Mesenchymal Tumors of the Liver: Whats New and Unusual (My - - PDF document

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 hemangioma), 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

• f mesenchymal tumors, especially within the spectrum of vascular lesions, so my personal perspective
• f 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/vascular tumor 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 angiosarcoma. 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 hemangioendothelioma, 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 neoplasm, 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, infantile 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 Neoplasms 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 Telangiectasia (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 thrombosis 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 telangiectasias can lead to a much larger vascular network

• f 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) Sarcoma: 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

• ne 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 1

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 Angiosarcoma

What is NOT Angiosarcoma

Focus on Angiomyolipoma: Problem variants that still lead to diagnostic errors

Epithelioid, inflammatory, trabecular

The Benign and Probably Benign HEMANGIOMA VARIANTS VASCULAR MALFORMATIONS

VASCULAR TUMORS Cavernous Hemangioma (CH)

Not true arterial

• r venous

architecture

No organized muscle bundles No elastic laminas Not capillary-like

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Cavernous Hemangioma (CH)

Not true arterial

• r venous

architecture

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

Cavernous Hemangioma-like vessels in adjacent liver

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Giant Cavernous Hemangioma

38 yr old woman, in liver failure.

 Explant, right lobe with giant hemangioma  Left Lobe: Smaller, irregularly shaped CHs and

transitional areas with HLVs admixed with liver, as well as smaller hemangiomas

Giant Cavernous Hemangioma

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

Artery Nerve Duct

“Metatastatic” and “Invasive” Cavernous Hemangioma

Cavernous Hemangioma Variant

Diagnoses: Giant Cavernous Hemangioma 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 Mattis, S Fischer, H Makhlouf, W Tsui, S Cho, L Ferrell. Poster at USCAP Mar 2010, published Mod Pathol Supple 1, 2010.

5/12/2014 4

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)

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, 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.

Vascular Malformations

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

Periportal fibrosis, Elastochrome stain Periductal fibrosis (as early ischemic lesion)

5/12/2014 5 Vascular Malformations:

More Severe or Advanced Lesions

Extension of lesions into sinusoids Thrombosis within vessels and sinusoids

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

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

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Small Vessel Hemangioma

Small channels, thin walls, bland nuclei Only focal fibrotic areas

Small Vessel Hemangioma

Small channels with thin walls, no organized muscle

Low Mib1 (Ki-67) rate

Small Vessel Hemangioma

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

Small Vessel Hemangioma

Edge of lesion, trichrome Edge of lesion, reticulin

5/12/2014 7

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.

Epithelioid Hemangioendothelioma Elastochrome stain: Central vein involvement by tumor

Elastochrome: trichrome plus EVG stain highlights vein wall elastic fibers

Epithelioid Hemangioendothelioma

Angiosarcoma- like pattern of scaffolding growth

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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

Epithelioid pattern High MiB1 (Ki-67) rate

Angiosarcoma

Scaffolding growth pattern along sinusoids CD34 and expanded sinusoidal growth

Angiosarcoma

Cystic change (upper right) Congestion Necrosis Sinusoidal growth

5/12/2014 9

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 pseudopapillary pattern

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 epithelioid

hemangioendothelioma, but overlapping cases may be seen

5/12/2014 10 Undifferentiated (Embryonal) Sarcoma of the Liver

What else is NOT angiosarcoma

Undifferentiated (Embryonal) Sarcoma

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

• bservation)

Undifferentiated (Embryonal) Sarcoma Undifferentiated (Embryonal) Sarcoma

Cystic areas common Related to extensive necrosis (right)

5/12/2014 11

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

5/12/2014 12

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.

5/12/2014 13

Angiomyolipoma

Classic features:

Fat, Epithelioid, Spindle cells

Angiomyolipoma

Epithelioid Cells Spindle Cells

Angiomyolipoma

HMB-45: stains stronger

• n epithelioid cells

SMA: usually stains spindle cells

Problem Case: Trabecular Angiomyolipoma

5/12/2014 14

Problem Case: Trabecular Angiomyolipoma

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

Problem case: Angiomyolipoma, Inflammatory and Trabecular

HMB-45 SMA

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Angiomyolipoma, Mixed variant

Fatty areas Trabecular areas

Angiomyolipoma, Mixed variant

Inflammatory areas, 10x

Angiomyolipoma, Mixed variant

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

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