibrolamellar carcinoma (Arch Pathol Lab Med 2004;128:222)

Gross description
=========================================================================

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

Micro description
=========================================================================

● Sheets and cords 1-3 cells thick of normal appearing hepatocytes with variable glycogen
● Prominent “free floating” arterial vessels and draining veins are present throughout tumor; intact reticulin framework
● Pseudoglands may be present
● May have cytoplasmic globules (PAS+, diastase resistant, alpha-1-antitrypsin+, AFP-), 10% have multinucleation
● 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
● No atypia, no prominent nucleoli, no intranuclear vacuoles
● No angiolymphatic invasion, no/rare extramedullary hematopoiesis, no epithelioid granulomas, no decreased reticulin framework
● No/rare mitotic figures; no portal tracts; no central veins or connection with biliary system

Three major subtypes: (a) inflammatory/telangiectatic; (b) steatotic; with HNF-1α gene mutation; (c) with β-catenin activation; (d) also an additional unclassified/miscellaneous subgroup (Hepatology 2009;50:481)

(a) inflammatory: previously misclassified as telangiectatic focal nodular hyperplasia; 40-55% of hepatocellular adenomas; increased risk of bleeding but small risk of malignant transformation
● Due to mutations involving interleukin-6
● Strong expression of serum amyloid associated protein A2 (SAA-2) and CRP on IHC
● Inflammation and peliosis at histology

(b) steatotic: 35%-50% of hepatocellular adenomas; no risk of malignant transformation
● Develop familial adenomatosis and MODY-3 diabetes mellitus
● Lack of expression of liver fatty acid binding protein (LFABP) on immunohistochemistry

(c) with β-catenin activation: 10%-18% of hepatocellular adenomas
● Affects men and women; increased risk of malignancy; associated with androgen therapy and glycogen storage disease
● Strong diffuse overexpression of glutamine synthetase and nuclear β catenin staining (Hum Pathol 2002;33:852)

Micro images
=========================================================================



14 year old with subsequent fibrolamellar carcinoma (Figures A-D)


ER and PR staining

Positive stains
=========================================================================

● ER, PR

Negative stains
=========================================================================

● p53

Differential diagnosis
=========================================================================

● 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


Atypical hepatocellular adenoma

General
=========================================================================

● Androgen related tumors that regress with androgen withdrawal
● Only rarely metastasize

Micro description
=========================================================================

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

Differential diagnosis
=========================================================================

● 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

General
=========================================================================

● <25 cases reported (Am J Surg Pathol 2011;35:927, Surg Today 2011;41:881)
● Due to phenobarbitol, long-term oral contraceptives, obesity
● Male predominance
● Black pigment present

Case reports
=========================================================================

● 2 men without Dubin-Johnson syndrome (Am J Surg Pathol 2000;24:1429)

Gross description
=========================================================================

● Solitary and multiple; 2.5-16 cm

Micro description
=========================================================================

● 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)

Differential diagnosis
=========================================================================

● Well-differentiated hepatocellular carcinoma



Benign tumors

Hereditary hemorrhagic telangiectasia


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called Osler-Weber-Rendu syndrome
● Autosomal dominant disorder with systemic fibrovascular dysplasia (Arch Pathol Lab Med 2001;125:1219)
● 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)

Clinical features
=========================================================================

● Usually asymptomatic, symptomatic liver involvement in neonates (Pediatrics 2011;127:e1615)
● 3 clinical subtypes including high-output cardiac failure, portal hypertension, or biliary disease
● High prevalence of focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), intrahepatic shunts, ischemic cholangiopathy and sinusoidal dilatation (Eur J Gastroenterol Hepatol 22:1253)
● 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 Pathol 2004;35:266)

Gross description
=========================================================================

● Telangiectatic lesions throughout liver

Micro description
=========================================================================

● Primary abnormality is thought to be dilatation of intrahepatic arteries
● Dilated vascular spaces lined by normal endothelial cells are surrounded by fibrous stroma
● Characteristic periportal telangiectasia, 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)
● May have nodular transformation of liver
● Necrosis due to rupture of telangiectasia (acute hepatic disruption), in late stages due to abnormal hepatic vascularisation

Micro images
=========================================================================



Dilated arteries, vein and sinusoids


Three-dimensional reconstruction



Benign tumors

Heterotopia


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Heterotopic tissue in liver: 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, heart, pleura and pericardium

4 types:
● Accessory liver lobe: attached to liver by stalk
● Small accessory lobe
● Ectopic liver without connection to main liver
● Microscopic ectopic liver



Benign tumors

Inflammatory myofibroblastic tumor


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon lesion
● ALK1+: neoplastic lesion with intermediate biologic behavior
● ALK1-: considered reactive
● Also called inflammatory pseudotumor
● In extrapulmonary tumors, recurs locally in 25%; 8% metastasize
● Usually children and young adults; mean age 37 years but all ages, 75% male
● Associated with occlusive phlebitis and chronic cholangitis
● Rarely associated with sarcoma or follicular dendritic cell tumor
● Symptoms: fever, upper abdominal pain, jaundice

Treatment
=========================================================================

● Excision, occasionally regresses spontaneously

Gross description
=========================================================================

● Well-circumscribed, solitary (70%), 1-25 cm, variegated cut surface, may extend into vena cava or soft tissue, predominantly right lobe

Micro description
=========================================================================

● 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)
Aggressive morphologic features: p53+, ganglion-like cells, mitotic figures (Mod Pathol 1999;12:279); also epithelioid and round cell morphology, nuclear membrane staining of ALK (in contrast to diffuse cytoplasmic staining in benign (Am J Surg Pathol 2011;35:135)

Positive stains
=========================================================================

● Vimentin (>90%), smooth muscle actin (80%), muscle specific actin (80%), desmin (40%), CD68 (40%), pankeratin (30%), p53 (30%), ALK1 (50%)

Negative stains
=========================================================================

● S100, CD21, myoglobin

Differential diagnosis
=========================================================================

● Follicular dendritic cell tumors (CD21+, CD35+), Hodgkin lymphoma (stromal cells are CD15+, CD30+), IgG4 related pseudotumor (high ratio of IgG4+/IgG+ plasma cells, prominent lymphoid aggregates, absent ALK1 rearrangement, obstructive phlebitis, Mod Pathol 2011;24:606)
● Leiomyoma, organizing abscess, postoperative spindle cell nodule, sclerosing hemangioma, solitary fibrous tumor, spindle cell carcinoma or sarcoma



Benign tumors

Intraductal papillary neoplasms of biliary tract


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon tumor arising from peribiliary glands (AJR Am J Roentgenol 2011;197:1111)
● 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
● Associated with Clonorchis sinensis infection (Virchows Arch 2008;453:589)
● Often are carcinomas
● Risk factor for cholangiocarcinoma, biliary obstruction, recurring ascending cholangitis

Micro description
=========================================================================

● Papillary fronds with fine vascular cores
● Epithelial cells are either pancreaticobiliary type, have gastric or intestinal differentiation with goblet cells and Paneth cells, or have oncocytic cells (Hum Pathol 2009;40:1543)
● Production of extracellular intraductal mucin less common than pancreatic IPMNs
● However, mucin-producing IPMN of bile ducts show striking similarities to pancreatic IPMN and nonmucin producing IPM of bile ducts is heterogenous disease (Am J Surg Pathol 2011;35:512)
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

Positive stains
=========================================================================

● Claudin18 (Virchows Arch 2011;459:73)
● Pancreatobiliary: MUC1, MUC5AC, MUC6
● Intestinal: MUC2, CDX2, MUC5AC
● Gastric: MUC5AC
● Oncocytic: MUC5AC, MUC6

Negative stains
=========================================================================

● p53, CK20, MUC2 (except in intestinal type, Hum Pathol 2002;33:503)

Molecular description
=========================================================================

● KRAS activating mutations (29%), 18q- (31%), no loss of DPC4 (Hum Pathol 2003;34:902)



Benign tumors / conditions

Juvenile xanthogranuloma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Non-Langerhans cell histiocytic disorder, usually through age 19 years
● Usually solitary cutaneous lesion, but rarely involves liver, may cause hepatic failure, may regress (Am J Surg Pathol 2003;27:579)

Micro description
=========================================================================

● Predominantly portal infiltrate spilling over into the adjacent lobule, but sparing the biliary tree
● Spindle cells mixed with mononuclear cells or forming short fascicles
● Diffuse giant cell transformation; may have Touton giant cells

Positive stains
=========================================================================

● Vimentin, CD68 and factor XIIIa

Negative stains
=========================================================================

● S100, CD1a



Benign tumors

Leiomyoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Solitary nodule resembling leiomyoma elsewhere; may resemble metastatic well differentiated leiomyosarcoma

Clinical features
=========================================================================

● For diagnosis, should be no primary leiomyomas elsewhere in body
● Arises from mesenchymal tissue of the liver - smooth muscle cells of vessels or biliary tree
● Higher prevalence in patients with immunosuppression or organ transplantation (HIV or EBV infection)
● Metastasis and recurrence may develop in histologically benign leiomyomas

Micro description
=========================================================================

● Spindle cell proliferation with elongated nuclei, eosinophilic cytoplasm; may have abundant T cells
● No nuclear atypia, hemorrhage or necrosis
● Criteria for malignancy: increased mitotic rate (>1/10 high power fields), cellular atypia with nuclear pleomorphism, dense cellularity and degenerative changes

Differential diagnosis
=========================================================================

● GIST: cells don't resemble smooth muscle, CD117+



Benign tumors

Lipoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, usually incidental finding

Case reports
=========================================================================

● Woman with Hepatitis B and multiple hepatic lipomas (Eur J Gastroenterol Hepatol 2007;19:807)
● Associated with hepatocellular carcinoma and polycystic liver disease (Dig Surg. 2001;18:323)

Gross description
=========================================================================

● Solitary, 1-20 cm

Micro description
=========================================================================

● Mature fat or brown fat (hibernoma)

Differential diagnosis
=========================================================================

● Angiomyolipoma
● Focal fatty change
Pseudolipoma: rare, small, encapsulated lesion of mature lipocytes in immediate subcapsular region, presumed to arise from adherent appendix epiploica



Benign tumors

Lymphangioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Very rare - <25 cases reported (Hepatol Int 2010;4:784, Surg Today 2010;40:883)
● Male predominance, age ranges from newborn to 66 years; 1-25 cm, solitary

● Liver involvement is part of multicentric process affecting other organs, particularly spleen
● May be congenital or benign slow growing tumor derived from proliferating lymph ducts, inflammatory and fibrotic processes or genetic predisposition
● May represent mesenchymal hamartoma

Gross description
=========================================================================

● Well-defined solid and cystic tumor with or without spotty calcification

Gross images
=========================================================================



Cystic and smooth mass includes gallbladder

Micro description
=========================================================================

● Cystic tumor with colloid-like content and attenuated endothelial-like cells, no atypia

Micro images
=========================================================================



Multiple cystic spaces lined by endothelium

Positive stains
=========================================================================

● CD31, CD34, D2-40, LYVE-1, Prox-1

Differential diagnosis
=========================================================================

● Hemangioma: negative for lymphatic endothelial markers



Benign tumors

Mesenchymal hamartoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Well-circumscribed, solitary myxoid mass with fluid filled cysts, with architecturally abnormal bile ducts in prmitive myxoid stroma (Arch Pathol Lab Med 2006;130:1567)
● Third most common tumor of liver in pediatric age group (after hepatoblastoma and infantile hemangioma)
● Formerly called cavernous lymphangioadenomatoid tumor, cystic hamartoma, benign mesenchymoma

Clinical features
=========================================================================

● 8% of pediatric liver tumors
● 75% < age 1 year; rarely adults; 60-70% male
● Right lobe predilection
● Usually asymptomatic
● Serum AFP usually normal or mildly elevated; occasionally markedly elevated
● Either neoplastic or a developmental anomaly in bile duct plate formation, possible hepatic stellate (Ito) cell origin (Pathol Res Pract. 2010;206:532)
● Rarely associated with undifferentiated embryonal sarcoma (Pediatr Dev Pathol 2001;4:482) - are pathogenetically related (Genes Chromosomes Cancer 2007;46:508)
● Adult cases are usually women with abdominal pain, more prominent fibrosis and a lesser myxoid component than childhood cases, usually no extramedullary hematopoiesis (Hum Pathol 2002;33:893)

Case reports
=========================================================================

● 10 month old girl with cytogenetic analysis (Arch Pathol Lab Med 2006;130:1216)
● 15 month old asymptomatic boy with large hepatic mass (Case of the Week #61)

Treatment
=========================================================================

● Excision (curative, but surgery has high mortality for large masses)
● Liver transplantation may be necessary (J Clin Pathol 2006;59:542)

Gross description
=========================================================================

● 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
=========================================================================



Well demarcated tumor with solid grey cut surface, slightly nodular appearance, isolated small hemorrhagic areas

Micro description
=========================================================================

● Epithelial and mesenchymal components
● Branching bile ducts without atypia in loose, myxoid stroma with myofibroblast-like cells, dilated vessels and lymphatics
● May resemble breast fibroadenoma at low power
● Also normal appearing hepatocytes with retention of normal cell plate architecture, 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
=========================================================================


       

       
Various images

Positive stains
=========================================================================

● CK7, vimentin, smooth muscle actin, desmin, actin, Glypican-3 (Hum Pathol 2012;43:695)

Negative stains
=========================================================================

● CK20

Molecular description
=========================================================================

● Interstitial deletion near 19q13.4 (Cancer Genet Cytogenet 2004;153:60)

Molecular images
=========================================================================



Figures 3 and 4

Electron microscopy description
=========================================================================

● Myofibroblastic features

Differential diagnosis
=========================================================================

● Bile duct adenoma (no hepatocyte islands) or cystadenoma (adults)
● Bile duct hamartoma: usually multiple with fibrous background
● Embryonal sarcoma: marked cellularity and atypical cells, eosinophilic PAS-D globules
● Infantile hemangioendothelioma: more vascular
● Infantile hemangioma: females more common, vascular channels of variable size
● Mixed epithelial mesenchymal hepatoblastoma: epithelial component has embryonal and fetal hepatocytes; mesenchymal component has spindle cells, osteoid, cartilage



Benign tumors

Myelolipoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Tumor of fat and bone marrow hematopoietic cells resembling adrenal tumor
● Rare extraadernal sites: spleen, mediastinum, testis and liver
● Histogenesis not clear
● Neoplastic or metaplastic changes or emboli from bone marrow, or embryonic rests of hematapoietic tissue (J Gastrointestin Liver Dis 2010;19:105)

Case reports
=========================================================================

● Associated with hepatocellular carcinoma (AJR Am J Roentgenol 1994;163:1111)

