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38. Rahman A, Assifi MM, Pedroso FE, et al. Is resection equivalent to transplantation for early
cirrhotic patients with hepatocellular carcinoma? A meta-analysis. J Gastrointest Surg.
2012;16(10):1897–909.
39. Proneth A, Zeman F, Schlitt HJ, Schnitzbauer AA. Is resection or transplantation the ideal
treatment in patients with hepatocellular carcinoma in cirrhosis if both are possible? A systematic review and metaanalysis. Ann Surg Oncol. 2014;21(9):3096–107.
40. Sapisochin G, Castells L, Dopazo C, et al. Single HCC in cirrhotic patients: liver resection or
liver transplantation? Long-term outcome according to an intention-to-treat basis. Ann Surg
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41. Afdhal N, Everson G, Calleja JL, et al. Sofosbuvir and ribavirin for the treatment of chronic
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response and safety. J Hepatol. 2014;60(1 Suppl):S28.
T. Pham et al.
85© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_8
Chapter 8
Hepatic Epithelioid Hemangioendothelioma
John F. Renz
Abstract This manuscript provides a concise surgical review of hepatic epitheliod
hemangioendothelioma. A detailed review of diagnosis, pre-surgical radiologic
evaluation, surgical techniques, including liver transplantation, and post-surgical
care of the patient with hepatic epitheliod hemangioendothelioma is presented.
Keywords Hepatic epitheliod hemangioendothelioma • Liver surgery • Liver transplantation • Hepatobiliary surgery • Liver tumor
Introduction
Hepatic Epitheliod Hemangioendothelioma (HEHE) remains a diagnostic and
therapeutic challenge to the practicing hepatobiliary surgeon. With less than 1000
reported cases since its initial description by Weiss and Enzinger in 1982 [ 1 ] and a
widely variable clinical course, HEHE remains a diagnosis that affords the clinician
a unique opportunity to tailor therapy to the patient. Infantile hemangioendothelioma,
a rare neonatal vascular tumor associated with congestive heart failure, thrombocytopenia, and consumptive coagulopathy, is a unique clinical entity that will not be
addressed in this manuscript [ 2 ].
Presentation
HEHE is a vascular tumor of endothelial cell origin with an incidence of approximately
1/1,000,000 population [ 3 ]. Since the initial series of 32 patients reported by Ishak
in 1984 [ 4 ], our understanding of this rare disease has evolved through collective
case reports, database surveys, and meta analyses. HEHE expresses a slight female
J. F. Renz (*)
University of Chicago Medicine , 5841 S. Maryland, Room J517 MC5027 ,
Chicago , IL 60637 , USA
e-mail:
jrenz@surgery.bsd.uchicago.edu
86
preponderance (3:2) and is most often diagnosed in the fourth decade of life [ 5 ].
Presentation can vary widely from an incidental fi nding on routine imaging
described in approximately 25 % of new cases to overt liver failure . Extra-hepatic
involvement is present in over a third of patients at the time of diagnosis [ 5 , 6 ]. The
most frequent presentation includes a history of intermittent right upper quadrant
pain , malaise, and weight loss. As the indolent tumor replaces more hepatic volume,
late fi ndings of hepatomegaly, jaundice , hepatic outfl ow obstruction (Budd-Chiari
syndrome), Kasabach-Merritt syndrome, hemorrhage secondary to tumor rupture,
and acute liver failure emerge [ 7 – 10 ]. The presence of symptoms at diagnosis has
been validated as a poor prognostic indicator by MVA [ 11 ]. To date, no clear risk
factors predisposing to HEHE have emerged; however, oral contraceptives, vinyl
chloride, viral hepatitis, and trauma to the liver have been implicated in its development [ 5 , 12 ]. Notably, HEHE is not associated with chronic liver disease [ 5 ]. This
affords the physician typically normal hepatic parenchyma to accommodate medical, radiologic , or surgical therapy.
