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MESENCHYMAL TUMORS OF THE LIVER: WHAT’S NEW AND UNUSUAL(MY PERSPECTIVE)

CURRENT ISSUES IN ANATOMIC PATHOLOGYMAY 23, 2014Linda Ferrell, MD, UCSF

Mesenchymal TumorsFocus on Vascular Tumors � Benign and the “Probably Benign” �Newly-described and variant lesions

�Malignant�Distinction of benign/low grade lesions from Angiosarcoma�What is NOT Angiosarcoma

Focus on Angiomyolipoma: Problem variants that still lead to diagnostic errors�Epithelioid, inflammatory, trabecular

The Benign and Probably BenignHEMANGIOMA VARIANTSVASCULAR MALFORMATIONS

VASCULAR TUMORS Cavernous Hemangioma Variants

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Cavernous Hemangioma (CH)

Not true arterial or venous architecture

No organized muscle bundlesNo elastic laminasNot capillary-like

Cavernous Hemangioma

Incidental (Autopsy finding

Giant CH, with organized thrombosis and sclerosis

Sclerosis within Cavernous Hemangioma

Sclerosis of thrombosed, ischemic zones with scar formation.

“Neo-vessels”Recanalizedchannels

Cavernous Hemangioma: What is often “not seen”….

�Hemangioma-like vessels (HLV) in adjacent liver commonly seen with giant CH� Ref: Kim GE, Thung SN, Tsui WMS, Ferrell LD. Hepatic

Cavernous Hemangioma: Under-Recognized Associated Histologic Features. Liver Int'l, 26:334-38, 2006.�Low mitotic/proliferative rate <5%�Present in almost 80% (16/19) of CH >5 cm�Retain composition of vascular walls in CH

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Giant Cavernous Hemangioma Cavernous Hemangioma-like vessels in adjacent liver

Giant Cavernous Hemangioma

Explant, right lobe38 yr old woman, in liver failure.

Giant Cavernous Hemangioma

Left Lobe: Smaller, irregularly shaped CHs and transitional areas with HLVs admixed with liver

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Giant Cavernous Hemangioma

Right Lobe CH Left lobe HLV Lesion extending into hilum around arteries, nerves and ducts Omental Lesion

Artery

NerveDuct

“Metatastatic” and “Invasive” Cavernous Hemangioma

Cavernous Hemangioma VariantDiagnoses: Giant Cavernous Hemangioma and

Cavernous Hemangiomatosis� CH-like vessels throughout liver, involving

hilum� Lung, spleen, omentum involved with CH-like

lesionsProblematic cavernous hemangioma variants and other benign mimics:

A Mattis, S Fischer, H Makhlouf, W Tsui, S Cho, L Ferrell. Poster at USCAP Mar 2010, published Mod Pathol Supple 1, 2010.

Vascular Malformations�Hereditary Hemorrhagic Telangiectasia (HHT) arterial-venous malformations�also known as Osler-Weber-Rendu

�Other Arterial and Venous Malformations with similar features �(may or may not be HHT)

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Vascular Malformations Contributors and co-authors of 2 abstracts:� Cho S, Paradis V, Pai R, Bioulac-Sage P, Alves V, Souza T,

Makhlouf H, Schirmacher P, Evason K, Ferrell L. Histopathologic Features of Extensive Hepatic Vascular Malformations. Mod Path 23 (Supple 1):352A, 2010.

� Cho S, Wanless I, Sempoux C, Paradis V, Pai R, Thung S, Bioulac-Sage P, Balabaud C, Makhlouf H, Schirmacher P Alves V, Souza T, Evason K, Ferrell L. FNH-Like Lesions and Glutamine Synthetase Expression in the Liver in Hereditary Hemorrhagic Telangiectasia. Mod Path, 24 (Supple 1):358A, 2011.

Vascular Malformations

Spectrum:Early, mildToLate, severe

Early or mild lesions can look much different than advanced or severe lesions probably primarily due to thrombosis and ischemic effects

Vascular Malformations: Early Lesions or Mild Involvement

Periportal fibrosis, Elastochromestain

Periductal fibrosis (as early ischemic lesion)

Vascular Malformations: More Severe or Advanced Lesions

Extension of lesions into sinusoids Thrombosis within vessels and sinusoids

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Vascular MalformationsSevere sinusoidal changes

Vascular Malformations: More Severe or Advanced LesionsHemangioma-like changes, extensive sinusoidal dilation

Cavernous hemangioma-like transformationn

Small Vessel Hemangioma

Rare

Newly described

� Small vascular channels with thin walls

� Bland endothelial cells with low proliferative rate <10% (CH <5%)

� Intermediate tumor cell density� Irregular “infiltrative” growth pattern at border �abnormal liver architecture mimics HCC� scaffolding effect mimics angiosarcoma

Small Vessel HemangiomaSmall channels, thin walls, bland nuclei

Only focal fibrotic areas (no wide walls as in CH)

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Small Vessel HemangiomaSmall channels with thin walls, no organized muscle Low Mib1 (Ki-67) rate

Small Vessel HemangiomaCenter of lesion, bland endothelial cells

Edge of lesion, with altered cell plate width

Small Vessel Hemangioma

Edge of lesion, trichrome Edge of lesion, reticulin

Small Vessel Hemangioma � Small vessel hepatic hemangioma (SVH): Exact outcome not

definitive, so now recommending excision and followup.� Differentiation from angiosarcoma: AS has higher

proliferative rate (>15%) and subset + for P53 and GLUT1, but negative in small vessel hemangioma

References� Gill R, Sempoux C, Makhlouf H, Thung S, Alves V, Ferrell L.