Gross description
=========================================================================

● Fatty lesion with grayish-red appearance

Micro description
=========================================================================

● Fat and bone marrow hematopoietic cells



Benign tumors

Nodular regenerative hyperplasia


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Nodular hyperplasia diffusely affecting entire liver, but with no/minimal fibrous septa

Clinical features
=========================================================================

● 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 (Arch Pathol Lab Med 2004;128:49), HIV, CHF, Felty syndrome
● May be part of the early noncirrhotic stages of primary biliary cirrhosis
● May be due to moderate to severe sclerosis of small portal veins, portal venous thrombosis or arteriosclerosis causing heterogeneous blood flow, variable ischemia and reactive hepatocyte hyperplasia
Laboratory findings: mildly elevated alkaline phosphatase, gamma GT, normal alpha fetoprotein

Gross description
=========================================================================

● 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 description
=========================================================================

(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 compressed central veins

Differential diagnosis
=========================================================================

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



Partial nodular transformation

General
=========================================================================

● Very rare, focal form of nodular regenerative hyperplasia, usually perihilar region
● Portal hypertension usually prominent due to portal venous thrombosis

Micro description
=========================================================================

● 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
● Nodules are larger than nodular regenerative hyperplasia



Benign tumors

Paraganglioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Very rare benign tumor that may arise from adrenal rests

Case reports
=========================================================================

● 46 year old man (Am J Surg Pathol 2002;26:945)

Treatment
=========================================================================

● Excision

Gross description
=========================================================================

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

Micro description
=========================================================================

● 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) by IHC or ISH
● Sustentacular cells are S100+

Negative stains
=========================================================================

● Albumin mRNA, keratin, CD10, vimentin, smooth muscle actin

Differential diagnosis
=========================================================================

● Fibrolamellar hepatocellular carcinoma: broad fibrous bands, atypia, invasion, HepPar1+
● Neuroendocrine tumors: no absence of Zellballen or sustentacular cells



Benign tumors

Perivascular epithelioid cell tumor (PEComa)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Mesenchymal tumor with dual melanocytic and myoid differentiation
● Related tumors include angiomyolipoma, clear cell sugar tumor of lung, lymphangioleiomyomatosis
● Rarely associated with tuberous sclerosis complex
● More common in females
● Rare malignant cases with metastasis (Arch Pathol Lab Med 2006;130:1219)

Case reports
=========================================================================

● 13 year old girl with tumor in ligamentum teres hepatis (Am J Surg Pathol 2000;24:1295)

Gross description
=========================================================================

● Well-defined, tan-white homogenous cut surface, no hemorrhage, no necrosis

Micro description
=========================================================================

● 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
Criteria for malignancy: size > 5 cm, infiltration into surrounding tissue, high nuclear grade and cellularity, mitotic index > 1 per 50 hpf, necrosis, and vascular invasion (Hum Pathol 2010;41:1)

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● HMB45, MelanA/Mart1, microphthalmia transcription factor, PAS+ diastase sensitive, smooth muscle actin

Negative stains
=========================================================================

● Cytokeratin, desmin, EMA, S100, CD34, CD68, CD99, ER, PR

Electron macroscopy description
=========================================================================

● Numerous degenerated mitochondria, glycogen, thin filaments with focal densities, premelanosomes, subplasmalemmal densities

Differential diagnosis
=========================================================================

● Hepatocellular carcinoma, epithelioid angiomyolipoma



Benign tumors

Pseudocyst


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● By definition, no true epithelial lining
● Single, often involves left lobe
Causes: trauma, ischemia, pancreatitis

Gross description
=========================================================================

● May be large, contain blood or bile; may become secondarily infected

Micro description
=========================================================================

● Fibrous lining, may contain hemosiderin, bile, macrophages and inflammatory cells in the wall, intracystc necrotic debris
● May resolve spontaneously



Benign tumors

Pseudolipoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare tumor embedded in cavity on liver surface
● Also called pseudolipoma of Glisson’s capsule, coelomic fat ectopia
● Represents trapped appendix epiploica, often related to prior surgery
● Very rare in women

Case reports
=========================================================================

● 69 year old man with incidental finding (Arch Pathol Lab Med 2003;127:503)

Gross description
=========================================================================

● 0.5-2cm, solitary, encapsulated, smooth, yellow-white, hard nodule of fat necrosis, calcification, ossification

Micro description
=========================================================================

● Thick fibrous capsule surrounding necrotic mature fat cells with degenerative changes including calcification

Gross/micro images
=========================================================================



Mineralized nodule composed of cells with homogenized basophilic material



Benign tumors

Reactive bile ductule proliferation


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Bile ductular proliferation due to ductular metaplasia of hepatocytes and from proliferation of pre-existing bile ductules
● Associated with cirrhosis, submassive hepatic necrosis, biliary tract disorders, atrophy and focal nodular hyperplasia

Gross description
=========================================================================

● Often multiple irregular nodules

Micro description
=========================================================================

● Periductular neutrophils common
● No angulated structures, usually no dense fibrosis (except with atrophy), variable bile in portal tract or periportal area

Positive stainss
=========================================================================

● Neuroendocrine stains (Am J Pathol 1990;137:1019)

Differential diagnosis
=========================================================================

● Adenocarcinoma: particularly confusing after chemotherapy, has more severe atypia with irregular nuclear membranes, prominent nucleoli, hyperchromasia, increased N/C ratio, desmoplasia, infiltrative cells
● Bile duct adenoma: solitary, subcapsular, with collapsed lumina, prominent lymphocytes
● Bile duct hamartoma: angulated ducts embedded in sclerotic stroma



Benign tumors / conditions

Reactive lymphoid hyperplasia / pseudolymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called pseudolymphoma, may mimic lymphoma (Mod Pathol 2010;23:244, Am J Surg Pathol 1999;23:302)
● Rare, < 50 cases reported
● Age range 15–81 years; female predominance
● Usually incidental finding, right lobe predilection
● Associated with chronic liver disease, extrahepatic autoimmune disorders and malignancies
● May be concomitant hepatic and pancreatic involvement (Clin Res Hepatol Gastroenterol 2012;36:e71)
● May be immune mediated
● No associated systemic manifestations
● Resection is curative

Case reports
=========================================================================

● 69 year old woman with stage I renal cell carcinoma and hepatic mass (Arch Pathol Lab Med 2001;125:577)

Gross description
=========================================================================

● Well-circumscribed, tan, non-encapsulated, solitary (multiple in 20%) rubbery nodule, 0.5-5.5 cm

Micro description
=========================================================================

● Prominent lymphoid follicles with germinal centers, tingible-body macrophages and polymorphic small lymphocytes

Micro images
=========================================================================





Various images

Positive stains
=========================================================================

● CD20

Negative stains
=========================================================================

● BCL2 does not stain germinal centers; no light chain restriction

Differential diagnosis
=========================================================================

Autoimmune hepatitis
Castleman's disease
● Chronic hepatitis B or Hepatitis C infection
MALT or other low grade lymphoma - lymphoepithelial lesions, cellular atypia, light chain restriction
Primary biliary cirrhosis



Benign tumors

Solitary fibrous tumor


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called localized fibrous tumor/localized fibrous mesothelioma
● Rare; fewer than 40 reported cases in liver; may arise from beneath liver capsule
● Predominantly occur in women (2:1); age range 27-83 years
● Associated with hypoglycemia

Case reports
=========================================================================

● 66 year old Italian man (Arch Pathol Lab Med 2003;127:e255)

Treatment
=========================================================================

● Complete surgical resection with long term follow up

Gross description
=========================================================================

● Solitary mass, well circumscribed, encapsulated, often 15 cm or more, with bulging, solid, gray-white cut surface, highly vascular

Micro description
=========================================================================

● Patternless architecture, alternating hypocellular and hypercellular areas
● Spindle cells without atypia mixed with hyalinized collagen
● Mild atypia; rare mitotic figures; no necrosis
● Criteria for malignancy: high cellularity and mitotic activity (>4/10hpf), pleomorphism, necrosis, and local invasion

Gross/micro images
=========================================================================



H&E and CD34

Positive stains
=========================================================================

● CD34, BCL2, vimentin, CD99

Negative stains
=========================================================================

● Cytokeratin, EMA, CD117, S100, smooth muscle actin, desmin, chromogranin, synaptophysin

Differential diagnosis
=========================================================================

● Inflammatory pseudotumor: plasma cells, obliterative phlebitis, SMA+, CK+
● Leiomyoma: SMA+
● Sclerosed hemangioma: CD34 in endothelial cells only, elastic fibers around vessels



Benign tumors

Solitary necrotic nodules


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● <100 cases reported
● May represented sclerosed hemangiomas, prior parasitic infection, trauma, bile duct hamartomas, ischemia
● Usually males, >75% in right lobe, all on hepatic surface (Case Rep Gastroenterol 2008;2:149)
● May regress spontaneously (Hepatol Int 2010; 4:649) or be associated with malignancy (J Gastrointest Surg 2010;14:536)

Treatment
=========================================================================

● Resection

Gross description
=========================================================================

● 0.2 to 2.5 cm, single or multiple (more appropriate term is fibrosing necrotic nodule), below anterior border of liver

Micro description
=========================================================================

● Hyalinized fibroelastic capsule surrounds necrotic core
● Variable calcification, cholesterol, foam cells, and some inflammatory cells
● AFB and fungal stains negative

Micro images
=========================================================================


       
Various images



Dysplasia

Liver cell dysplasia


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● By definition, dysplastic foci measure <1 mm in diameter, detected in livers on microscopic exam incidentally in biopsies or resected specimens with or without cirrhosis and are often multiple
● Apparent precursor lesion of hepatocellular carcinoma
● Iron free foci in genetic hemochromatosis (resistance to hemosiderin accumulation) are proliferative lesions associated with a high incidence of hepatocellular carcinoma (Hepatology 1993;18:1363)

Micro description
=========================================================================

● Large cells with abundant cytoplasm and relatively normal nuclear/cytoplasmic ratio (large cell change) or small cells with minimal basophilic cytoplasm and increased N/C ratio (small cell change)
● Both have enlarged, pleomorphic nuclei, clumped chromatin, thick nuclear membranes, prominent nucleoli
● Large cell change may be dysplastic or reactive (Hepatol 2006;45:734)
● Small cell change may represent a more “advanced” lesion than large cell change (Hepatology 2007;45:968)



Dysplasia

Borderline nodule


Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 19 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called high grade dysplastic nodule, 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
● Usually 1 cm (or < 1.5cm); may be single or multiple
● 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 description
=========================================================================

● Frequently multiple, may be single, coexists with macroregenerative nodule (which they grossly resemble), usually less than 2 cm

Micro description
=========================================================================

● 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
● Few and scarred portal tracts seen
● Unpaired or nontriadal arteries are present
● Sinusoidal capillarization

Positive stains
=========================================================================

● Sinusoids positive for factor VIII and CD34

Differential diagnosis
=========================================================================

● 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 in the absence of cholestasis, disrupted reticulin framework, clonelike clear/fatty, iron or copper containing foci; GPC-3+, HSP-70+, Glutamine synthatase+ (Hepatology 2007;45:725); ductular reaction absent (CK7/CK19 negative)



Dysplasia

Macroregenerative nodule


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 August 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 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 description
=========================================================================

● 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 description
=========================================================================

● 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

Differential diagnosis
=========================================================================

● High grade dysplastic nodule: increased cellularity and unpaired arteries are useful to distinguish dysplastic nodules from large regenerative nodules of cirrhotic livers



Hepatocellular carcinoma - General


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Malignant tumor with hepatocellular differentiation
● 85% of hepatic malignancies (30% in children); major cause of cancer death worldwide, but varies by country (see below)

Terminology
=========================================================================

● Also called liver cell carcinoma; recommended to NOT describe as hepatoma, which implies a benign process

Epidemiology
=========================================================================

● #5 most common malignancy worldwide (250,000 cases worldwide), #3 most frequent cause of cancer related death; causes 20-40% of cancer deaths in China, Japan, sub-Saharan African
● Highest rates of disease in Korea, Taiwan, southeast China and Mozambique and countries endemic for viral hepatitis; also high in Africa, moderately high in France and Italy; rare in North America
● Rates vary due to differences in risk factors: chronic hepatitis B (HBV) or hepatitis C (HCV); infant HBV carriers have 200x risk; aflatoxin exposure (developing countries), smoking, cirrhosis (85% in West with HCC have cirrhosis)
● Other less common risk factors are Thorotrast exposure (historical), androgenic steroids, tyrosinemia
● Higher rates in blacks vs. whites (4:1); 70% male
● Most patients are age 60+ years with cirrhosis or ages 20-40 years without cirrhosis, occasionally are second tumors in Wilm’s tumor patients

Pathophysiology
=========================================================================

Aflatoxins (mycotoxins): produced by Aspergillus flavus (aflatoxin B1) and Aspergillus parasiticus, which contaminate grain, particularly peanuts stored in warm and humid conditions in tropical and subtropical regions; aflatoxin B1 is potent carcinogen 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 alcoholism, alpha-1-antitrypsin deficiency, HCV, hereditary tyrosinemia (40% develop HCC even with dietary control), non-alcoholic fatty liver disease, primary hemochromatosis; due to stimulation of hepatocellular division in background of ongoing necrosis and inflammation; classic HCC occurs without chronic liver disease in old age or associated with hepatocellular adenomas with β-catenin gene mutations (Hepatology 2009;50:481)
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 and receptors for insulin-like growth factor I; HBV X binds to p53; associated with β-catenin accumulation; cirrhosis is variable; HBV vaccination dramatically reduces HCC incidence
Hepatitis C virus: HCC is rare in absence of cirrhosis because HCV lacks direct carcinogenic role

Prognostic factors
=========================================================================

● 5 year survival: 10% overall to 50% in tumors <=5 cm with resection; death usually within 1 year from cachexia, GI bleeding, liver failure or rupture of tumor
Favorable: low stage, encapsulation, single lesion, tumor size < 5 cm, fibrolamellar variant, no cirrhosis, no vascular invasion and 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: microscopic vascular invasion, high nuclear grade (grade 3 of 3)
Factors that are not prognostic: age, gender and HBV status

Clinical features
=========================================================================

