Mesenchymal Tumors of the Liver: What’s New and Unusual (My Perspective)

Linda D Ferrell, MD, University of California, San Francisco

Introduction

Mesenchymal tumors of the liver are relatively uncommon (except cavernous ), so many pathologists are not as familiar with variations from the more typical appearances as described in many standard texts (See General References 1-4) and/or have not had significant experience with the rare variant types of mesenchymal lesions. Recently, there has been more focus on unusual and rare forms of mesenchymal tumors, especially within the spectrum of vascular lesions, so my personal perspective of these newly-descried and unusual variants will be the focus of this presentation.

Cavernous Hemangioma, with Hemangioma-like Vessels in adjacent liver

Cavernous hemangioma (CH) is the most common form of mesenchymal/ in the liver, but an under-recognized feature is the presence of multiple smaller clusters or foci of vascular structures in the liver adjacent to a large/giant CH; these have been designated as hemangioma-like vessels (HLV) (5,6). The structure of HLVs is identical to the architecture of the large vascular spaces seen in CH, with a predominantly collagenous wall with disorganized and somewhat scant smooth muscle and elastic fiber content. This wall is lined by cytologically bland/unremarkable endothelial cells with very low proliferative index (<2%). HLVs tend to be located in the periportal region, and may be single or multiple as a cluster.

Other unusual variants of CH have also been recently described (7) that include CHs involving >50% of the liver, multifocal forms within the liver, and those with HLVs extending into and around the structures of the hilum. In addition, rarely, CH may be associated with similar benign lesions in the lung, spleen, and omentum.

Small Vessel Hemangioma (SVH)

This type of hemangiomatous tumor is rare, and can be a diagnostic challenge, especially in the distinction from . In our recent review of a small series of cases collected from an international group of pathologists (8), we found these lesions consist of small caliber vascular structures with an anastomosing pattern. The walls of the structures are thin, with only minimal collagenous framework, if visible at all, and are lined by small, usually rounded endothelial nuclei that are CD34 and CD31 positive. The cellularity of the endothelial lining is more than that of CH and the proliferative rate is also somewhat increased as compared to CH, with a rate of 4-10% as stained with Mib-1 (Ki-67). The edges of the lesions are typically irregular, with the small vascular structures percolating into the adjacent sinusoidal architecture which can mimic a pattern of scaffolding growth typical of angiosarcoma. But in the case of this lesion, there is no significant cytologic atypia, the proliferative rate is lower than seen with angiosarcoma, and the extension along the sinusoids is less prominent. Of note, however, this pattern of growth can alter the background liver architecture to the extent that the hepatic plates can become distorted, with plates greater than 2-3 cells in thickness. This feature then mimics the widened trabeculae of well-differentiated hepatocellular carcinoma. (Similar plate changes can also be seen in vascular malformations of the liver, see below). Some features comparing angiosarcoma to this lesion are noted in the following table.

Table 1. Immunohistochemical findings in vascular tumors (8,9)

Tumor type CD31 CD34 P53 Mib1 (Ki-67) PI GLUT-1 SVH (n=6) 100% 100% 0% 4% (0-10%), n=7 0%, n=5 CH (n=10) 100% 100% 0% 0% 0% EHE (n=8) 88% 88% 38% 6% (0-12%) 38% AS (n=6 or7) 100% 80% 29% (n=7) 32% (15-50%), n=7 50%, n=7 SVH= small vessel hemangioma, CH= Cavernous hemangioma, EHE= epithelioid , AS= angiosarcoma, PI= Proliferative index, CD31, CD34, p53, Mib1, and GLUT all represent immunohistochemistry findings.

Infantile Hemangioma

This tumor typically presents early in life with heart failure if the tumor is large. The structure of the vessels can be variable from zone to zone, both in size as well as components to the vascular walls. Degenerative and/or involutional changes, as well as intratumoral hemorrhage is common. Very large vessels can also be seen in these lesions (personal observation). Some of the small vascular structures can look much like the small vessel hemangioma described above, but other larger spaces with thicker walls have the appearance more like that of CH. The large zones of degenerative, myxoid to fibrous areas, with focal calcifications can make biopsy diagnosis somewhat difficult as these areas may completely lack a vascular pattern. The edge of the lesion can also be very unusual in appearance as the tumor also insinuates along the sinusoids to grow along the liver plates, causing abnormal clusters of hepatocytes. Ductular components are often seen entrapped within the tumor, and can be especially prominent at the periphery. These ductules may not be true bile ducts, but rather may represent a reactive metaplastic process when the hepatocytes, which are entrapped by the tumor as it grows along the sinusoids, transform to a more ductular phenotype. These ductular elements, as well as the hepatocytic changes at the edge of the lesion can mimic features of hepatoblastoma or maybe get confused with mesenchymal harmartoma on small samples, so it may be useful to remember this particular feature when examining biopsy specimens.