Diagnosis
As HEHE lies variably within the spectrum between hemangioma and angiosacroma,
diagnosis requires integration of radiologic , histologic, and immunologic data. For
the diagnosis of HEHE, magnetic resonance imaging (MRI) is emerging as the
preferred therapy over ultrasound and computed tomography ( CT ) [ 13 ]. HEHE is
described radiographically as two types: nodular and diffuse. The nodular type is an
early manifestation of HEHE characterized by independent peripheral lesions,
ranging from <1 cm to several centimeters in diameter, within the liver. Presentation
typically involves both hepatic lobes with a preponderance of tumor in the right
hepatic lobe. As the disease progresses, the multifocal tumors coalesce into bulky
subcapsular disease throughout the liver defi ning the advanced diffuse form of
HEHE. Capsular retraction develops secondary to scarring and fi brosis [ 14 ].
When evaluating a CT , the bulk of disease is best appreciated on unenhanced
imaging where intra-tumoral calcifi cation and capsular retraction can be appreciated.
Contrast CT fi ndings include arterial phase marginal enhancement that may appear
target-like and is often described as a “halo.” The concentric zonal or target- like
appearance refl ects the histology of an avascular, central stomal region with fi ngerlike tumor projections extending peripherally along hepatic sinusoids. These areas
become isodense to hepatic parenchyma on post-contrast imaging [ 14 , 15 ]. On
MRI, the central, hypocellular regions may demonstrate previous hemorrhage,
thrombus, necrosis, or calcifi ciation with low signal T-1 weighting with T-2 hyperintesity. Gadolinium administration optimally demonstrates the peripheral halo
with progressive centripetal fi lling on subsequent images. The key fi ndings for any
cross-sectional imaging modality are: multiple heterogeneous lesions, subcapsular
location, capsular fl attening or retraction, and peripheral delayed contrast
enhancement with centripetal fi lling [
16 ]. The utility of FDG-PET is variable.
J.F. Renz
87
FDG-PET has not proven sensitive in screening or diagnosis : however, when it is
positive in approximately 40 % of cases, it can be useful in monitoring response to
therapy [ 17 ].
Suggestive radiologic fi ndings must be followed by histologic and immunologic
analysis to secure the diagnosis of HEHE. Adequate tissue can be obtained by percutaneous , ultra-sound-guided liver biopsy or diagnostic laparoscopy . HEHE is an
endothelial cell origin tumor with an appearance of spindle-shaped endothelial cells
multiplying along vascular planes. The histology is variable within the spectrum of
hemangioma to angiosarcoma but the tumor characteristically expresses Factor
VIII-related antigen, CD34 (human hematopoietic progenitor cell antigen), and
CD31 (platelet endothelial cell adhesion molecular 1). Immunoanalysis for at least
two of these three antigens is necessary to secure the diagnosis. Therefore, precise
pathologic interpretation is integral to identifying malignant features of HEHE and
predicting clinical behavior [ 5 ].
Potential genetic translocations associated with HEHE have been postulated
[ 18 ]; however, the rarity of the disease has impeded linkage analysis. Serum chem-
istries and standard tumor markers are non-diagnostic at presentation with one
exception: an elevated CA19-9 is a negative prognostic factor for HEHE and should
guide the clinician toward biliary origin malignancies [ 11 ].
Treatment
The wide clinical spectrum of disease at presentation and its variable biologic
behavior afford the clinician the opportunity to utilize a variety of therapeutic
modalities in “tailoring” therapy to the HEHE patient. The incidence of HEHE has
prevented the establishment of guidelines and resulted in the application of a
multitude of successful therapeutic endeavors ranging from chemotherapy to liver
transplant ation .