Symptoms: abdominal pain, ascites, hepatomegaly and obstructive jaundice; also systemic manifestations
Laboratory: elevated serum AFP (70% sensitive); AFP sensitivity reduced in alcohol-related cirrhosis (65% sensitive), tumors arising in non-cirrhotic liver (33% sensitive), tumors 2 cm or less (25% sensitive)
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; des-gamma-carboxy prothrombin (DCP / protein induced by vitamin K absence or antagonist-II / PIVKAII): more specific than serum AFP and poor prognostic marker; abnormal prothrombin produced by HCC, associated with early portal vein invasion, intrahepatic metastasis and capsular infiltration
Other causes of elevated serum AFP: chronic hepatitis, cirrhosis, fetal death, fetal neural tube defect, fetal distress, hepatoblastoma, hepatoid adenocarcinoma, massive liver necrosis, normal pregnancy, yolk sac tumors of gonads
Metastases: initially within liver, distant metastases late to adrenal gland, bone, lung, porta hepatis lymph nodes
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 / transarterial chemoembolization (causes ongoing necrosis, Mod Pathol 2002;15:110); if present, indicate degree of ablation and grade residual viable tumor

Case reports
=========================================================================

● 22 year old woman with focal hepatic glycogenosis after 6 years of azathioprine therapy (Hum Pathol 2000;31:874)
● 48 year old man with lymphangitis carcinomatosis in lung (Arch Pathol Lab Med 2003;127:e11)

Gross description
=========================================================================

● 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 (< 1%), usually on posterior and inferior surfaces of right lobe
● Liver usually cirrhotic, often enlarged

Gross images
=========================================================================



Various images


Involvement of inferior vena cava and other large vessels

Micro description
=========================================================================

● Patterns are trabecular (most common) with 4+ cells surrounded by layer of flattened endothelial cells; also clear cell, giant cell, pelioid (vascular lakes), pseudoglandular (acinar with proteinaceous material or bile in lumina, may resemble thyroid follicles), sarcomatoid, solid (compact)
● Presence of sinusoidal vessels surrounding tumor cells is an important diagnostic feature
● Scanty stroma, from well-differentiated to bizarre (often within same tumor)
● Cells are polygonal with distinct cell membranes, abundant granular eosinophilic cytoplasm, higher N/C ratio than normal, round nuclei with coarse chromatin and thickened nuclear membrane; may have prominent nucleoli
● Common features are portal vein thrombosis, vascular invasion, mitotic figures
● Variable: abundant fat, bile (5-33%), bile canaliculi, copper, intracellular hyaline bodies (round or oval homogeneous eosinophilic hyaline bodies with surrounding halo containing p62, 9%), intranuclear pseudoinclusions, Mallory’s hyaline (Mallory Denk bodies, 2-25%), no central veins, pale bodies consisting of fibrinogen mimicking HBsAg-containing ground-glass change (6%); rarely is undifferentiated
● Minimal desmoplasia

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 and 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

Combined hepatocellular-cholangiocarcinoma: <1% of primary liver carcinomas; unequivocal hepatocellular and cholangiocarcinoma that are intimately admixed (World J Gastroenterol 2009;15:3940); increased CA19-9 and AFP; controversy regarding behavior

Diffuse cirrhosis like HCC: diffuse and extensive liver involvement by small cirrhosis-like nodules that evade clinical and radiographic detection (Am J Surg Pathol 2010;34:935); small number of reported cases

Steatohepatitic HCC: recently described variant associated with metabolic dysfunction such as non-alcoholic fatty liver disease (Hum Pathol 2012;43:737, Am J Surg Pathol 2010;34:1630); slightly firmer than classic HCC (due to fibrosis) and more yellow (due to steatosis); histology shows steatosis, hepatocyte ballooning, Mallory Denk Bodies, inflammation and pericellular fibrosis within neoplastic tissue

Micro images
=========================================================================



Left to right: trabecular, pseudoglandular and acinar, trabecular and pseudoglandular patterns

                 
Smaller tumor cells   Thick cords without    Vascular invasion      Liver tumor and vascular
infiltrate normal     lobules                      invasion in lung
hepatocytes

           
H&E and HepPar1   pCEA           AFP           H&E and CD10

                    
pCEA in hepatocellular carcinoma         Post radiofrequency ablation
vs. cholangiocarcinoma

                
Acinar (pseudoalveolar) pattern        Solid pattern with loss of cell
resembling cholangiocarcinoma         plate architecture (reticulin stain)

                
Adenocarcinoma staining             MOC31 in hepatocellular
with MOC31, pCEA and CD10         carcinoma vs. cholangiocarcinoma

Positive stains
=========================================================================

● Must differentiate trapped normal hepatocytes from tumor cells when interpreting 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); also albumin mRNA ISH, alpha-1-antitrypsin (55-93%), CAM 5.2 (CK 8/18), CD10 (52%), CEA-Gold 5 (76%), copper (7-41%), transferrin
● 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

● Recommended panels:
(a) To differentiate from metastatic carcinoma: Arginase1+, HepPar1+, and Glypican3+ (Am J Clin Pathol 2012;138:203)
(b) To differentiate from nonmalignant lesions: positivity for 2 of 3: Glypican-3/GPC-3 (cytoplasmic and canalicular), HSP-70 and Glutamine synthetase (Hepatology 2007;45:725, J Hepatol 2009;50:746); adding clathrin heavy chain may be helpful (Hepatology 2011;53:1549)
(c) To differentiate from nonmalignant lesions: GPC-3 plus CD34 complete staining pattern (Am J Surg Pathol 2008;32:433)

Negative stains
=========================================================================

● Keratins: AE1-AE3, CK7 (positive in 20%), CK13, CK19 (positive in <10%, if positive, marker of adverse prognosis, Histopathology 2006;49:138), CK20, keratin903 (> 90%)
● EMA, monoclonal CEA (positive in 0-10%), CD15, mucin (mucicarmine), MOC31 and BerEP4

Molecular description
=========================================================================

● 50-92% hyperploid or aneuploid

Electron microscopy description
=========================================================================

● Numerous mitochondria, microbodies and abundant glycogen
● Intracytoplasmic bile products (bile canaliculi, peroxisomes)

Differential diagnosis
=========================================================================

Adenoma / macroregenerative nodule (difficult if small sample): no cirrhosis in adenoma, not trabecular, no extensive pseudoglandular growth pattern, different clinical history, reticulin framework slightly maintained, minimal atypia, no mitotic figures; no thick fibrous pseudocapsule; negative for GPC-3 and AFP
Angiomyolipoma, epithelioid: spindle cell component, thick walled vessels, HMB45+, actin+, CK-
Focal nodular hyperplasia: no cytologic atypia, no ductular reaction, arteries are abnormally structured; note that "focal nodular hyperplasia-like nodules" may be present in cirrhotic livers and mimic HCC on imaging

Metastatic tumors or contiguous spread:
● Adenocarcinoma (hepatoid) from stomach or lung: no cirrhosis; CK7+, CK19+, CK20+, TTF1+ (lung), CDX-2+ (colorectal); HepPar1-
● Adenocarcinoma (poorly differentiated) or cholangiocarcinoma: desmoplastic stroma, mucin+, CK7+, CK19+
● Breast: CK7+, ER+, GCDFP15+, Mammaglobin+
● Melanoma
● Neuroendocrine tumors from pancreas or small bowel: no cirrhosis; similar trabecular pattern but smaller cells, inconspicuous nucleoli, stippled chromatin, CK7+, CDX2+ (small bowel)
● Ovarian carcinomas: CK7+, ER+, WT1+
● Prostate: PSA+, PAP+
● Renal cell carcinoma: PAX2+, HepPar1-, RCC+; make sure biopsy is NOT from renal mass
● Thyroid: CK7+, TTF1+, thyroglobulin+



Hepatocellular carcinoma

Cytology


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 90% sensitive and specific for hepatocellular carcinoma
● Cell blocks helpful for obtaining stains (reticulin stain shows no framework)
● False positives due to regenerative nodules
● False negatives in well-differentiated tumors
● Complications: tumor may track along needle path (Korean J Hepatol 2011;17:106)

Cytology description
=========================================================================

● Gross inspection of the hypercellular smears reveals trails of particulate tissue imparting a granular pattern of spread
● Granules consist of cohesive clusters of malignant hepatocytes with arborizing, tongue-like projections of broad cords wrapped by peripheral endothelium
● Rows of transgressing endothelium are accompanied by basement membrane material, resembling pink "tram-lines"
● Polygonal tumor cells with abundant eosinophilic cytoplasm, central hyperchromatic nuclei or variable prominent nucleoli, malignant cells separated by sinusoidal epithelial cells, increased nuclear to cytoplasmic ratio, trabecular pattern and atypical naked nuclei
● 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)
● Variable rosettes or acini (pseudoglandular pattern), tumor giant cells, malignant spindle cells; also variable bile, hyaline globules, Mallory’s hyaline and cytoplasmic vacuoles

Cytology images
=========================================================================



Left to right: well, moderately and poorly differentiated HCC


Various images


Breast mass representing metastatic disease

Differential diagnosis
=========================================================================

● Reactive hepatocytes: finely granular chromatin, cells maintain cohesion (Arch Pathol Lab Med 2002;126:670)
Focal nodular hyperplasia
Hepatic adenoma



Hepatocellular carcinoma

Clear cell variant


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Predominant appearance of neoplastic hepatocytes with abundant clear cytoplasm
● Predominant in 5-16% of cases, but some clear cells present in 20-40% of cases
● Clear cytoplasm is due to cytoplasmic fat or glycogen
● May need to hunt for typical hepatocellular carcinoma to rule out metastatic tumor

Clinical features
=========================================================================

● Elevated serum AFP (92%), may have hypoglycemia or hypercholesterolemia
● Similar prognosis as classic hepatocellular carcinoma (World J Gastroenterol 2010;16:764)

Micro description
=========================================================================

● Trabecular, pseudoacinar, solid or mixed patterns of large number of neoplastic hepatocytes with abundant clear cytoplasm (glycogen or lipid) and round nuclei
● May have bland nuclear features
● May have intracytoplasmic bile (5-33%)
● Usually no intratumoral fibrosis except in areas of hemorrhage and necrosis
● Must distinguish from HCC variant with foamy histiocytes (Case Rep Gastroenterol 2010;4:286)

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 and pan-keratin


Various images

Positive stains
=========================================================================

● Polyclonal CEA (canalicular pattern, 63%), HepPar1 (82-97%, Mod Pathol 2000;13:874)
● ISH for albumin mRNA (93%, Am J Surg Pathol 2000;24:177)
● Ubiquitin (for Mallory bodies)

Negative stains
=========================================================================

● EMA and LeuM1 (positive in clear cell renal cell carcinoma)

Differential diagnosis
=========================================================================

● Metastatic renal (PAX2+, EMA+), adrenal (inhibin+, MelanA+, calretinin+) or ovarian carcinoma: no classic hepatocellular carcinoma present
● Balloon cell melanoma: S100+, HMB45+, MelanA+, HepPar1-, pCEA-
● Clear cell neuroendocrine tumors: chromogranin+, synaptophysin+, MOC31+
Epithelioid angiomyolipoma: HMB45+, SMA+



Hepatocellular carcinoma

Fibrolamellar variant


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Common variant in young adults 20-40 years with better prognosis than classic HCC, characterized by well-differentiated oncocytic cells in background of dense acellular collagen bundles
● Some consider a distinct entity due to different clinical and histologic features (eMedicine) ● Etiology unknown, but not associated with cirrhosis

Clinical features
=========================================================================

● <10% of HCC, but 35% of patients <50 years old; no gender preference
● Similar symptoms to classic HCC
● Rarely associated with gynecomastia and Budd-Chiari syndrome
● Not associated with hepatitis B virus, cirrhosis or metabolic abnormalities
● 5 year survival is 60-75%, better than classic hepatocellular carcinoma (Cancer 2006;106:1331)
● Metastasizes to abdominal lymph nodes, peritoneum and 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

Case reports
=========================================================================

● 14 year old girl with tumor developing 5 years after hepatocellular adenoma (Arch Pathol Lab Med 2004;128:222)
● 18 year old man with large abdominal mass (Case of the Week #161)
● 27 year old woman with central HCC within fibrolamellar HCC (Hum Pathol 2002;33:765)

Treatment
=========================================================================

● Aggressive surgery (Am J Gastroenterol 2009;104:2617)
● Early detection of relapse with multimodality therapy improves survival (Eur J Surg Oncol 2009;35:617)

Gross description
=========================================================================

● Single (75%), large (mean 13 cm), hard, scirrhous, well-circumscribed, bulging, white-brown tumor with fibrous bands throughout and central stellate scar
● Only liver tumor that is more common in left lobe, but may involve both lobes
● Variable bile staining, hemorrhage and necrosis

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Nests, sheets or cords of well-differentiated oncocytic cells in background of dense, acellular collagen bundles arranged in parallel lamellae that may contain small, thick-walled vessels
● Cells are large and polygonal with well-defined cell borders, abundant granular and eosinophilic cytoplasm due to abundant mitochondria, often pale bodies (ground glass cells) or PAS+ hyaline globules, vesicular nuclei and 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
● Variable: focal nuclear pleomorphism, conventional hepatocellular carcinoma, trabecular, adenoid or pelioid patterns

Micro images
=========================================================================





Various images

       
Various images

           
Pale bodies      Trichrome        CK7           CK20

           
HepPar        Ki67           pCEA           Vimentin

Cytology description
=========================================================================

● Discohesive cells with inconspicuous strands of collagen; may contain bile

Cytology images
=========================================================================



Various images

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 and CAM 5.2 (CK 8/18)

Negative stains
=========================================================================

● Mucin (if present, call combined hepatocellular carcinoma-cholangiocarcinoma), alpha fetoprotein

Molecular description
=========================================================================

● Often diploid
● Overall fewer chromosomal abnormalities than classic HCC; tumors with no cytogenetic changes amay be less aggressively (Mod Pathol 2009;22:134)

Electron microscopy description
=========================================================================

● 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

Differential diagnosis
=========================================================================

Adenosquamous carcinoma with sclerosis
Cholangiocarcinoma: glandular, mucin+
Focal nodular hyperplasia: usually 5 cm or less, fibrous stroma contains bile ductules and inflammatory cells, no bile staining grossly and no hepatocyte atypia
Hepatocellular carcinoma, sclerosing variant: no oncocytes, smaller tumor cells, pseudoglandular pattern common
Metastatic carcinoma with sclerotic stroma
Other neuroendocrine tumors
Paraganglioma: may have nesting pattern at biopsy, round nuclei without atypia, vascular stroma but typically no dense fibrosis and positive for neuroendocrine markers (Am J Surg Pathol 2002;26:945)


Clear cell variant of fibrolamellar carcinoma

General
=========================================================================

Case reports: 59 year old woman with clear cells apparently due to ballooning and rarefactive changes of mitochondria (Arch Pathol Lab Med 2001;125:1235)

Gross images
=========================================================================



Well circumscribed tumor

Micro images
=========================================================================


               
Classic fibrolamellar foci and clear cell foci   Antimitochondrial antibody stain