Epithelioid Hemangioendothelioma

This presentation will not spend any significant time to review this , but it should be noted that in rare cases, cellular areas with less stromal component, nuclear atypia and a scaffolding pattern of growth like that of angiosarcoma can be rarely seen in these lesions; in such a case, it is possible that this may represent a more aggressive component (personal observation). Angiosarcoma

The routine morphology of angiosarcoma (AS) has been well-described (1-4). There are some features that are actually somewhat common, though, that are worth reviewing in more detail, particularly those that mimic other less aggressive lesions already discussed above. One of these features is the scaffolding pattern of growth that can also be seen in many of the vascular lesions including the small vessel hemangioma, , and endothelial hemangioendothelioma. However, in AS, the proliferative rate is typically higher (see table 1 above) and cellular atypia is more pronounced. As in these other vascular lesions, AS also can alter the hepatic plate architecture as it spreads along the sinusoids, leading to entrapment of hepatocytes in plates and clusters. As the tumor progresses, these entrapped hepatocytes degenerate, resulting in a fibrous core lined by the tumor cells, and on sections, these remnants can appear as either as anastomosing vascular spaces, or as “papillary” structures as viewed on the glass slide.

Mimics of Vascular

Vascular malformations

Although these are not true neoplasms, the changes seen associated with these lesions, especially in larger lesions that are typical of Hereditary Hemorrhagic (Osler-Weber-Rendu Syndrome), may have many overlapping features with the other benign vascular neoplasms discussed above, as well as lead to significant hepatic plate architectural abnormalities as already described in the small vessel hemangioma (see above), and to nodular transformation of the liver in the form of focal nodular hyperplasia-like lesions (10, 11). The primary vascular abnormalities typically consist of highly irregular muscular vessels in increased numbers that are present within the connective tissue areas of the liver (portal and hilar areas), and the subsequent consequences of the abnormal blood flow through these lesions end up resulting in and ectasias of these vessels. This, in turn, causes secondary changes in the liver that probably are primarily associated with vascular flow abnormalities and/or ischemic events. The ischemic complications can range from infarction of both lobular and portal structures as an acute serious complication of thrombosis, or may be more limited as a chronic effect such as periduct fibrosis. The flow abnormalities can lead to “capillarization” of the sinusoids (transformation to CD34 positivity), with formation of telangiectatic sinusoids that usually begins in the periportal regions. Over time, though, these can lead to a much larger vascular network of structures that resemble the morphology of cavernous hemangioma, or can also alter the hepatic plate architecture to the point that plates are widened as a mimic of the wide plates of HCC.

Undifferentiated (Embryonal) :

This presentation will not discuss this entity in detail, as this is well-described in many general texts (1- 4). We would note, however, that this lesion lacks vascular markers, even though it can typically show focal positivity for alpha-1-antitrypsin, as well as a variety of other markers (12, 13). In addition, Glypican-3 can also be positive, and in our experience at UCSF, the giant cells may show this positive staining. The primary reason, however, to present this case as part of this presentation is to point out that this tumor can also infiltrate the liver sinusoids in a similar pattern to that seen in the vascular neoplasms, and so mimic a scaffolding pattern of growth that could be mistaken for angiosarcoma. (In fact, this very feature has been recently misinterpreted in a case report as an embryonal sarcoma with both mesenchymal hamartomatous elements and angiosarcoma. Of note, I had reviewed this case as one of three expert consultants, none of the three consultants made this interpretation as reported, nor were any of the consultants mentioned in the report. I intentionally have not referenced this paper in this handout.)