At the moment, the benchmark therapies remain surgical and, whenever possible,
resection is preferred [ 5 , 6 ]. Historically, the bulk of disease at diagnosis has favored
liver transplant ation ; however, recent advances in surgical technique coupled with
the fact that HEHE typically occurs in the setting of otherwise normal hepatic
parenchyma have opened the possibility of good outcomes in the setting of repetitive
surgical resection versus liver transplantation. Grotz et al. reported a retrospective
series of 30 HEHE patients treated by surgical resection (SR), liver transplantation
(LTX), medical therapy, or no therapy at the Mayo Clinic between 1984 and 2007
[ 6 ]. While patients were not randomized to SR or LTX, the group maintained a very
aggressive protocol toward SR whenever possible. At a median follow- up of
>41 months, the SR group, which contained approximately the same number of patients
as the LTX group, demonstrated comparable disease-free survival and overall
survival as LTX with a lower incidence of post-operative complications and period
of hospitalization. The 1-, 3-, and 5-year overall survival for SR was 100 %, 86 %,
and 86 % versus 91 %, 73 %, and 73 % for LTX, respectively. The 1-, 3-, and 5-year
8 Hepatic Epithelioid Hemangioendothelioma
88
disease-free survival for the SR group was 78 %, 62 %, and 62 % versus 64 %, 46 %,
and 46 % for LTX, respectively. Hospital stay and the occurrence of Clavien ≥ stage
IV complications were lower in SR but did not achieve statistical signifi cance.
Clinicopathologic predictors of prolonged disease-free survival have been
proposed by Grotz et al. based upon their retrospective series data but have not been
prospectively validated. These include: largest tumor size ≤10 cm, total tumor number ≤10, and hepatic involvement ≤4 segments [ 6 ]. This led the authors to advo-
cate for SR as the surgically preferred option for patients with HEHE “regardless of
bilobar distribution provided the hepatic disease can be resected [ 6 ].” The recent
description of liver partition with portal vein ligation for staged hepatectomy
described by Schlitt and others offers a new opportunity to dramatically extend the
realm of hepatic resection and thereby avoid liver transplant ation [ 19 ]. However,
one must remember that HEHE is a widely variable disease entity and Grotz et al.
concede the biologic behavior of each presentation factored largely into their
decision to recommend curative surgical therapy [ 6 ]. An alternative strategy of
hepatectomy followed by carbon-ion radiotherapy has also been advocated [ 20 ].
Intent to cure must remain the goal as palliative surgical debulking has been demonstrated to enhance progression [ 21 ].
Liver transplantation has proven a durable therapy for the treatment of
HEHE. Initially described by Marino et al. in 1988 [ 22 ], the application of LTX to
patients with extensive bilateral disease has yielded excellent results on three continents [ 11 , 23 , 24 ]. Mehrabi et al. performed a meta analysis from 1984 through
2005 identifying 402 cases [ 5 ]. Of this group, 45 % were treated by LTX, 25 %
received no treatment, 21 % received chemotherapy and/or radiation therapy, and
only 9 % SR. Within this group, the 1- and 5-year survival for LTX were 96 % and
55 % respectively. These results were bested only by the SR group that demonstrated 1- and 5-year survival of 100 % and 75 %, respectively. However, it is impossible to determine through meta analysis the extent of disease approached through
SR. Notably, the authors identifi ed extra-hepatic disease in 37 % of patients at the
time of diagnosis but the presence of extra-hepatic disease did not portend a poor
prognosis.
The unique fi nding of extra-hepatic disease not impacting long-term survival
was confi rmed by Lerut et al. who reported the results of the European Liver
Transplant Registry in 2007 [ 23 ]. In their analysis of 59 patients followed for a
median of greater than 6 years, the disease-free survival at 1-, 5-, and 10-years postLTX were 90 %, 82 %, and 64 %, respectively. Overall recurrence in the cohort was
24 % with a median time to recurrence of 49 months. The extent of disease reported
in referring to LTX included bilobar tumor 96 %, >15 tumor nodules 86 %, pre-LTX
therapy 30 %, lymph node invasion 30 %, and extra-hepatic disease 17 %. In this
context, the overall results obtained with LTX were excellent and led the authors to
conclude pre-existing extrahepatic disease as well as lymph node localization are
not contraindications to LTX. Vascular invasion upon histologic examination
reduced overall patient survival but not disease-free survival. Thus, the pattern of
continual treatment of a low grade malignant tumor with a slowly progressive
phenotype re-emerged as the authors’ inclusion of extra-hepatic disease was limited
J.F. Renz
89
to that amenable to surgical resection with or without radiation therapy. The fi nding
of carcinomatosis excluded LTX [ 23 ].