Electron microscopy images
=========================================================================



Distended membrane bound vesicles represent dilated mitochondria



Hepatocellular carcinoma

Oncocytic variant of hepatocellular carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Oncocytes predominate without fibrous stroma of fibrolamellar variant
● Cytoplasm is intensely eosinophilic with coarse granules
● Oncocytes are present in fibrolamellar variant and occasionally in classic hepatocellular carcinoma

Cytology images
=========================================================================



Oncocytic hepatocytes of fibrolamellar hepatocellular carcinoma (for reference)



Hepatocellular carcinoma

Pleomorphic (giant cell) variant of hepatocellular carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update September 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● < 1% of all hepatocellular carcinomas, although 15% have some tumor giant cells
● Multinucleated tumor giant cells predominate, marked loss of cell cohesion (Am J Clin Pathol 1990;93:111)

Case reports
=========================================================================

● Infant with syncytial giant cell variant (Ann Diagn Pathol 2007;11:61)
● 50 year old man presenting with atrial metastasis (Indian J Pathol Microbiol 2011;54:632)

Gross images
=========================================================================



Multifocal gray tumor nodules in cirrhotic liver

Micro images
=========================================================================



Pleomorphic tumor giant cells in background of cirrhosis


Pleomorphic tumor giant cells



Hepatocellular carcinoma

Sarcomatoid variant of hepatocellular carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called spindle cell hepatocellular carcinoma, pseudosarcomatous
● Diffuse collection of spindle cells resembling fibrosarcoma or malignant fibrous histiocytoma, but with classic hepatocellular carcinoma is also present
● Note: 1-9% of all hepatocellular carcinomas have prominent sarcomatoid pattern

Clinical features
=========================================================================

● Mean age 62 years old, range 46-84 years, usually men
● Metastases common, often to lung and lymph nodes
● Most patients die of disease

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● 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, chondroid differentiation (Pathol Int 2000;50:919)

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● Cytokeratin (60%), alpha fetoprotein
● Variable HHF35, smooth muscle actin, desmin, CD68 and S100

Differential diagnosis
=========================================================================

● Collision tumor
● Carcinoma with foci of spindle shaped epithelial cells



Hepatocellular carcinoma

Sclerosing variant


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Variant with fibrous septa separating trabecular cell plates, but no lamellar fibrosis
● Also called scirrhous carcinoma
● May not be a distinct histopathologic entity

Clinical features
=========================================================================

● 1-4% of all hepatocellular carcinoma
● Associated with hypercalcemia and hypophosphatemia, but not with bone metastases
● Better prognosis (Hepatogastroenterology 2009;56:1086)

Gross description
=========================================================================

● Single, subcapsular, unencapsulated, large, lobulated, 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 and usually no cirrhosis
● Cirrhosis usually similar to classic HCC

Micro description
=========================================================================

● 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, are smaller, lack vesicular nuclei and prominent nucleoli and have less abundant and granular cytoplasm
● No apparent endothelial sinusoidal cells

Positive stains
=========================================================================

● AFP

Negative stains
=========================================================================

● Mucin

Differential diagnosis
=========================================================================

Cholangiocarcinoma: similar if neoplastic cells arranged as narrow tubular structures resembling bile ductules
Metastatic carcinoma of pancreas: usually less dense sclerosis
Fibrolamellar variant: less diffuse fibrosis; has radiating fibrous bands, central scar, lamellar fibrosis, usually no cirrhosis
Epithelioid hemangioendothelioma: CD34+, factor VIII+, mucin-
Post-chemoradiation therapy



Hepatocellular carcinoma

Small hepatocellular carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 27 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Defined as tumor less than 2 cm
● Detected by screening of patients with chronic liver disease

Clinical features
=========================================================================

● May have normal serum AFP
● Good prognosis
● Two types: (a) gross and histologic features similar to classic HCC (small HCC of distinct nodular type), (b) "early HCC", well-differentiated with indistinct margins (vaguely nodular type)
● Early HCC is distinguished from dysplastic nodule by stromal invasion, absence of ductular reaction, and panel of HSP70, Glypican 3 and Glutamine Synthetase (72% sensitive, 100% specific for early HCC if at least 2 markers are positive, Hepatology 2007;45:725); inclusion of clathrin heavy chain (CHC) improves diagnostic accuracy (Gut 2012;61:10)
● Radiologically, early HCC is hypovascular, isovascular or very rarely hypervascular

Gross description
=========================================================================

● Vaguely nodular type: either not 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

Gross images
=========================================================================



Early HCC

Micro description
=========================================================================

● Usually well-differentiated morphology with irregular thin trabeculae 2-3 cells thick
● Nuclear density is 2x normal, mild but definite nuclear atypia (hyperchromasia, irregular nuclear borders)
● Unpaired arteries present; no substantial paucity of reticulin fibers
● Enlarging nodules have less differentiated foci centrally
● 40% have fatty or clear cell change, often with Mallory bodies
● May invade stroma or portal tract, but vascular invasion and intrahepatic metastases are rare

Micro images
=========================================================================



Early HCC

   
Associated with Hepatitis C



Leukemia / lymphoma

Leukemia


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

Gross description
=========================================================================

● Usually hepatomegaly, but no discrete nodules except for SLL / CLL
● Lymphoblastic lymphoma only rarely presents in liver with no involvement of blood or marrow

Acute T/B cell leukemia / lymphoma
=========================================================================

Micro: pleomorphic lymphocytes, sinusoidal pattern of infiltration with less hepatocellular injury

Acute myeloid leukemia
=========================================================================

Case reports: erythroleukemia (AML-M6) in newborn with hepatic failure (Arch Pathol Lab Med 2003;127:1362)
Positive stains: myeloperoxidase, Leder stain


Erythroleukemic blasts

Chronic lymphoblastic leukemia
=========================================================================

● Liver involvement common
Micro: periportal infiltrate of monomorphic small lymphocytes with minimal cytoplasm

Chronic myelogenous leukemia
=========================================================================

● Liver involvement common (50%)
Micro: sinusoidal infiltrate of various myeloid precursors
● Resembles surgical hepatitis (margination reaction of neutrophils in liver sinusoids related to prolonged surgery)

Hairy cell leukemia
=========================================================================

● Hepatomegaly in up to 1/3
● Associated with pancytopenia
Micro: portal and sinusoidal infiltration, clear cytoplasm, round / reniform nuclei, appears as “beads on a string” along sinusoids; may have angiomatous spaces (World J Gastroenterol 2009;15:4453)
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



Leukemia / lymphoma

Lymphoma-general


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● 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



Leukemia / lymphoma

Lymphoma-primary


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare; ~ 100 cases reported; <1% of all extranodal lymphomas, 0.01% of non-Hodgkin lymphoma (Cancer 1972;29:252)
● Clinical disease due mainly to liver involvement, without systemic disease or distal lymphadenopathy
● 75% men, median age 55 years but all ages
● Symptoms: abdominal pain and hepatomegaly; may present with liver failure; associated with cirrhosis, immunocompromise
● Also associated with HBV (3% - 30%, Jpn J Cancer Res 2002;93:471), HCV (40%–60%, Clin Lymphoma Myeloma 2006;6:273) and EBV
● Pathogenesis of HCV-associated lymphoma involves chronic antigen stimulation of B-cell populations (J Clin Pathol 2007;60:1378)
● Most common subtype is diffuse large B cell lymphoma
● Two year survival of 66%; poor survival if cirrhosis or immunocompromise

Gross description
=========================================================================

● Large mass or multiple masses (30-35%) resembling carcinoma
● Variable hemorrhagic and necrosis

Micro description
=========================================================================

● May have diffuse sinusoidal infiltration

Differential diagnosis
=========================================================================

● Carcinoma: primary or metastatic
● CMV or EBV: need serology or stains to confirm
● Granulomas
● Hepatitis: polymorphic infiltrates with minimal atypia
● Inflammatory myofibroblastic tumor
● Primary biliary cirrhosis
● Venous outflow obstruction



Leukemia / lymphoma

Lymphoma-secondary


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Most hepatic lymphomas are secondary; 15% of staging biopsies are positive in liver; disease is usually disseminated with incidental hepatic involvement
● Most common hepatic lymphomas (primary or secondary) are diffuse large B cell (65%), peripheral NK/T cell (10%, but 50% of these cases at all sites have liver involvement), follicular (5%), MALT (2%)
● Also hepatosplenic T cell lymphoma, associated with splenic involvement, disseminated disease and incipient hepatic failure



Leukemia / lymphoma

Burkitt’s lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

Case reports
=========================================================================

● In children, only rarely reported (J Pediatr Hematol Oncol 2011;33:e368)
● Four men and one woman with mean age of 35 years, tumor arising post-transplant (Am J Surg Pathol 2003;27:818)



Leukemia / lymphoma

CLL/SLL


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2012, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● 78 year old woman with acute liver failure (Curr Oncol 2011;18:39)

Micro images
=========================================================================



Various images



Leukemia / lymphoma

Diffuse large B cell lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

General
=========================================================================

● Most common non Hodgkin lymphoma of liver (Leuk Lymphoma 1998;29:293)

Case reports
=========================================================================

● 56 year old man with intravascular lymphomatosis affecting liver, omentum and bone marrow (Arch Pathol Lab Med 1999;123:952)
● 67 year old man (Hepat Mon 2011;11:203)
● 70 year old man whose tumor has spindle cell component (Virchows Arch 2006;449:591)

Gross description
=========================================================================

● Bulky tan-white mass

Micro images
=========================================================================



Various images


Associated with Hepatitis C

Differential diagnosis
=========================================================================

Age-related EBV-associated B-cell lymphoproliferative disorders
Follicular lymphoma, high grade: usually some classic follicular lymphoma component present, t(14;18)+; CD10+
Mantle cell lymphoma, blastoid variant: CD5+, CyclinD1+
Plasmablastic lymphoma: HIV+, immunoblastic morphology



Leukemia / lymphoma

Follicular lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

General
=========================================================================

● 1-4% of primary hepatic lymphomas

Case reports
=========================================================================

● 65 year old woman (J Clin Exp Hematop 2007;47:73)

Gross description
=========================================================================

● Diffuse pattern of miliary nodules

Micro images
=========================================================================



Primary follicular lymphoma of extrahepatic bile duct



Leukemia / lymphoma

Hepatosplenic alpha beta T cell lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 20 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● May be clinical variant of gamma-delta T cell lymphoma, but less common (Am J Surg Pathol 2001;25:285)
● Associated with thrombocytopenia, anemia, hepatosplenomegaly, B symptoms, but usually no lymphadenopathy
● Mean age 36 years old, but wide range; female preponderance
● Aggressive clinical course leading to death

Case reports
=========================================================================

● 12 year old boy with hepatosplenomegaly, anemia and thrombocytopenia (Am J Surg Pathol 2001;25:970)
● 16 year old boy with jaundice, splenomegaly, anemia, thrombocytopenia (Am J Surg Pathol 2000;24:459)
● 20 year old man with hepatosplenomegaly, mild anemia and thrombocytopenia (Am J Surg Pathol 2000;24:1027)
● 20 year old woman with S100+ lymphoma (Arch Pathol Lab Med 2003;127:e119)

Micro description
=========================================================================

● Sinusoidal lymphoid infiltrate within liver, splenic red pulp and bone marrow of small-medium sized atypical lymphoid cells with scant / moderate cytoplasm, round / oval nuclei, slightly dispersed chromatin and indistinct nucleoli
● Marked periportal infiltrates in CD57+ cases

Micro images
=========================================================================



H&E, CD45RO and S100

Positive stains
=========================================================================

● CD2, CD3, CD8 (61%), CD16 (44%), CD45RO, CD57 (40%), TIA1, reticulin and T cell receptor alpha-beta chains

Negative stains
=========================================================================

● CD4, CD5

Molecular description
=========================================================================

● Isochromosome 7q



Leukemia / lymphoma

Hepatosplenic gamma-delta T cell lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 20 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, < 100 cases reported
● Usually young or middle aged men with massive hepatosplenomegaly and elevated liver function tests, B symptoms (fever, night sweats, weight loss) but no significant nodal involvement, pancytopenia, aggressive clinical course (median survival 8 months)
● Refractory to chemotherapy
● Often occurs after solid organ transplantation, but reduction in immunosuppression does not affect clinical course in Crohn’s disease patients

Case reports
=========================================================================

● 45 year old man with leukemic disease 5 years after renal transplant and continous immunosuppression with cyclosporine A and prednisolone (Hum Pathol 2002;33:253)

Micro description
=========================================================================

● Sinusoidal lymphoid infiltrate of liver (3+ lymphocytes fill / expand sinusoid), 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 and T cell receptor gamma-delta chains

Negative stains
=========================================================================

● CD4, CD5, CD8, CD57, T cell receptor alpha-beta chain and EBV

Molecular description
=========================================================================

● Isochromosome 7q (i7q10 in 2/3), trisomy 8 and Y-

Differential diagnosis
=========================================================================

CMV and EBV have sinusoidal infiltrate but less bulky portal inflammation, hepatocyte ballooning, lobular disarray, higher levels of transaminases
Drug related hepatitis



Leukemia / lymphoma

Hodgkin lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 20 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Liver involvement found in 55% of Hodgkin patients at autopsy and 5-10% at liver biopsy
● Rare in classical Hodgkin lymphoma unless extensive involvement of lymph nodes and spleen; most common in lymphocyte depleted and mixed cellularity subtypes

Gross description
=========================================================================

● Either diffuse miliary nodules or bulky, tan-white masses

Micro description
=========================================================================

● Atypical mononuclear cells with prominent nucleoli present in portal tracts; background of polymorphous inflammatory infiltrate
● Epithelioid cell granulomas in 8–12%
● May see vanishing bile duct syndrome with ductule proliferation
● Reed-Sternberg cells are rare
● Granulomatous hepatitis may precede clinical expression of Hodgkin lymphoma

Micro images
=========================================================================



Left: numerous eosinophils and rare Reed-Sternberg cells; right: CD30+ R-S cells

Positive stains
=========================================================================

● CD15, CD30, PAX5, OCT2 , BOB1

Differential diagnosis
=========================================================================

● Abscess
Inflammatory myofibroblastic tumor
● Dendritic cell tumor: CD21+, CD35+



Leukemia / lymphoma

Lymphoplasmacytic lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

General
=========================================================================

● Most cases are Waldenstorm macroglobulinemia (IgM hypergammaglobulinemia), rarely IgA (J Med Assoc Thai 2009;92 Suppl 3:S65)
● Waldenstrom’s macroglobulinemia is most commonly associated with lymphoplasmacytic lymphoma, but can rarely occur with other types of B cell lymphoma (Am J Surg Pathol 2003;27:1104)