Angiomyolipoma

An excellent review of the variants of AML was originally published by Tsui, et al (14), and additional texts also expand on these variants (15,16). The trabecular and inflammatory variants may represent the most diagnostically challenging, so one should be aware that these tumors can have a complex vascular or sinusoidal-like pattern, as well as an extremely prominent inflammatory component that could be mistaken for inflammatory pseudotumor or even a lymphoproliferative lesion.

References from my personal perspective used for this presentation

General

1. Ferrell LD. Benign and Malignant Tumors of the Liver. In: Surgical Pathology of the GI Tract, Liver, Biliary Tract, and Pancreas, Odze R, Goldblum J, and, 2rt ed, W.B. Saunders, Chap 47, pg.1291, 2009.

2. Ferrell LD and Kakar S. Tumors of the Liver, Gallbladder and Biliary Tree. In: Diagnostic Histopathology of Tumors, Fletcher C (ed), 4rd Ed, Elsevier, Edinburgh, Chap 10, pg. 477, 2013.

3. Ferrell LD, Gill R, and Geisinger KR. Neoplasms and Tumor-Like Conditions of the Liver. In: Silverberg's Principles and Practice of Surgical Pathology and Cytopathology, Wick M, Livolsi V, Pfeifer J, Stelow E, Wakely P (eds), 5th Ed, in press for 2014.

4. Goodman Z, Terracciano LM and Wee A. Tumours and tumour-like lesions of the liver, chap 14. In: MacSween's Pathology of the Liver, Burt AD, Portmann BC and Ferrell LD (eds), 6th Ed, Elsevier, Edinburgh, 2012, pp. 361-401.

Lesion-specific

5. Kim GE, Thung SN, Tsui WMS, Ferrell LD. Hepatic Cavernous Hemangioma: Under-Recognized Associated Histologic Features. Liver Int'l, 26:334-38, 2006.

6 Ferrell LD. Cavernous Hemangioma Variants, Chap 29.1. In: Liver Pathology, Consultant Pathology Series, Demos Medical Publishers, 2011, Ferrell L Kakar S and (eds), 2011. 7. Mattis AN, Fischer S, Makhlouf H, Tsui W, Cho S, Ferrell L. Problematic Cavernous Hemangioma Variants and Other Benign Mimics. Mod Pathol 23 (Supple 1): 364A, 2010.

8. Gill R, Alves V, Makhlouf H, Sempoux C, Thung S, and Ferrell L. Small Vessel Hepatic Hemangioma, an Atypical Hemangioma Variant in Adult Liver. Mod Path, 25(supple 2): 413A, 2012.

9. Gill R, Sempoux C, Makhlouf H, Thung S, Amancio TT, Alves V, and Ferrell L. GLUT1 Expression in Adult Hepatic Vascular Neoplasms. Mod Path 26 (supple 2): 402A, 2013.

10. 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 Pathol 23 (Supple 1):352A, 2010.

11. Cho S, Wanless I, Paradis V, Pai R, Bioulac-Sage P, Alves V, Souza T, Makhlouf H, Schirmacher P, 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.

12. Frankel WL and Zhou X. Embryonal Sarcoma, Chap 32.2. In: Liver Pathology, Consultant Pathology Series, Demos Medical Publishers, 2011, Ferrell L Kakar S and (eds), 2011.

13. Kiani B, Ferrell LD, Qualman S, Frankel WL. Immunohistochemical analysis of embryonal sarcoma of the liver. Applied Immunohistochem Mol Morphol 14:193-7, 2006.

14. Tsui WMS, Colombari R, Bonetti F, Portmann BC, Thung SN, Ferrell LD, Nakanuma Y, Snover DC, Bioulac-Sage P. Hepatic Angiomyolipoma: Delineation of Unusual Morphological Variants. Amer J Surg Pathol, 23:34-48, 1999

15. Cortese CM and Nakhleh RE. Angiomyolipoma, Chap 32.3. In: Liver Pathology, Consultant Pathology Series, Demos Medical Publishers, 2011, Ferrell L Kakar S and (eds), 2011.

