MESENCHYMAL TUMORS OF THE LIVER: WHAT S NEW AND UNUSUAL (MY PERSPECTIVE) CURRENT ISSUES IN ANATOMIC PATHOLOGY MAY 23, 2014 Linda Ferrell, MD, UCSF Mesenchymal Tumors Focus on Vascular Tumors Benign and the Probably Benign Newly-described and variant lesions Malignant Distinction of benign/low grade lesions from What is NOT Focus on Angiomyolipoma: Problem variants that still lead to diagnostic errors Epithelioid, inflammatory, trabecular VASCULAR TUMORS The Benign and Probably Benign HEMANGIOMA VARIANTS VASCULAR MALFORMATIONS Cavernous Hemangioma Variants 1
Cavernous Hemangioma (CH) Cavernous Hemangioma Not true arterial or venous architecture Incidental (Autopsy finding Giant CH, with organized thrombosis and sclerosis No organized muscle bundles No elastic laminas Not capillary-like Sclerosis within Cavernous Hemangioma Sclerosis of thrombosed, ischemic zones with scar formation. Neo-vessels Recanalized channels 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 2
Giant Cavernous Hemangioma Cavernous Hemangioma-like vessels in adjacent liver Giant Cavernous Hemangioma Giant Cavernous Hemangioma Explant, right lobe 38 yr old woman, in liver failure. Left Lobe: Smaller, irregularly shaped CHs and transitional areas with HLVs admixed with liver 3
Giant Cavernous Hemangioma Metatastatic and Invasive Cavernous Hemangioma Right Lobe CH Left lobe HLV Lesion extending into hilum around arteries, nerves and ducts Omental Lesion Duct Artery Nerve Cavernous Hemangioma Variant Diagnoses: Giant Cavernous Hemangioma and Cavernous Hemangiomatosis CH-like vessels throughout liver, involving hilum Lung, spleen, omentum involved with CH-like lesions Problematic 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) 4
Vascular Malformations 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. Spectrum: Early, mild To Late, 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 Vascular Malformations: More Severe or Advanced Lesions Periportal fibrosis, Elastochrome stain Periductal fibrosis (as early ischemic lesion) Extension of lesions into sinusoids Thrombosis within vessels and sinusoids 5
Vascular Malformations Severe sinusoidal changes Vascular Malformations: More Severe or Advanced Lesions Hemangioma-like changes, extensive sinusoidal dilation Cavernous hemangioma-like transformationn Small Vessel Hemangioma 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 channels, thin walls, bland nuclei Only focal fibrotic areas (no wide walls as in CH) 6
Small Vessel Hemangioma Small Vessel Hemangioma Small channels with thin walls, no organized muscle Low Mib1 (Ki-67) rate Center of lesion, bland endothelial cells Edge of lesion, with altered cell plate width Small Vessel Hemangioma Small Vessel Hemangioma Edge of lesion, trichrome Edge of lesion, reticulin 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. 7
Epithelioid Hemangioendothelioma Malignant Vascular Tumors Epithelioid Hemangioendothelioma Epithelioid Hemangioendothelioma Epithelioid Hemangioendothelioma Central vein invasion Elastochrome stain*, central vein invasion - like pattern of scaffolding growth *Elastochrome: trichrome plus EVG stain; highlights vein wall elastic fibers 8
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 Epithelioid pattern High MiB1 (Ki-67) rate 9
Scaffolding growth pattern along sinusoids CD34 and expanded sinusoidal growth Cystic change Congestion Necrosis Sinusoidal growth (higher magnification) Cystic change (upper right) Congestion Necrosis Sinusoidal growth Scaffolding pattern of growth surrounds hepatocytes 10
Scaffolding pattern of growth surrounds hepatocytes Scaffolding pattern of growth with fibrosis of cell plate areas : Highlights Sinusoidal growth results in anastomosing channels and pseudopapillary pattern 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 epithelioid hemangioendothelioma, but overlapping cases may be seen 11
Undifferentiated (Embryonal) Sarcoma What else is NOT angiosarcoma Undifferentiated (Embryonal) Sarcoma of the Liver Typically younger patients; tumor of uncertain etiology Can 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 Morphol 14:193-7, 2006. Glypican-3 can be positive in giant cells (personal observation) Undifferentiated (Embryonal) Sarcoma Undifferentiated (Embryonal) Sarcoma Cystic areas common Related to extensive necrosis (right upper area) 12
Undifferentiated sarcoma, tumor edge with growth along sinusoids PASD + 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 DIAGNOSIS as per three expert consultants Authors got confused about peripheral growth Angiomyolipoma Problem variants Epithelioid, Trabecular, and Inflammatory Problem Case 37-year-old woman 11 cm pedunculated mass No cirrhosis or other risk factors for HCC Mass noted during routine gynecologic exam, no symptoms 13
HCA, HCC? Reticulin Stain Reticulin Stain: too much loss for HCA HCC or Not? 14
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 Angiomyolipoma Classic features: Epithelioid Cells Spindle Cells Fat, Epithelioid, Spindle cells 15
Angiomyolipoma Problem Case: Trabecular Angiomyolipoma HMB-45: stains stronger on epithelioid cells SMA: usually stains spindle cells HMB-45 Problem case: Inflammatory Angiomyolipoma Focal dense to scattered diffuse T-cell infiltrate Problem case: Angiomyolipoma Inflammatory and Trabecular Case with both inflammatory and trabecular background 16
5/23/2014 Problem case: Angiomyolipoma, Inflammatory and Trabecular HMB-45 SMA Angiomyolipoma, Mixed variant Inflammatory areas, 10x Angiomyolipoma, Mixed variant Fatty areas Trabecular areas Angiomyolipoma, Mixed variant HMB-45 Inflammatory foci with absent staining (SMA only rare + cell, not shown) 17
SPECIAL THANKS TO ALL WHO HAVE CONTRIBUTED TO THE REFERENCED STUDIES: WE WOULDN T HAVE THIS DATA WITHOUT THESE COLLABORATION 18