Case report
=========================================================================

● 72 year old man with peliosis hepatis (Arch Pathol Lab Med 2004;128:1283)

Micro description
=========================================================================

● Portal tracts and sinusoids markedly expanded by small, plasmacytoid lymphocytes

Micro images
=========================================================================



Various images



Leukemia / lymphoma

Mucosal associated lymphoid tissue (MALT) lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

General
=========================================================================

● Rare, <50 cases reported; represents 3% of cases of hepatic lymphoma (Int J Hematol 2008;88:418)
● Mean age 60 years, slight female predominance
● Occasionally associated with liver cirrhosis, primary biliary cirrhosis, Hepatitis B and Hepatitis C infection

Treatment
=========================================================================

● Local excision; tumor is indolent

Case reports
=========================================================================

● 57 year old woman with primary biliary cirrhosis (Arch Pathol Lab Med 2000;124:604)
● 69 year old woman (Arch Pathol Lab Med 1999;123:716)
● 75 year old woman post lumpectomy and radiation therapy for invasive ductal carcinoma of breast (Case of the Week #260)

Clinical images
=========================================================================



Solitary or multiple tan, subcapsular nodule


CT scan of Case of Week #260

Micro description
=========================================================================

● Extensive diffuse sheets of small B-cells in the interfollicular areas
● Centrocyte-like cells surround reactive B cell follicles and form lymphoepithelial lesions with bile ducts (Am J Surg Pathol 1995;19:571, Mod Pathol 1998;11:404)
● May arise in settings of chronic inflammation including viral hepatitis
● Note: reactive follicles and lymphoepithelial lesions are non specific

Micro images
=========================================================================


Case of Week #260



Top row: H&E; bottom row: (left to right): CD20, bcl2, Ki-67


Left to right: negative for CD5, CD10, Cyclin D1 (staining of non-MALT cells only)

   
Entrapping bile ducts   CD20


Atypical lymphocytes entrapping islands of hepatocytes


Various images

Cytology images
=========================================================================



Case of Week #260 - fine needle aspirate

Molecular description
=========================================================================

● t(11;18)(q21;q21), t(1;14)(p22;q23), t(14;18)(q32;q21), 37 and t(3;14)(p14.1;q32)

Differential diagnosis
=========================================================================

Reactive lymphoid hyperplasia: not clonal, T cells predominate in interfollicular areas
Inflammatory myofibroblastic tumor: no diffuse sheets of extrafollicular B-cells, no evidence of B cell clonality
Lymphoplasmacytic lymphoma: high levels of serum IgM paraprotein; cryoglobulinemia
Post-transplant lymphoproliferative disease: history of transplantation and frequent EBV positivity



Leukemia / lymphoma

Nodal CD8+ cytotoxic peripheral T-cell lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

General
=========================================================================

● Most peripheral T-cell lymphomas are CD4+; CD8+ tumors are rare
● Associated with disseminated intravascular coagulation (DIC) and hemophagocytic syndrome
● Poor prognosis
Sites: lymph node (all), liver, bone marrow and CNS

Case reports
=========================================================================

● Four men and seven women aged 5 to 82 years (Mod Pathol 2002;15:1131)

Micro description
=========================================================================

● Neoplastic cells (small to large) with irregular / elongated nucleus with dense chromatin and indistinct nucleoli; also macrophages containing necrotic material

Micro images
=========================================================================



Large cells and small cleaved cells


CD8         Perforin       Granzyme B    TIA1

Positive stains
=========================================================================

● CD3, CD8, perforin, TIA1 and granzyme B



Leukemia / lymphoma

Splenic marginal zone lymphoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 29 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

See also Lymphoma and plasma cell neoplasms chapter

General
=========================================================================

● Liver is often involved (Am J Surg Pathol 2000;24:1581)

Micro description
=========================================================================

● Diffuse infiltration of portal spaces by medium-sized, monocytoid B cells and smaller centrocyte-like cells
● Occasional sinusoidal infiltration by small lymphocytes

Micro images
=========================================================================



Various images



Other malignancies

Angiosarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare (10-30 annual cases in US), but most common hepatic primary sarcoma in adults (2% of all primary liver tumors)

Causes
=========================================================================

● 25-42% associated with exposure to androgen steroids, arsenic, Thorotrast (radiocontrast agent thorium dioxide, used through 1950's, detect its α particle emissions via autoradiography), vinyl chloride
● Patients with exposure to Thorotrast or vinyl chloride may have synchronous cholangiocarcinoma or hepatocellular carcinoma
● Rarely associated with chemotherapy, copper sulfate, estrogens, hereditary hemochromatosis, phenelzine, radiotherapy
● Cases with above known causes 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

Clinical features
=========================================================================

● 75% men, usually age 50+ years; rare in children
● Non-operative biopsy may cause severe bleeding and death
● Most patients die within 6 months from hepatic failure or intraabdominal bleeding
● Metastasizes widely, often to lung (vinyl chloride cases usually don't have distant metastases)

Case reports
=========================================================================

● 71 year old man with metastatic hepatic epithelioid angiosarcoma (Arch Pathol Lab Med 2001;125:968)

Gross description
=========================================================================

● 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

Gross images
=========================================================================



Vascular lesion with dense fibrosis


White-tan mass with red-brown foci and several blood-filled spaces

Micro description
=========================================================================

● 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
● Precursor stage has endothelial hypertrophy and hyperplasia
● 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 and 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
=========================================================================



Various images


FNA and H&E


FNA, AE1 / AE3, pleomorphic epithelial cells in sinusoidal pattern and CD31

Positive stains
=========================================================================

● CD34, CD31, factor VIII related antigen and Ulex europaeus lectin type 1 (may not be present in poorly vasoformative areas)
● Also Prox-1 (reflect the lymphatic endothelial phenotype), Claudin-5

Negative stains
=========================================================================

● Keratin (but positive in 12-35%)

Molecular description
=========================================================================

● 50% of vinyl chloride associated cases have A:T to T:A transversion in p53

Electron microscopy description
=========================================================================

● Weibel-Palade bodies

Differential diagnosis
=========================================================================

Epithelioid hemangioendothelioma: less atypia, less mitotic activity, less necrosis, often prominent fibrous and hyalinized stroma
Fibrosarcoma: very rare; not particularly vascular; CD31 negative
Hepatocellular carcinoma: atypical hepatocytes, normal endothelial cells
Kaposi’s sarcoma: HIV+, have extrahepatic nodules, portal distribution and lack angiosarcomatous foci
Peliosis hepatis
Reactive bile ductule proliferation, reactive lymphoid hyperplasia: reactive, lack atypical endothelial lining cells



Other malignancies

Biliary cystadenocarcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare cystic neoplasm of biliary origin; <100 cases reported; < 5% of all intrahepatic tumors
● Cysts represent dilated intrahepatic bile ducts invaded by tumor cells with a colloid carcinoma-like pattern, such as IPMN of pancreas
● May be associated with intraductal oncocytic papillary neoplasm

Clinical features
=========================================================================

● 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 have intraabdominal dissemination as terminal event
● Clinical differentiation from cystadenoma: older age, male gender, shorter symptom duration are suggestive of biliary cystadenocarcinoma
● 50% survival at 4 years, better prognosis if spindle-cell stroma

Radiology images
=========================================================================



MRI: multiple cysts and solid lesion

Case reports
=========================================================================

● 43 year old woman with tumor exhibiting oncocytic differentiation (Arch Pathol Lab Med 2004;128:e25)
● 71 year old man with multiple tumors resembling oncocytes (Mod Pathol 2001;14:1304)

Gross description
=========================================================================

● 5-20 cm cysts, may have blood tinged fluid, solid areas and large papillary masses

Gross images
=========================================================================



Multiple cysts and solid lesion

Micro description
=========================================================================

● 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 (not found in men); extensive stromal and hepatic parenchymal invasion; woman also have features of cystadenoma
● Rarely adenosquamous, hepatoid or oncocyte-like features; malignant diagnosis is based on stromal invasion

Micro images
=========================================================================



Oncocytic tumor


Papillary oncocytic tumor within fibrous cyst wall


Various images

Positive stains
=========================================================================

● CK7, AE1/AE3, HepPar1; variable CEA and C19-9

Negative stains
=========================================================================

● CK20, mucin, AFP, calretinin, CD31 and chromogranin

Electron microscopy description
=========================================================================

● Numerous mitochondria

Differential diagnosis
=========================================================================

● Metastases from pancreas, ovary and appendix



Other malignancies

Carcinoid tumor


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 31 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Well-differentiated neuroendocrine tumor
● Very rare as primary hepatic tumor (<100 cases reported); usually represents metastasis from GI tumor (small intestinal primaries may be very small)
● Slightly more frequent in females
● 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 (Arch Pathol Lab Med 2003;127:1200)

Case reports
=========================================================================

● 51 year old man with Zollinger Ellison syndrome (Cases J 2009;2:6346)
● 62 year old woman (World J Surg Oncol 2008;6:91)

Treatment
=========================================================================

● Surgical resection

Gross images
=========================================================================



62 year old woman with tan gray tumor that has soft, fish-flesh cut surface

Micro description
=========================================================================

● Nested, trabecular or microacinar architecture
● Composed of small, uniform tumor cells with granular chromatin and round nuclei
● Often stromal hyalinization

Micro images
=========================================================================



62 year old woman with primary hepatic carcinoid tumor


Primary liver tumor in patient with ZE syndrome


Liver metastases from colon primary


A/B: liver metastases from lung primary



Other malignancies

Carcinosarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● Malignant tumor containing intimate mixture of carcinomatous (either hepatocellular carcinoma or cholangiocellular carcinoma) and sarcomatous elements; sarcomatous component may be chondrosarcomatous, fibrosarcoma, leiomyosarcomatous, osteosarcoma, rhabdomyosarcoma, undifferentiated (WHO)
● Also called "malignant mixed tumor"
● Predominantly older men
● Risk factors similar to HCC, including cirrhosis, hepatitis B infection
● Very poor prognosis due to sarcomatous component (Am J Surg Pathol 2007;31:817)

Case reports
=========================================================================

● 84 year old man whose tumor had components of adenocarcinoma and chondrosarcoma (Arch Pathol Lab Med 2000;124:888)

Gross images
=========================================================================



Gray-white tumor with necrosis

Micro images
=========================================================================



Tubular structures and chondrosarcoma


Various images



Other malignancies

Cholangiocarcinoma (intrahepatic / peripheral)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Adenocarcinoma arising from intrahepatic bile duct epithelial cells
● Also called bile duct carcinoma

Clinical features
=========================================================================

● 10% of primary liver cancers
● Diagnosis of exclusion - must rule out metastatic adenocarcinoma
● High prevalence in southeast and eastern Asia, including Korea
● 10-20% are associated with chronic bile stasis or cholangitis due to anabolic steroids, autosomal dominant polycystic disease, choledochal cysts, congenitally dilated hepatic ducts (Caroli’s disease), congenital hepatic fibrosis, intrahepatic lithiasis (5-10%), liver flukes Clonorchis sinensis or Opisthorchis viverrini, primary sclerosing cholangitis, Thorotrast
● Rarely associated with neoplastic transformation of von Meyenburg complexes (Am J Surg Pathol 2000;24:1131)
● Not associated with cirrhosis
● Usually age 60+ years; no gender preference; but mean age 40 years in those with primary sclerosing cholangitis or chronic inflammatory bowel disease
● 50-75% metastasize to regional lymph nodes, adrenals, brain, lungs, vertebrae or elsewhere at autopsy
● 50% metastasize to perihilar, peripancreatic or para-aortic nodes
● Death usually within 6 months; 5 year survival in resectable cases is 30%
● Poor prognostic factors: lymphatic or intrahepatic metastases (Am J Surg Pathol 1999;23:892)
Klatskin tumor: hilar tumor arising at confluence of left and right hepatic ducts; clinically detected early due to obstruction
● Laboratory: normal AFP, occasional hypercalcemia

Classification
=========================================================================

● Liver Cancer Study Group of Japan: mass-forming, periductal infiltrating, intraductal growth types (Radiographics 2009;29:683)


Morphologic classification

Case reports
=========================================================================

● 55 year old woman with synchronous, small cholangiocarcinoma and small hepatocellular carcinoma arising in two different dysplastic nodules, in an explant cirrhotic liver (Mod Pathol 2002;15:1096)
● 61 year old woman with history of Caroli’s disease with extensive pulmonary vascular spread in the form of carcinomatous arteriopathy (Arch Pathol Lab Med 2002;126:717)

Gross description
=========================================================================

● 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
=========================================================================



Various images


Mass forming cholangiocarcinomas


Periductal infiltrating cholangiocarcinoma


Klatskin tumor

Micro description
=========================================================================

● 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
● Tumor spreads along hepatic plates, duct walls, via nerves (perineural invasion in 81%), but not sinusoidal
● Stroma may be circumferential around glands; associated with neutrophils
● Variable vascular invasion; no bile production
● Patterns: adenosquamous, clear cell, colloid, lymphoepithelioma-like, mucoepidermoid, osteoclast giant cell, rhabdoid, sarcomatous, signet ring
● Bile ductular carcinoma: composed of small glands resembling reactive bile ductules, NCAM+ (Histopathology 2007;51:390)
● Cholangiolocellular carcinoma: cholangiocarcinoma, hepatocellular carcinoma and background cirrhosis; must differentiate from hepatocellular carcinoma with CK19+, CK7+ (Histopathology 2006;49:138)

Micro images
=========================================================================



Various images


Mass forming cholangiocarcinomas

     
Cholangiocarcinoma    Arising in Caroli’s disease Associated with multiple von Meyenburg complexes


Comparison: hepatocellular carcinoma versus cholangiocarcinoma (left to right): H&E, MOC31, pCEA


Various images

Cytology description
=========================================================================

● Abundant, finely granular cytoplasm

Positive stains
=========================================================================

● Mucin (almost always), CEA (cytoplasmic and luminal, not canalicular), CAM 5.2, AE1-AE3, keratin 903 (74%), CK7 (90-96%) and CK19 (84%); reduced CK903 (Mod Pathol 2002;15:1181)
● Also CK20 (30-70%, more often positive in non-peripheral tumors, Am J Surg Pathol 2000;24:870), EMA, amylase, PTH-related peptide, p53 (10-94%), PCNA, MOC31 and BerEP4
● Also MUC1, MUC4, CD151, p27, COX2, fascin, tenascin, metallothionine
● MMP7 may be a favorable prognostic factor (Hum Pathol 2008;39:710)

Negative stains
=========================================================================

● AFP, HepPar1

Molecular description
=========================================================================

● Kras mutations
● Downregulation of β-catenin, aberrant expression and activation of ErbB, HGF, IL6