16. Ferrell LD. Angiomyolipoma, Inflammatory Variant, Chap 32.4. In: Liver Pathology, Consultant Pathology Series, Demos Medical Publishers, 2011, Ferrell L and Kakar S (eds), 2011. 5/12/2014

Mesenchymal Tumors

MESENCHYMAL TUMORS OF Focus on Vascular Tumors THE LIVER:  Benign and the “Probably Benign” WHAT’S NEW AND UNUSUAL  Newly-described and variant lesions (MY PERSPECTIVE)  Malignant Distinction of benign/low grade lesions from Angiosarcoma What is NOT Angiosarcoma CURRENT ISSUES IN ANATOMIC PATHOLOGY Focus on Angiomyolipoma: Problem MAY 23, 2014 variants that still lead to diagnostic errors  Epithelioid, inflammatory, trabecular Linda Ferrell, MD, UCSF

Cavernous Hemangioma (CH)

VASCULAR TUMORS Not true arterial or venous The Benign and Probably Benign architecture HEMANGIOMA VARIANTS No organized VASCULAR MALFORMATIONS muscle bundles No elastic laminas Not capillary-like

1 5/12/2014

Cavernous Hemangioma (CH) Sclerosis within Cavernous Hemangioma

Not true arterial Sclerosis of or venous thrombosed, ischemic zones architecture with scar formation.

No organized muscle bundles “Neo-vessels” No elastic laminas Recanalized Not capillary-like channels

Cavernous Hemangioma: Cavernous Hemangioma-like vessels What is often “not seen”…. in adjacent liver

 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 5/12/2014

Giant Cavernous Hemangioma Giant Cavernous Hemangioma

38 yr old woman, in liver failure. Right Lobe CH Left lobe HLV  Explant, right lobe with giant hemangioma

 Left Lobe: Smaller, irregularly shaped CHs and transitional areas with HLVs admixed with liver, as well as smaller

“Metatastatic” and “Invasive” Cavernous Hemangioma Cavernous Hemangioma Variant

Lesion extending into hilum around Omental Lesion Diagnoses: Giant Cavernous Hemangioma arteries, nerves and ducts and Cavernous Hemangiomatosis  CH-like vessels throughout liver  Lung, spleen, omentum involved with CH- like lesions

Problematic cavernous hemangioma variants and other benign mimics: A Nerve Mattis, S Fischer, H Makhlouf, W Tsui, S Cho, L Ferrell. Poster at USCAP Duct Mar 2010, published Mod Pathol Supple 1, 2010. Artery

3 5/12/2014

Vascular Malformations Vascular Malformations

Contributors and co-authors of 2 abstracts:  Hereditary Hemorrhagic Telangiectasia  Cho S, Paradis V, Pai R, Bioulac-Sage P, Alves V, Souza T, (HHT) arterial-venous malformations Makhlouf H, Schirmacher P, Evason K, Ferrell L. Histopathologic Features of Extensive Hepatic Vascular also known as Osler-Weber-Rendu Malformations. Mod Path 23 (Supple 1):352A, 2010.

 Cho S, Wanless I, Paradis V, Pai R, Bioulac-Sage P, Alves V, Souza T, Makhlouf H, Schirmacher P, Evason K, Ferrell  Other Arterial and Venous L. FNH-Like Lesions and Glutamine Synthetase Expression Malformations with similar features in the Liver in Hereditary Hemorrhagic Telangiectasia. Mod Path, 24 (Supple 1):358A, 2011. (may or may not be HHT)

Vascular Malformations: Vascular Malformations Early Lesions or Mild Involvement

Periportal fibrosis, Periductal fibrosis (as early Spectrum: Early or mild lesions can look much Elastochrome stain ischemic lesion) Early, mild different than advanced or severe lesions probably primarily due to To thrombosis and ischemic effects Late, severe

4 5/12/2014

Vascular Malformations: Vascular Malformations More Severe or Advanced Lesions Severe sinusoidal changes

Extension of lesions into Thrombosis within vessels sinusoids and sinusoids

Vascular Malformations: More Severe or Advanced Lesions Small Vessel Hemangioma

Hemangioma-like changes, Cavernous hemangioma-like Rare  Small vascular channels with thin extensive sinusoidal dilation transformationn walls  Bland endothelial cells with low Newly proliferative rate <10% (CH <5%) described  Intermediate tumor cell density  Irregular “infiltrative” growth pattern at border  abnormal liver architecture mimics HCC  scaffolding effect mimics angiosarcoma

5 5/12/2014

Small Vessel Hemangioma Small Vessel Hemangioma

Small channels with thin walls, Small channels, thin Only focal fibrotic areas Low Mib1 (Ki-67) rate walls, bland nuclei no organized muscle

Small Vessel Hemangioma Small Vessel Hemangioma

Center of lesion, bland Edge of lesion, with endothelial cells altered cell plate width Edge of lesion, trichrome Edge of lesion, reticulin

6 5/12/2014

Small Vessel Hemangioma Epithelioid Hemangioendothelioma

 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.