Data from the United Network for Sharing on 110 transplanted patients between
1987 and 2005 were reported by Rodriguez et al. in 2008 [ 24 ]. Their analysis was
limited through inclusion of children transplanted for the infantile variant of HEHE
and a relatively short median follow-up of only 24 months. The authors reported
patient and allograft survival on a cohort including adults and children with an
overall mortality related to HEHE recurrence of 16 %, presumably all in adults as
the pediatric form is thought to be benign. Unfortunately, their study was not powered to determine the effect of extra-hepatic disease at LTX [ 24 ]. When considering
LTX, it is imperative to exclude angiosarcoma as its biologic behavior is an absolute
contraindication [ 25 ].
Disease recurrence has been widely reported as distant as 12 years following
LTX and is best approached with surgery and radiation therapy where applicable [ 5 ,
26 ]. A role for adjuvant chemotherapy in the management of post-LTX recurrence
is theoretically attractive but unproven.
Alternative Therapies
The epithelial-cell origin of HEHE and its consistent over-expression of vascular
endothelial growth factor (VEGF) have made it a natural target for anti-angiogenic
therapy [ 27 ]. To date, medical therapy alone has delivered inferior results to surgical
therapy [ 5 , 6 ]; however, a variety of chemotherapeutics have been reported to affect
HEHE in individual cases. These include thalidomide, doxorubicin, 5-fl uorouracil,
vincristine, cyclophosphamide, interferon-alpha 2B, bevacizumab, sunitinib, and
lenalidomide [ 28 – 33 ]. Chevreau reported results of a European multicenter, phase
II trial of15 patients utilizing sorafenib [ 34 ]. Their early results were indeterminant,
but as more information is elicited on the genetic composition of HEHE, the promise of medical therapy, particularly in highly aggressive disease prompting acute
liver failure as well as very slowly progressing indolent disease is promising.
Summary
HEHE is a rare disease with a widely variable presentation and clinical course.
Accurate diagnosis through a combination of radiology, histology, and immunochemistry is challenging but essential for anticipating the tumor’s biologic behavior.
Ultimately, the biologic behavior guides the practitioner to the most appropriate
course of therapy with surgery , either resection or transplantation, the preferred
avenue for cure. However, further scientifi c understanding of this unique biologic
entity may yield superior outcomes through anti-angiogenic therapy.
8 Hepatic Epithelioid Hemangioendothelioma
90
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14. Amin S, Chung H, Jha R. Hepatic epithelioid hemangioendothelioma: MR imaging fi ndings.
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15. Radin D, Craig J, Colletti P, Ralls P, Halls J. Hepatic epithelioid hemangioendothelioma.
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16. Roth C, Mitchell D. Hepatocellular carcinoma and other hepatic malignancies: MRI imaging.
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17. Dong A, Dong H, Wang Y, Gong J, Lu Z, Zou C. MRI and FDG PET/CT fi ndings of hepatic
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18. Woelfel C, Liehr T, Weise A, et al. Molecular cytogenetic characterization of epithelioid
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of the liver successfully treated with Sorafenib. Rare Tumor. 2012;4:34–9.
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8 Hepatic Epithelioid Hemangioendothelioma
93© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_9
Chapter 9
What Is the Best Way to Screen Cirrhotic
Patients for Hepatocellular Carcinoma
in the United States?