Differential diagnosis
=========================================================================

Benign bile duct proliferations: smaller, no atypia and incidental
Epithelioid hemangioendothelioma: vascular markers+, mucin-
● Extrahepatic biliary tree
Hepatocellular carcinoma with ductular differentiation
Metastatic adenocarcinoma: most likely from breast, colon (CK7- / CK20+ [strong]), gallbladder, pancreas; exclude based on clinical and radiographic findings


Intraductal cholangiocarcinoma

Gross description
=========================================================================

● Pink-white papillary excrescences within dilated ducts

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● Papillary and flattened epithelium
● Non-invasive 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

Micro images
=========================================================================



Various images

Differential diagnosis
=========================================================================

Intraductal lesions without high grade dysplasia:
Adenomatosis
Biliary papillomatosis
Intraductal adenoma


Lymphoepithelioma-like cholangiocarcinoma

General
=========================================================================

● Rare, < 10 cases reported (Am J Surg Pathol 2001;25:516, Mod Pathol 2001;14:527)
● Asian men and women ages 41-67 years, usually EBV related
● May have better prognosis than ordinary cholangiocarcinoma

Gross description
=========================================================================

● 3-12 cm, yellow-white and firm; may have tumor satellites; no cirrhosis

Micro description
=========================================================================

● 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
=========================================================================


           
Focal granulomatous reaction  CK19          EBER


Neoplastic glands with dense lymphoplasmacytic infiltrates

Positive stains
=========================================================================

● CK7, CK19, AE1-AE3 and EBER-1 (in situ hybridization)

Negative stains
=========================================================================

● CK20, CEA

Differential diagnosis
=========================================================================

● Metastatic lymphoepithelioma-like carcinoma from other sites



Other malignancies

Combined hepatocellular carcinoma - cholangiocarcinoma


Reviewers: Nat Pernick, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Tumor with unequivocal, intimately mixed elements of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (ChC) (WHO)
● Must distinguish from separate HCC and ChC arising in same liver, which are either separated or intermixed (“collision tumor”)
● Includes "transitional" types with primarily features intermediate between hepatocellular carcinoma and cholangiocarcinoma (Am J Surg Pathol 2002;26:989)
● < 5% of primary hepatic carcinomas
● Aggressive, with 5 year survival of 18% overall and 24% after resection (worse than pure hepatocellular carcinoma or cholangiocarcinoma, Clin Med Pathol 2008;1:43)
● Poor prognosis and high rate of tumor recurrence after liver transplantation (Liver Transpl 2011;17:934)
Laboratory: serum alpha-fetoprotein usually normal, usually negative for Hepatitis B and C serum markers

Case reports
=========================================================================

● 53 year old man with Hepatitis B and weight loss (Cases J 2009;2:6789)

Gross description
=========================================================================

● 3-16 cm, solitary or multiple tumor nodules
● Pale-tan to bile stained, variably fibrotic and hemorrhagic or necrotic

Gross images
=========================================================================



Poorly circumscribed mass with extensive necrosis

Micro description
=========================================================================

● Intimate admixture of tumor cells with features of unequivocal hepatocellular carcinoma and cholangiocarcinoma (cuboidal / columnar cells with amphophilic cytoplasm, inconspicuous nucleoli, gland formation and mucin)
● May have sarcomatoid component or cirrhosis
● Transitional tumors have no distinct hepatocellular or cholangiocarcinoma-like areas; 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

Micro images
=========================================================================



Various images


Left: H&E; right: CK7

Positive stains
=========================================================================

● Albumin mRNA by ISH (96%); cytokeratin, EMA and mucicarmine in glandular areas

Differential diagnosis
=========================================================================

Hepatocellular carcinoma with pseudoglandular spaces but not true glands
● Undifferentiated carcinoma: features suggestive but not diagnostic of both tumor types, may represent metastatic diseases



Other malignancies

Congenital primitive epithelial tumor


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 30 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● Only case report identified to date - with focal rhabdoid features (Hum Pathol 2000;31:259)



Other malignancies

Epithelial myoepithelial carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

Case reports
=========================================================================

● 37 year old man with primary tumor (Zhonghua Wai Ke Za Zhi 2006;44:1477)
● 67 year old man with incidental finding and unclear if primary or metastases from oral lesion 50 years prior (Am J Surg Pathol 1999;23:349)



Other malignancies

Epithelioid hemangioendothelioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Endothelial derived neoplasm with unpredictable clinical course, usually intermediate between hemangioma and angiosarcoma
● Often misdiagnosed

Clinical features
=========================================================================

● Mean age 47 years, but occurs at any age, 60% women
● No predisposing factors; occasional cases reported in vinyl chloride workers, women on oral contraceptives, hepatitis B/C patients, following hepatic trauma
● Symptoms: abdominal pain, weight loss, hepatic venous outflow obstruction; 40% are asymptomatic
● FNA not recommended, as even small biopsies can be misleading
● Indolent and slow growing; 5 year survival of 43%
● 50% have extrahepatic involvement at diagnosis, which does not preclude long survival
● Metastases to abdominal lymph nodes, lung, omentum or peritoneum, spleen
● Radiologic calcifications in 20%; peripheral nodules with capsular retraction by CT scan

Prognostic factors
=========================================================================

● High cellularity is unfavorable, but histology is otherwise not prognostic

Case reports
=========================================================================

● 35 year old woman with multiple FNH and cavernous hemangiomas (Arch Pathol Lab Med 1999;123:846)
● 83 year old man with incidental tumor (Arch Pathol Lab Med 2002;126:225)
● Tumor with t(1;3)(p36.3;q25) (Am J Surg Pathol 2001;25:684)

Treatment
=========================================================================

● Resection, liver transplantation

Gross description
=========================================================================

● Multiple (80%), tan-gray, firm, circumscribed and focally confluent nodules up to 12 cm with infiltrative borders
● May involve venous structures as intravascular proliferations or fibrothrombotic occlusions
● Remaining liver is unremarkable

Gross images
=========================================================================



Mottled tumor with cavernous hemangioma


Various images

Micro description
=========================================================================

● 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
● 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 and no /rare mitotic figures
● Extramedullary hematopoiesis present; may have myxoid areas; often has infiltrative margins, inflammatory infiltrate; adjacent liver usually normal

Micro images
=========================================================================



Various images


Microvascular channels and intracytoplasmic vacuoles


Intracytoplasmic vacuoles and projection into vein


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
● Occasionally NSE, smooth muscle actin (25%)

Negative stains
=========================================================================

● Usually AE1/AE3, CK7 and CK20 [but keratin may stain trapped hepatocytes and bile ductules], alpha fetoprotein, bile, CEA, HepPar1, mucin

Cytology images
=========================================================================



Various images

Molecular description
=========================================================================

● t(1;3)(p36.3;q25) has been reported

Electron microscopy description
=========================================================================

● Weibel-Palade bodies, intermediate filaments

Differential diagnosis
=========================================================================

Angiosarcoma: infiltrative, freely anastomosing vascular channels, more atypia
Leiomyosarcoma
Scirrhous cholangiocarcinoma
Sclerosed hemangioma: well circumscribed, no venous invasion, no atypia
Sclerotic hepatocellular carcinoma
● Signet ring adenocarcinoma



Other malignancies

Erdheim-Chester disease


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Very rare disorder (< 100 cases described) of unknown etiology with systemic xanthogranulomatous histiocytosis
● 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 or retro-orbital space
● Death in 60% due to respiratory and heart failure

Treatment
=========================================================================

● Oral steroids, chemotherapy or radiotherapy in severe cases

Case reports
=========================================================================

● 32 year old man with vertebral destruction and liver involvement (Arch Pathol Lab Med 2003;127:e337)
● Biliary manifestation of Erdheim-Chester disease mimicking Klatskin's carcinoma (Am J Gastroenterol 2007;102:452)

Micro description
=========================================================================

● Diffuse infiltration of large, foamy histiocytes, lymphocytic aggregates and fibrosis
● Rare Touton-like giant cells

Micro images
=========================================================================



CT scan, H&E, CD68 and EM




Various images


Macrophages in (A) testis, (B) thyroid, (C) lymph node, (D) Testis: CD68

Positive stains
=========================================================================

● CD68

Negative stains
=========================================================================

● CD1a, S100

Electron microscopy description
=========================================================================

● No Birbeck granules



Other malignancies

Fibrosarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 28 December 2012, last major update August 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
=========================================================================

● < 50 cases reported
● Usually solitary masses in men age 40+ years
● 20% associated with cirrhosis, 20% associated with hypoglycemia
● May appear post-transplant
● May be malignant version of solitary fibrous tumor (Int J Surg 2008;6:396), see also J Hepatobiliary Pancreat Surg 2007;14:595 (malignant transformation of SFT to fibrosarcoma)

Case reports
=========================================================================

● 39 year old man with sclerosing epithelioid fibrosarcoma infiltrating inferior vena cava (World J Gastroenterol 2009;15:4204)

Gross images
=========================================================================



Sclerosing epithelioid fibrosarcoma

Micro images
=========================================================================



Sclerosing epithelioid fibrosarcoma



Other malignancies

Follicular dendritic cell tumors


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare tumor, ~15 cases reported in liver (Hepatobiliary Pancreat Dis Int 2011;10:443), ~ 100 cases reported at all sites, usually lymph nodes, head and neck
● Usually Asian women, mean age 47 years, range 19 to 82 years
● Usually associated with Epstein–Barr virus (EBV), weight loss, fever
● Indolent behavior; may recur without causing death
● Inflammatory pseudotumor-like variant: marked female predominance; selective localization in intra-abdominal sites, especially liver and spleen; frequent systemic symptoms; indolent behavior; prominent lymphoplasmacytic infiltration; consistent association with EBV (Am J Surg Pathol 2001;25:721)

Case reports
=========================================================================

● 51 year and 57 year old women with 30-bp deletion in Exon 3 of LMP1 gene in tumor (Mod Pathol 2001;14:354)
● 82 year old man with EBV- tumor (Arch Pathol Lab Med 2005;129:1480)

Gross description
=========================================================================

● Solitary, fleshy, often > 10 cm (range, 4-20 cm) with focal hemorrhage and necrosis; surrounding liver tissue unremarkable

Gross images
=========================================================================



Well circumscribed tumor with hemorrhage and necrosis

Micro description
=========================================================================

● 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 and variable nuclear atypia with some cells resembling Reed-Sternberg cells
● Focal spindle cell fascicles; occasional vessels with fibrinoid deposits

Micro images
=========================================================================



Various images-liver




Various images-sites other than liver


Inflammatory pseudotumor–like variant (site unspecified) composed of loosely arranged spindle to oval cells (A) with prominent mixed inflammatory infiltrate consisting primarily of lymphocytes and plasma cells (B)

Positive stains
=========================================================================

● CD21 / CD35 (best), CD23, CNA.42, EBV-LMP1 (focal/weak), EBV (in situ hybridization)

Negative stains
=========================================================================

● ALK1, CD30, CD1a

Electron microscopy description
=========================================================================

● Long, thin cytoplasmic processes connected by desmosomes

Molecular images
=========================================================================



EBER in situ hybridization

Differential diagnosis
=========================================================================

Hodgkin lymphoma
Inflammatory myofibroblastic tumor
Sarcomas



Other malignancies

Gastrointestinal stromal tumor (GIST)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Almost all cases represent metastatic GIST
● <10 reports of primary hepatic GIST (see below); hypothesized to originate from progenitors of mesenchymal cells capable of differentiation toward a pacemaker cell phenotype

Case reports
=========================================================================

● 17 year boy with positive HBV (World J Gastroenterol 2009;15:3704)
● 37 year old man with lung metastases (Front Biosci 2006;11:498)
● 53 year old man with abdominal discomfort (Arch Med Sci 2012;8:392)
● 79 year old woman with malignant primary liver GIST (Arch Pathol Lab Med 2003;127:1606)

Gross description
=========================================================================

● Firm, homogenous and tan-brown with necrosis
● May have satellite nodules

Gross images
=========================================================================



Large tumor with necrotic center

Micro description
=========================================================================

● Spindle cells arranged in short fascicles
● Variable mitotic figures

Micro images
=========================================================================



Various images


Various images (not necessarily liver)

Positive stains
=========================================================================

● CD117, vimentin and variable CD34

Negative stains
=========================================================================

● Keratin, CD31, desmin, smooth muscle actin and S100



Other malignancies

Germ cell tumors


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 1 January 2013, last major update January 2013
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● < 1% of all liver neoplasms, mostly children < 3 years old, 50% are malignant
● Usually teratoma, choriocarcinoma, yolk sac tumor
● Teratoma: uncommon, usually girls < 1 year old

Case reports
=========================================================================

● 3 year old boy with primary hepatic mixed germ cell tumor (Acta Oncol 2007;46:1198)
● 3 year old boy with mixed hepatoblastoma and teratoma of liver (Diagn Pathol 2009;4:37)
● 34 year old man with primary mixed germ cell tumor with sarcomatous component (World J Gastroenterol 2010;16:652)

Gross description
=========================================================================

● Large, cystic, calcified

Gross images
=========================================================================



Teratoma

Micro description
=========================================================================

● Teratomas: derivatives of all 3 cell layers; often cystic, lined by ectoderm with skin appendages or endoderm; rarely have neuroendocrine differentiation (Histopathology 2003;43:306)
● May have other liver tumor component (hepatoblastoma)

Micro images
=========================================================================



Primary mixed germ cell tumor (yolk sac tumor and immature teratoma)


Primary mixed germ cell tumor (yolk sac tumor and embryonal carcinoma)


Teratoma

Molecular images
=========================================================================



Primary mixed germ cell tumor (yolk sac tumor and immature teratoma)

Differential diagnosis
=========================================================================

Hepatoblastoma
● Metastatic disease: see Nihon Kokyuki Gakkai Zasshi 2007;45:318



Other malignancies

Hepatoblastoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Malignant liver neoplasm almost exclusively in infants, composed exclusively of immature hepatocytic elements (WHO)
● Most common primary liver tumor in children (50% of liver malignancies in children)
● Existence in adults is controversial (J Hepatol 2012;56:1392)

General
=========================================================================

● Can be congenital; 90% occur by age of 5 years, 70% by age of 2 years; 2/3 male, prevalence of 1 per 120,000 (1 per million children under age 15 years)
● Associated with familial colonic polyposis (APC gene, 500x risk), glycogen storage disease, hemihypertrophy (Beckwith-Wiedemann syndrome), Li-Fraumeni syndrome, low birth weight infants, Simpson-Golabi-Behmel syndrome, trisomy 18, Wilm’s tumor; not associated with cirrhosis
● Also associated with adenomatoid transformation of Bowman’s capsular epithelium in kidney
● Metastases to adrenal glands, bone marrow, brain, lung, lymph nodes (regional)
● Variable virilization due to hCG production by multinucleated giant cells
● Laboratory: thrombocytosis (Arch Dis Child 1993;69:171), elevated serum AFP (75%)
● Note: diagnosis difficult on needle biopsy; must sample generously