Small Vessel Hepatic Hemangioma Variant in Adult Liver. Mod Pathol 25(Supple 2): 413A, 2012.

� Gill R, et al. GLUT-1 expression in adult hepatic vascular neoplasms. Mod Pathol 26(Supple 2): 2013.

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Epithelioid HemangioendotheliomaMalignant Vascular Tumors

Epithelioid Hemangioendothelioma

Epithelioid Hemangioendothelioma

Central vein invasion Elastochrome stain*, central vein invasion

*Elastochrome: trichrome plus EVG stain; highlights vein wall elastic fibers

Epithelioid Hemangioendothelioma

Angiosarcoma- like pattern of scaffolding growth

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Angiosarcoma

Angiosarcoma

� Most aggressive form of vascular malignancy

� Highest proliferative rate� Epithelioid or spindle cell forms� Cystic and/or solid� Known for the typical feature of

“scaffolding” growth pattern

Angiosarcoma Angiosarcoma

Epithelioid pattern High MiB1 (Ki-67) rate

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AngiosarcomaScaffolding growth pattern along sinusoids

CD34 and expanded sinusoidal growth

Angiosarcoma

Cystic change Congestion NecrosisSinusoidal growth

Angiosarcoma (higher magnification)

Cystic change (upper right)CongestionNecrosisSinusoidal growth

Angiosarcoma

Scaffolding pattern of growth surrounds hepatocytes

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Angiosarcoma

Scaffolding pattern of growth surrounds hepatocytes

Angiosarcoma

Scaffolding pattern of growth with fibrosis of cell plate areas

Angiosarcoma

Sinusoidal growth results in anastomosing channels and pseudopapillarypattern

Angiosarcoma: Highlights� High proliferative rate and cytologic atypia� - Early pattern of growth typically along sinusoids (scaffold-like); Atypical endothelial cells, dilated sinusoids

� - Later pattern of growth can be pseudopapillary to solid; irregularly-shaped blood filled spaces

� - Lacks the stromal prominence of epithelioidhemangioendothelioma, but overlapping cases may be seen

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Undifferentiated (Embryonal) Sarcoma of the Liver

What else is NOT angiosarcoma

Undifferentiated (Embryonal) Sarcoma

Typically younger patients; tumor of uncertain etiologyCan be cystic due to necrosis/degeneration with irregular edges!! (Pattern similar to angiosarcoma scaffolding)Immunohistochemistry� Reactive with alpha-1-antitrypsin, alpha-1- antichymotrypsin, vimentin

� Occasional cytokeratin positivity� Some CD10 and p53 positivity� Negative hepatocyte-Ab, muscle, S-100 and CD34� Ref: Kiani B, Ferrell LD, Qualman S, Frankel WL. Immunohistochemical Analysis

of Embryonal Sarcoma of the Liver. Applied Immunohistochem Mol Morphol14:193-7, 2006.

� Glypican-3 can be positive in giant cells (personal observation)

Undifferentiated (Embryonal) Sarcoma

Cystic areas commonRelated to extensive necrosis(right upper area)

Undifferentiated (Embryonal) Sarcoma

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Undifferentiated sarcoma, tumor edge with growth along sinusoidsPASD + globules Also Alpha-1-antitrypsin +

Undifferentiated Embryonal Sarcoma

Problem with Literature Search� Int J Surg Pathol. 2012 Jun;20(3):297-300. Embryonal

(undifferentiated) sarcoma of the liver with peripheral angiosarcoma differentiation….

� THIS IS NOT THE CORRECT DIAGNOSISas per three expert consultants

� Authors got confused about peripheral growth

AngiomyolipomaProblem variantsEpithelioid, Trabecular, and Inflammatory

Problem Case

� 37-year-old woman� 11 cm pedunculatedmass

� No cirrhosis or other risk factors for HCC

� Mass noted during routine gynecologic exam, no symptoms

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HCA, HCC? Reticulin Stain

Reticulin Stain: too much loss for HCA HCC or Not?

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Keratin and HMB-45 Angiomyolipoma, epithelioid variant

Ref: Tsui WMS, et al. Hepatic Angiomyolipoma: Delineation of Unusual Morphological Variants. Amer J Surg Pathol, 23:34-48, 1999.

Angiomyolipoma

Classic features:

Fat,Epithelioid,Spindle cells

Angiomyolipoma

Epithelioid Cells Spindle Cells

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Angiomyolipoma

HMB-45: stains stronger on epithelioid cells

SMA: usually stains spindle cells

Problem Case: Trabecular Angiomyolipoma

HMB-45

Problem case:Inflammatory AngiomyolipomaFocal dense to scattered diffuse T-cell infiltrate

Problem case: AngiomyolipomaInflammatory and Trabecular

Case with both inflammatory and “trabecular” background

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Problem case: Angiomyolipoma, Inflammatory and TrabecularHMB-45 SMA

Angiomyolipoma, Mixed variant

Fatty areas Trabecular areas

Angiomyolipoma, Mixed variant

Inflammatory areas, 10x

Angiomyolipoma, Mixed variant

HMB-45Inflammatory foci with absent staining(SMA only rare + cell, not shown)

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SPECIAL THANKS TO ALL WHO HAVE CONTRIBUTED TO THE REFERENCED STUDIES:WE WOULDN’T HAVE THIS DATA WITHOUT THESE COLLABORATION