Elastochrome stain: Central vein Epithelioid Hemangioendothelioma involvement by tumor

Elastochrome: Angiosarcoma- like pattern of scaffolding growth trichrome plus EVG stain highlights vein wall elastic fibers

7 5/12/2014

Angiosarcoma Angiosarcoma

 Most aggressive form of vascular Epithelioid pattern High MiB1 (Ki-67) rate malignancy

 Highest proliferative rate

 Epithelioid or spindle cell forms

 Cystic and/or solid

 Known for the typical feature of “scaffolding” growth pattern

Angiosarcoma Angiosarcoma

Scaffolding growth pattern CD34 and expanded along sinusoids sinusoidal growth Cystic change (upper right) Congestion Necrosis Sinusoidal growth

8 5/12/2014

Angiosarcoma Angiosarcoma

Scaffolding Scaffolding pattern of pattern of growth growth with surrounds fibrosis of hepatocytes cell plate areas

Angiosarcoma Angiosarcoma: Highlights

 High proliferative rate and cytologic atypia Sinusoidal growth results in  - Early pattern of growth typically along sinusoids anastomosing (scaffold-like); Atypical endothelial cells, dilated channels and sinusoids pseudopapillary  - Later pattern of growth can be pseudopapillary to pattern solid; irregularly-shaped blood filled spaces

 - Lacks the stromal prominence of epithelioid hemangioendothelioma, but overlapping cases may be seen

9 5/12/2014

Undifferentiated (Embryonal) Sarcoma

Typically younger patients; tumor of uncertain etiology What else is NOT angiosarcoma Can be cystic due to necrosis/degeneration with irregular edges!! (Pattern similar to angiosarcoma scaffolding) Undifferentiated (Embryonal) Immunohistochemistry  Reactive with alpha-1-antitrypsin, alpha-1- Sarcoma of the Liver 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)

10 5/12/2014

Undifferentiated sarcoma, tumor Undifferentiated Embryonal Sarcoma edge with growth along sinusoids

PASD + globules Also Alpha-1-antitrypsin + 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

Problem Case

Angiomyolipoma  37-year-old woman  11 cm pedunculated mass Problem variants  No cirrhosis or other risk factors for HCC Epithelioid, Trabecular, and  Mass noted during routine gynecologic exam, no symptoms Inflammatory

11 5/12/2014

HCA, HCC? Reticulin Stain: too much loss for HCA

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.

12 5/12/2014

Angiomyolipoma Angiomyolipoma

Classic Epithelioid Cells Spindle Cells features:

Fat, Epithelioid, Spindle cells

Problem Case: Angiomyolipoma Trabecular Angiomyolipoma

HMB-45: stains stronger SMA: usually stains on epithelioid cells spindle cells

13 5/12/2014

Problem Case: Problem case: Trabecular Angiomyolipoma Inflammatory Angiomyolipoma

Focal dense to scattered diffuse T-cell infiltrate HMB-45

Problem case: Angiomyolipoma Problem case: Angiomyolipoma, Inflammatory and Trabecular Inflammatory and Trabecular

Case with HMB-45 SMA both inflammatory and “trabecular” background

14 5/12/2014

Angiomyolipoma, Mixed variant Angiomyolipoma, Mixed variant

Fatty areas Trabecular areas Inflammatory areas, 10x

Angiomyolipoma, Mixed variant THANKS FOR THE INVITATION TO PRESENT THIS TOPIC HMB-45 Inflammatory AND SPECIAL THANKS TO ALL foci with WHO HAVE CONTRIBUTED TO THE absent REFERENCED STUDIES: staining WE WOULDN’T HAVE THIS DATA (SMA only rare + cell, WITHOUT THESE not shown) COLLABORATION

15