Staging
=========================================================================

Based on 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

Prognostic factors
=========================================================================

● Stage, age and sex
● Favorable: presence of osteoid
● Unfavorable: small cell / undifferentiated (Pediatr Blood Cancer 2009;52:328) and macrotrabecular patterns, increased mitotic activity; also AFP level < 100, nuclear beta catenin staining, low p27 / kip1, high cyclin D1, 4q deletions

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

Gross description
=========================================================================

● Usually right lobe
● Usually solid, variegated, tan-green, solitary (70%), variable hemorrhage and cysts
● Mean 10 cm (range 3-20 cm), well-circumscribed; often partially encapsulated
● May be calcified or ossified in prominent mesenchymal component

Micro description
=========================================================================

● 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 and no associated cirrhosis
● Rare rhabdoid cells


Epithelial type (56%)

General
=========================================================================

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 and 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 at the periphery
● Reduced reticulin, rare mitosis
● Cholangoblastic if ductular differentiation (CK7/19 positive) prominent
● Crowded fetal type: crowded cells and 2+ mitotic figures/10 hpf

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 and 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 / anaplastic pattern (3%):
● Most primitive form
● Definition: 70%+ small cell areas; however, even small foci should be reported becaues associated with poor prognosis
● Discohesive sheets of small uniform keratin+ cells with minimal cytoplasm, indistinct cell borders, oval hyperchromatic nuclei, variable prominent nucleoli and increased mitotic figures (Mod Pathol 2003;16:930)
● Resembles small cell carcinoma at other sites
● May have mucoid stroma, hyalinized septae; bile
● Loss of INI1 associated with rhabdoid phenotype

Gross images
=========================================================================



Epithelial hepatoblastoma


Patient with trisomy 18

Micro images
=========================================================================



Cholangioblastic pattern


Fetal pattern


Fetal pattern in patient with trisomy 18


Macrotrabecular pattern


Mixed fetal and embryonal patterns


Small cell pattern


Mixed epithelial mesenchymal type (44%)

General
=========================================================================

● 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
=========================================================================



Mixed pattern


Post-chemotherapy treatment effect

Positive stains
=========================================================================

● Alpha fetoprotein (negative in small cell type), chromogranin (fetal, epithelial subtypes, usually focal), CK8/18 (fetal, epithelial subtypes), CK19 (embryonal subtypes)
● Also EMA, HepPar1 (negative in small cell type), polyclonal CEA (canalicular pattern), vimentin
● Variable hCG, occasional HMB45 and melanin
● Beta catenin (nuclear) in small cell and embryonal types, Delta-like protein (DLK), glypican-3 (negative in small cell type), glutamine synthase

Negative stains
=========================================================================

● CD45 / LCA, desmin and neurofilament

Molecular description
=========================================================================

● Gain of Xq in 60%, gain of Xp in 43%, also trisomy 2q (2q+) and trisomy 20, 1p-, 2q-, 4q-, 4q+
● Fetal type usually diploid, embryonal often aneuploid (Hum Pathol 2003;34:864)
● Deletion or translocation of 22q in small cell type (Front Biosci (Elite Ed) 2012;4:1287); also FOXG1 overexpression (Hum Pathol 2007;38:400), Yin Yang 1 (YY1) protein (Virchows Arch 2011;458:453), SERPINB3 overexpression (Eur J Cancer 2012;48:1219)

Electron microscopy description
=========================================================================

● Immature hepatocytes

Differential diagnosis
=========================================================================

Hepatocellular carcinoma - resembles macrotrabecular variant of hepatoblastoma, uncommon in children, larger more pleomorphic tumor cells, no extramedullary hematopoiesis

Metastatic tumors: more common than hepatoblastoma, primary tumor cells should not resemble hepatocytes
Lymphoma
● Neuroblastoma
Rhabdomyosarcoma
Teratoma
Undifferentiated sarcoma
● Wilms’ tumor
Yolk sac tumor: rare yolk sac cells may be present in hepatoblastoma



Other malignancies

Infantile hemangioendothelioma / hemangioma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Most common hepatic mesenchymal tumor in childhood (20% of all pediatric hepatic tumors)

Clinical features
=========================================================================

● 90% are <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
● Associations: chromosomal abnormalities, developmental abnormalities, hemangiomas, mesenchymal hamartoma, Wilm's tumor (Virchows Arch A Pathol Anat Histopathol 1988;413:463)

Laboratory and Radiology
=========================================================================

● Normal AFP (usually), rarely elevated due to secretion from entrapped or nearby hepatocytes (Hum Pathol 2010;41:763)
● Xray: multiple small nodules

Treatment and prognosis
=========================================================================

● Spontaneous involution in 5-10% at 6-8 months; resection if solitary, otherwise steroids, interferon, radiation therapy, embolization or transplantation (World J Surg 2009;33:597)
● Poor prognostic factors: congestive heart failure, jaundice, multiple nodules, lack of cavernous differentiation
● 70% survival (almost always have benign behavior)
● Deaths (when they occur) are usually within 1 month of diagnosis, and due to congestive heart failure or platelet consumption leading to bleeding diathesis or massive hemoperitoneum

Case reports
=========================================================================

● 56 year old woman with breast DCIS and liver mass (Arch Pathol Lab Med 2001;125:931)
● With pulmonary metastases (J Pediatr Surg 2006;41:e49)

Gross description
=========================================================================

● Solitary or multiple, mean 4 cm (range 0.1 to 15 cm) and circumscribed but not encapsulated
● White-red-tan, soft and spongy
● Larger nodules may have hemorrhagic, fibrotic or calcified central areas

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● 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) and 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 and calcification; no / rare mitotic figures and no malignant spindle cell component
Type 2 change: equivalent to angiosarcoma (with aggressive behavior) with irregular branching vascular structures lined by pleomorphic, hyperchromatic endothelial cells, frequent mitotic activity

Micro images
=========================================================================



Various images


Bland cells with small / medium nuclei and nucleoli, factor VIII related antigen

Positive stains
=========================================================================

● Factor VIII related antigen, CD31, CD34 and GLUT1 (Hum Pathol 2004;35:200)

Differential diagnosis
=========================================================================

Angiosarcoma: adequate sampling is important; has solid sarcomatous areas, vascular and sinusoidal permeation, marked pleomorphism; may have history of exposure to toxins
Cavernous hemangioma: less common in children, lacks peripheral small vascular proliferation
Epithelioid hemangioendothelioma: intracellular vascular lumina containing RBCs
Hepatic vascular malformation with capillary proliferation: typically single large mass, malformed, irregular large vessels and Glut1-
Mesenchymal hamartoma: primitive mesenchymal stroma, not a vascular tumor



Other malignancies

Kaposi’s sarcoma (KS)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

See also Soft Tissue Tumors chapter

General
=========================================================================

● Malignant vascular neoplasm with blunt endothelial cells, erythrocyte extravasation, hemosiderin deposition, usually in HIV+ patients; incidental finding at autopsy in 15% with AIDS (WHO)
● Present in liver in 12-25% of fatal cases of KS elsewhere in body

Gross description
=========================================================================

● Hemorrhagic multifocal spongy nodules, 5-7 cm

Gross images
=========================================================================



Multiple dark brown lesions in large portal areas

Micro description
=========================================================================

● Spindle cells with hyaline globules and vasoformative channels with extravasated red blood cells
● Lesions centered on portal tracts

Micro images
=========================================================================



Spindle cells and slit-like vascular spaces

Positive stains
=========================================================================

● CD31, CD34

Differential diagnosis
=========================================================================

Bacillary peliosis hepatis



Other malignancies

Langerhans cell histiocytosis (LCH)


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

See also Lymph nodes-not lymphoma chapter

General
=========================================================================

● Neoplastic disorder of Langerhans cells, formerly called histiocytosis X
● Causes 15% of sclerosing cholangitis in children, usually affects intrahepatic bile ducts
● Remarkable selectivity for bile ducts, eventually causes biliary cirrhosis
● May only affect liver; also affects lymph nodes, skin
● Laboratory: Gamma glutamyl transpeptidase is sensitive indicator of liver infiltration in children with LCH

Case reports
=========================================================================

● 65 year old woman with sclerosing cholangitis 4 years after diagnosis of Langerhans cell histiocytosis (Hepatol Int 2010;4:653)

Micro description
=========================================================================

● Langerhans cells may surround bile ducts and infiltrate sinusoids in nodules or diffusely
● Associated with cirrhosis, sclerosing cholangitis, eosinophils, lymphocytes, plasma cells and neutrophils (Mod Pathol 1999;12:370)

Micro images
=========================================================================



Langerhans cell histiocytosis - site unspecified


Sclerosing cholangitis caused by LCH, but no LCH involvement of liver itself

Positive stains
=========================================================================

● S100, CD1a



Other malignancies

Leiomyosarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare (<30 cases reported) aggressive malignant smooth muscle neoplasm, usually post-menopausal women, characterized by neoplastic spindle cells (WHO)
● Tumors either primary in liver or arise in ligamentum teres or inferior vena cava
● Associated with HIV, post-transplantation in children and Budd-Chiari syndrome
● Usually causes death within 2 years

Case reports
=========================================================================

● Child with congenital immunodeficiency and multifocal EBV+ leiomyosarcoma involving liver, thyroid and lung (Am J Surg Pathol 1999;23:473)
● 26 year old man with EBV+ leiomyosarcoma post-cardiac transplant (Am J Surg Pathol 2000;24:614)
● 34 year old HIV+ man with multiple EBV+ tumors (Am J Surg Pathol 2000;24:614)

Micro images
=========================================================================



67 year old man

Micro images
=========================================================================



Liver metastases of rectal carcinoma (left) and primary hepatic leiomyosarcoma (right)


67 year old man with 1.3 kg mass

Differential diagnosis
=========================================================================

Epithelioid hemangioendothelioma



Other malignancies

Liposarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, < 10 cases reported
● Develops in non-cirrhotic liver
● Contraindication for liver transplantation

Case reports
=========================================================================

● 54 year old woman with myxoid liposarcoma (Arch Pathol Lab Med 2001;125:410)

Gross description
=========================================================================

● Large tumor with yellow-tan, fleshy mass, focal hemorrhage and necrosis as well as satellite tumor nodules
● Non-cirrhotic remaining liver

Gross images
=========================================================================



Metastatic tumor from leg primary

Micro description
=========================================================================

● 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


Various images


Metastatic tumor from leg primary has extensive round cell component

Positive stains
=========================================================================

● Vimentin, alpha smooth muscle actin (focal)

Negative stains
=========================================================================

● S100, keratin, HMB45, CD34

Electron microscopy images
=========================================================================



Intracellular lipid indents nucleus



Other malignancies

Lymphoepithelioma-like carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Very rare type of hepatocellular carcinoma with pleomorphic tumor cells mixed with numerous lymphocytes; tumor cells tend to be small with focal syncytial growth; most cases are actually variant of cholangiocarcioma; usually EBV+
● Better prognosis than hepatocellular carcinoma

Case reports
=========================================================================

● 39 year old woman with liver transplant for end stage liver disease secondary to chronic hepatitis C (Diagn Mol Pathol 2004;13:183)
● 47 year old woman with abdominal pain (World J Gastroenterol 2008;14:4694)
● 64 year old man with cirrhosis, EBV- tumor (Arch Pathol Lab Med 1999;123:441)

Micro description
=========================================================================

● Cords and trabeculae of large polygonal epithelial cells with marked lymphocytic infiltrate
● Blurred border at tumor margin; otherwise normal liver

Micro images
=========================================================================



Various images


Biliary tumor

Positive stains
=========================================================================

● Keratin (CK19), EMA

Negative stains
=========================================================================

● Vimentin, AFP, CEA, CK20, HMB4, CD30

Differential diagnosis
=========================================================================

Cholangiocarcinoma-lymphoepithelioma like variant: syncytial pattern of undifferentiated epithelial cells and glands in lymphocyte-plasma cell rich stroma; presence of glands differentiates this from lymphoepithelioma-like carcinoma



Other malignancies

Malignant fibrous histiocytoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare (<40 cases reported); mean age 58 years
● Usually solitary, 5-20 cm
● Poor prognosis; usually death within 1 year (World J Surg Oncol 2012 Jan 5;10:2); ezrin may have prognostic value (Am J Surg Pathol 2008;32:1144)

Gross images
=========================================================================



Various images

Micro description
=========================================================================

● 90% are storiform-pleomorphic type, 10% myxoid type

Micro images
=========================================================================



Various images


Combined MFH-HCC

Differential diagnosis
=========================================================================

Cholangiocarcinoma
Sarcomatoid hepatocellular carcinoma: cirrhosis present



Other malignancies

Malignant histiocytosis


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare neoplasm of abnormal histiocytes typically affecting liver, spleen, lymph nodes, bone marrow
● Also called histiocytic sarcoma

Micro description
=========================================================================

● Large cells with multilobed nuclei, abundant eosinophilic cytoplasm and erythrophagocytosis

Micro images
=========================================================================



Various images (head and neck)

Cytology images
=========================================================================



Various images

Positive stains
=========================================================================

● CD68, MAC387



Other malignancies

Mastocytosis


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 2 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

See also Chronic myeloid neoplasms chapter

General
=========================================================================

● Mast cell disorders have variable symptoms of diarrhea, weight loss, weakness, fractures or osteoporosis in 25%, arthralgia, flushing, bronchospasm
● 40-60% of cases have hepatic involvement
● May present as cholestatic disorder
● Associated with obliterative portal venopathy, venoocclusive disease, nodular regenerative hyperplasia, cirrhosis

Micro description
=========================================================================

● Round or spindled, degranulated mast cells in portal tracts and sinusoids; may be subtle
● Usually also portal fibrosis, 50% have extramedullary hematopoiesis

Micro images
=========================================================================



Various images

Positive stains
=========================================================================

● Tryptase, Leder stain



Other malignancies

Metastases to liver


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 4 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● In US, only 2% of hepatic malignancies in non-cirrhotic liver are hepatic primaries (i.e. 98% are metastases) vs. 77% are hepatic primaries in cirrhotic liver
● Direct extension is common from tumors of extrahepatic bile ducts, gallbladder, pancreas and stomach
● Metastases in adults often from breast, colon, lung, pancreas; in children from neuroblastoma, rhabdomyosarcoma, Wilm's tumor
● Unknown primary is often determined to be from lung, pancreas, stomach
● 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 primary is neuroendocrine carcinoma or neuroblastoma; also some cases of colon carcinoma with resection of hepatic metastases
● Should compare metastatic tumor to prior malignancies