Archita P. Desai and Helen S. Te
Abstract Hepatocellular carcinoma (HCC) continues to be a signifi cant cause of
mortality in the United States. However, HCC is curable if detected early in its
course. Cirrhosis is a well-established risk factor for HCC, but direct evidence
demonstrating the benefi t of screening for HCC in this population remains under
contention today. Ultrasound (US) every 6 months is currently the proposed screening methodology. Serum alpha-feto protein (AFP) has been dropped from screening
guidelines, yet recent prospective data reported an added effi cacy with the combination of serum AFP and US. Technological advances in cross-sectional imaging have
dramatically impacted the fi eld of hepatobiliary imaging, making them attractive
alternatives for HCC screening in selected populations. While computed tomography
(CT) does not appear to confer any signifi cant advantage to US performed by trained
personnel, magnetic resonance imaging (MRI) with hepatobiliary phase (HBP) and
diffuse weighted imaging (DWI) offers the best sensitivity and specifi city for HCC
largely due to its superiority in detecting and characterizing lesions <2 cm. Its costeffectiveness as a screening tool, however, remains to be seen.
Keywords Alpha-feto protein • Ultrasound • Computed tomography • Magnetic
resonance imaging • Hepatocellular cancer • Screening • Surveillance • Liver
transplantation
A. P. Desai
University of Arizona , 1501 N. Campbell Avenue, Rm 6309A ,
245136 , Tucson , AZ 85724 , USA
e-mail:
architadesai@deptofmed.arizona.edu
H . S . T e (
*)
University of Chicago Medical Center , 5841 S. Maryland Ave., MC 7120 ,
Chicago , IL 60615 , USA
e-mail:
hte@medicine.bsd.uchicago.edu
94
Introduction
Despite the continuing medical advances in the management of chronic liver
disease, the incidence of hepatocellular carcinoma (HCC) has steadily risen in the
past two decades. Globally, HCC has become the fi fth leading cause of cancer and
the second leading cause of cancer-related death in adult men [ 1 ]. In the United
States, the age-adjusted incidence rates have doubled since the mid 1980s [ 2 ], causing
similar increases in HCC-related mortality and hospitalization rates [ 3 , 4 ]. Although
the incidence of HCC appears to have plateaued in the past decade, HCC-related
deaths remain on the rise [ 5 , 6 ].
Hepatocellular carcinoma is curable if detected early in its course. Liver
transplantation for HCC cases that fall within the Milan criteria has demonstrated
excellent results with 5-year survival rates exceeding 70 %. Hepatic resection in
non-cirrhotic patients or in well-compensated cirrhotic patients with no portal
hypertension and no signifi cant liver functional impairment has led to 5-year
survival rates exceeding 70 % as well [ 7 ]. However, to achieve a cure, the diagnosis
must be made early, and early diagnosis is only possible if screening is performed.
Evidence demonstrating the benefi t of screening for HCC remains under contention
today. A meta-analysis found that evidence supporting the benefi t of HCC screening
in at-risk patients (cirrhotics and noncirrhotics) were of very low-strength [ 8 ]. While
cirrhosis is a well-established risk factor for HCC, there has been no randomized
controlled trial (RCT) performed in the US to validate the benefi t of HCC screening
in this population, partially due to ethical reasons and patient refusal [ 9 ]. Investigators
have resorted to modeling techniques to demonstrate the cost- effectiveness of HCC
surveillance in cirrhosis, and screening has been found to provide a survival benefi t
in targeted patients who are viable candidates for interventions at acceptable costs
[ 10 – 15 ]. In fact, the American Association for the Study of Liver Diseases (AASLD)
[ 7 ] and the European Association for the Study of the Liver (EASL) guidelines [ 16 ]
recommend HCC surveillance with an ultrasound every 6 months for patients with
cirrhosis of any cause, wherein the incidence of HCC is estimated to be 1.5 % per year
or greater [ 7 ]. However, the question remains, does biannual ultrasound provide the
best benefi t in screening cirrhotic patients for HCC in the United States in 2014?
Search Strategy
A literature search of English language publications from 2000 to 2014 was used to
identify published data on screening for HCC in cirrhotic patients using the PICO
outline (Table 9.1 ). Databases searched were PubMed, Medline and Cochrane
Evidence Based Medicine . Terms used in the search were “hepatocellular carcinoma/
screening/ cirrhosis ,” “liver cancer /screening/cirrhosis.” Manual searches of reference
lists from applicable studies were performed to identify any studies that may have
been missed by the computer-assisted search. As the quality of studies for each
A.P. Desai and H.S. Te