Case reports
=========================================================================

● 60 year old woman with female adnexal tumor of probable wolffian origin metastatic to liver (Arch Pathol Lab Med 2000;124:431)

Gross description
=========================================================================

● 90% are multiple, variable size, may replace entire liver and 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 description
=========================================================================

● Sinusoidal dilation, cholestasis, portal lymphocytic infiltrate or tumor


Metastatic carcinomatous cirrhosis

General
=========================================================================

● Metastatic carcinoma to liver, often from breast, that incites an extensive fibrotic reaction simulating cirrhosis

Case reports
=========================================================================

● 38 year old woman with infiltrating ductal carcinoma of breast with associated florid fibrosis (Arch Pathol Lab Med 2001;125:1084)

Xray images
=========================================================================



Marked hepatic contour irregularity is consistent with macronodular cirrhosis


Metastatic carcinoma

Gross images
=========================================================================



Macronodular cirrhosis


Breast carcinoma metastatic to liver

General
=========================================================================

● 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 (Arch Pathol Lab Med 2003;127:1591)
● Mammoglobin+ and GCDFP-15+

Micro images
=========================================================================



Metastatic breast carcinoma to liver


Colon carcinoma metastatic to liver

General
=========================================================================

● Resection of metastases may improve long term survival

Case reports
=========================================================================

● 62 year old man with rectal polyp with bone and liver metastases (Am J Surg Pathol 1999;23:838)

Gross description
=========================================================================

● Large umbilicated nodules with extensive necrosis and fibrosis, variable calcification

Gross images
=========================================================================



Colonic adenocarcinoma metastases

Micro description
=========================================================================

● Tubular, papillary or cribriform patterns of columnar cells with basophilic cytoplasm and elongated nuclei, extensive necrosis


Gatrointestinal stromal tumor (GIST) metastatic to liver

Micro description
=========================================================================

● Polygonal, spindle to epithelioid cells

Positive stains
=========================================================================

● CD117, vimentin

Negative stains
=========================================================================

● HepPar1, Glypican 3


Hepatoid adenocarcinoma metastatic to liver

General
=========================================================================

● May arise in lung or stomach

Micro images
=========================================================================



Gastric hepatoid adenocarcinoma metastatic to liver

Positive stains
=========================================================================

● AFP, CK8, CK19 and CK20 (Am J Surg Pathol 2003;27:1302)

Negative stains
=========================================================================

● CK7, HepPar1, Glypican-3


Melanoma metastatic to liver

Micro description
=========================================================================

● May replace hepatic cords and grow in trabecular pattern with endothelial lining


Pancreaticobiliary metastases to liver

Micro description
=========================================================================

● Atypical angulated glands with desmoplasia


Squamous cell carcinoma metastatic to liver

Case reports
=========================================================================

● 76 year old man with primary tumor in large intestine (Arch Pathol Lab Med 2001;125:1251)

Gross description
=========================================================================

● Soft nodules due to necrosis and keratinization

Micro images
=========================================================================



FNA, H&E and synaptophysin



Other malignancies

Neuroendocrine carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 3 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● < 100 cases reported; mean age > 40 years, more common in women (Arch Pathol Lab Med 2003;127:1200)
● Normal serum AFP but high serum NSE, chromogranin and synaptophysin levels
● Not associated with chronic liver disease / cirrhosis
● Presents with diarrhea and abdominal pain
● Amphicrine carcinoma: glandular (signet ring morphology, mucicarmine, PASD+, villin+, CDX2+) and neuroendocrine differentiation in same cells (Ann Diagn Pathol 2011;15:355)

Case reports
=========================================================================

● 50 year old man with collision tumor of HCC and high-grade neuroendocrine carcinoma (Virchows Arch 2006;449:376)

Gross description
=========================================================================

● Typically solitary, may be cystic

Micro description
=========================================================================

● Resembles poorly differentiated carcinomas with cellular pleomorphism, nuclear atypia, hyperchromasia and frequent mitotic figures
● May have signet ring morphology with intracytoplasmic vacuoles negative for mucin but positive for neuroendocrine markers (Semin Liver Dis 2010;30:422)

Micro images
=========================================================================



H&E and chromogranin (figures C/D)


H&E and chromogranin (figures C/D)

Positive stains
=========================================================================

● Chromogranin, synaptophysin

Electron microscopy description
=========================================================================

● Dense core granules

Differential diagnosis
=========================================================================

Carcinoid tumor: low (< 2/10 HPF) mitotic activity, minimal nuclear polymorphism



Other malignancies

Rhabdomyosarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Rare, but most common biliary tract tumor in children (1% of pediatric rhabdomyosarcoma), usually embronal subtype, usually infant males (WHO)
● May have secondary spread into liver
● Very rare in adults (< 15 cases reported to date), females > males
● Present with obstructive jaundice
● May be associated with undifferentiated sarcoma
● Poor prognosis

Treatment
=========================================================================

● Surgical resection, chemoradiation therapy

Gross description
=========================================================================

● Polypoid myxoid mass extending into bile duct

Micro description
=========================================================================

● Usually botyroid-type embryonal rhabdomyosarcoma with soft polypoid masses covered by biliary-type epithelium protruding into ductal lumen
● Cells are small, hyperchromatic with rare cross striations in eosinophilic cytoplasm
● Cambium layer (densely packed cells beneath biliary epithelium) is present, occasional tumor giant cells with cross-striations
● Myxoid stroma under cambium layer; no hyaline globules

Micro images
=========================================================================



Various images


Parataesticular embyronal rhabdomyosarcoma

Positive stains
=========================================================================

● Desmin, muscle specific actin, myoglobin and MyoD1

Electron microscopy description
=========================================================================

● May show thin and thick filaments

Differential diagnosis
=========================================================================

● Malignant rhabdoid tumor: negative for MyoD1, myoglobin



Other malignancies

Squamous cell carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Uncommon; <25 cases reported
● May arise from congenital cyst, teratoma, intrahepatic lithiasis, liver cirrhosis or epidermoid cysts
● Poor prognosis

Gross images
=========================================================================



Primary liver tumor

Micro images
=========================================================================



Primary liver tumor


Various images


Oropharyngeal tumor metastatic to liver



Other malignancies

Undifferentiated embyronal sarcoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Also called malignant mesenchymoma, mesenchymal sarcoma
● 9-15% of pediatric hepatic tumors (#3 after hepatoblastoma and hepatocellular carcinoma) - usually ages 6-10 years
● In children, often associated with mesenchymal hamartoma (Pediatr Dev Pathol 2011;14:111), rarely with vaginal embryonal rhabdomyosarcoma (Ann Diagn Pathol 2011;15:250)
● Rare in adults (Cancer 2008;112:2274)
● Appears to be a primitive mesenchymal neoplasm with possible foci of differentiated sarcoma, such as angiosarcoma
● Typically presents with pain, fever, abdominal mass and normal serum AFP (J Pediatr Surg 2008;43:1912)
● Good prognosis (Cancer 2002;94:252), but large tumors may rupture and cause death (J Pediatr Hematol Oncol 2007;29:63)

Treatment
=========================================================================

● Complete resection and chemotherapy (J Gastrointest Surg 2007;11:73), possibly liver transplant (J Pediatr Hematol Oncol 2012 Nov 6 [Epub ahead of print])

Case reports
=========================================================================

● 10 year old girl with abdominal pain and anorexia (Case of the Week #134)
● 16 year old girl with palpable liver mass, fever and vomiting (Arch Pathol Lab Med 2003;127:e163)
● 74 year old woman with tumor arising from mesenchymal hamartoma (Int J Surg Pathol 2012;20:297)(

Gross description
=========================================================================

● 10-30 cm, solitary, well-demarcated, soft tumor with cystic, gelatinous, hemorrhagic and necrotic foci

Gross images
=========================================================================



10 year old girl with 15 cm tumor


Adult with 16 cm tumor

Micro description
=========================================================================

● Variably cellular tumor with anaplastic, spindled / oval cells with prominent hyaline globules and ill-defined borders within pseudocapsule
● Nuclei have stippled chromatin, inconspicuous nucleoli
● Variably myxoid stroma with numerous thin-walled veins
● Also bizarre tumor cells with prominent eosinophilic cytoplasm and PAS+ diastase resistant hyaline globules
● Extramedullary hematopoiesis common, frequent mitotic activity
● Note that trapped hepatocytes and bile-duct structures are present at periphery
● Adults may have partial smooth muscle differentiation (Hum Pathol 2003;34:246)

Micro images
=========================================================================



Case of the Week #134


Left to right: PAS diastase, alpha-1-antitrypsin


Adult with adipophilin-positive vesicles


Adult with 16 cm tumor

Positive stains
=========================================================================

● PAS+ diastase resistant hyaline globules, vimentin, high Ki-67 index (Appl Immunohistochem Mol Morphol 2006;14:193)
● Glypican-3 (60%, Hum Pathol 2012;43:695), CD56, paranuclear dot-like CK, Bcl-2, alpha-1 antitrypsin and alpha-1 antichymotrypsin, variable muscle markers

Negative stains
=========================================================================

● Alpha fetoprotein (hyaline globules), keratin, myogenein

Electron microscopy description
=========================================================================

● Hyaline globules are lysosomal and possibly apoptotic bodies

Differential diagnosis
=========================================================================

Embryonal rhabdomyosarcoma: usually 2-6 years old, myxoid mass extending into bile duct, rhabdomyoblastic differentiation with cytoplasmic cross striations, cambium layer present, no diffuse anaplasia or hyaline globules, myogenin+ and myoD1+ (Pediatr Dev Pathol 2007;10:89)
Gastrointestinal stromal tumor: adults, CD117+, DOG1+, CD34+ (usually)
Hepatoblastoma, mixed form
● Hydatid cyst in endemic areas (J Pediatr Surg 2008;43:E1)
Mesenchymal hamartoma: usually < 1 year old, cystic, bland tumor cells and no giant cells
Sarcomatoid hepatocellular carcinoma
Sclerosing variant of hepatocellular carcinoma: rare in children, has intracellular bile, Mallory-Denk bodies, HepPar1+



Miscellaneous

TNM staging of hepatocellular carcinoma


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Classification excludes sarcomas and metastases to liver

Primary tumor (T)
=========================================================================

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
T1: solitary tumor without vascular invasion
T2: solitary tumor with vascular invasion or multiple tumors, none more than 5 cm
T3a: multiple tumors more than 5 cm
T3b: single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein
T4: tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum

Notes:
● Vascular invasion includes gross or microscopic involvement
● For T3, a major branch means the right or left portal vein, or right-middle or left hepatic vein
● Multiple tumors includes satellitosis, multifocal tumors and intrahepatic metastases

Regional lymph nodes (N)
=========================================================================

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis

Distant metastasis (M)
=========================================================================

M0: no distant metastasis
M1: distant metastasis

Stage grouping
=========================================================================

I:    T1 N0 M0
II:   T2 N0 M0
IIIA:  T3a N0 M0
IIIB:  T3b N0 M0
IIIC:  T4 N0 M0
IVA:  any T N1 M0
IVB:  any T any N M1



Miscellaneous

TNM staging of Intrahepatic bile duct tumors


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Includes combined hepatocellular and cholangiocarcinoma
● Excludes hepatocellular carcinoma, extrahepatic bile duct malignancies

Primary tumor (T)
=========================================================================

TX: primary tumor cannot be assessed
T0: no evidence of primary tumor
Tis: carcinoma in situ (intraductal tumor)
T1: solitary tumor without vascular invasion
T2a: solitary tumor with vascular invasion
T2b: multiple tumors, with or without vascular invasion
T3: tumor perforating the visceral peritoneum or involving the local extrahepatic structures by direct invasion
T4: tumor with periductal invasion

Notes:
● Vascular invasion includes gross or microscopic involvement
● For T3, a major branch means the right or left portal vein, or right-middle or left hepatic vein
● Multiple tumors includes satellitosis, multifocal tumors and intrahepatic metastases

Regional lymph nodes (N)
=========================================================================

NX: regional lymph nodes cannot be assessed
N0: no regional lymph node metastasis
N1: regional lymph node metastasis

Distant metastasis (M)
=========================================================================

M0: no distant metastasis
M1: distant metastasis

Stage grouping
=========================================================================

0:  Tis N0 M0
I:   T1 N0 M0
II:  T2 N0 M0
III: T3 N0 M0
IVA: T4 N0 M0 or any T N1 M0
IVB: any T any N M1



Miscellaneous

Frozen section


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● Accurate and reliable for intraoperative diagnosis of suspected liver lesions (J Clin Pathol 2006;59:352) - biliary hamartoma is most common entity confused with a malignant tumor
● Pre-transplant frozen section also used to evaluate donor livers for macrovesicular steatosis, although discrepancies exist with permanent sections in 7% (J Clin Med Res 2011;3:191)
● Optimally, should have clinical data and serum AFP levels available
● Should know if specimen is from a mass



Miscellaneous

Grossing


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

General
=========================================================================

● At least one section per 2 cm of tumor for large tumors, including tumor center and periphery
● Submit entire tumor, if can do so in 5 sections or less
● Adjacent and distant uninvolved liver
● Resection margins
● Portal and hepatic veins
● Porta hepatis
● Lymph nodes
● Gallbladder, if present
● Other tissues or organs
● Save intervening levels on biopsies for special stains



Miscellaneous

Features to report


Reviewers: Deepali Jain, M.D. (see Reviewers page)
Revised: 5 January 2013, last major update August 2012
Copyright: (c) 2004-2013, PathologyOutlines.com, Inc.

Gross features
=========================================================================

● Tumor location (left, right or both lobes), tumor margin as circumscribed or infiltrative
● Presence of hemorrhage, necrosis, central scar and bile
● Extension to adjacent structures
● Other unusual features: unusually large cirrhotic nodules

Micro features
=========================================================================

● Tumor histologic type, tumor grade (specify grading system) and pattern
● Number and size (3 dimensions) of tumor nodules
● Status of resection margins (ask surgeon which margins are important to evaluate)
● Severity of fibrosis (none, mild, moderate, severe, cirrhosis)
● Angiolymphatic invasion
● Mitotic rate
● Findings in non-malignant liver, including cirrhosis, iron deposition, other tumors, portal vein thrombosis, hepatocyte dysplasia and hepatitis
● Regional lymph nodes: number examined, number and location with metastatic tumor

Additional references
=========================================================================

Arch Pathol Lab Med 2000;124:41, CAP Protocol (2012)

End of Liver and intrahepatic bile ducts - Tumor > Superpage


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