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174 P. G a i n e s
Fig. 17.1 Clinical photograph showing typical port wine stain manifestation of capillary malfor-
mation and limb hypertrophy
Hypertrophy of Bone and Soft Tissues (Fig. 17.1)
• Commonly detected as a difference in shoe size.
• When limb discrepancy is likely to affect gait (projected limb length discrepancy
of 2 cm or greater), orthopedic correction is necessary.
• Other orthopedic abnormalities include polydactyly, syndactyly, and con-
tractures. When these interrupt normal function, surgical correction is
indicated.
Venous Abnormality (Fig. 17.2)
• Typically large and extensive.
• Normally occurs in childhood, and should not be misdiagnosed as simple
varicose veins when identified in an adult.
• The classical large lateral “vein of Servelle” only occurs in 30–55% of affected
limbs. The vein may drain into internal iliac, external iliac, profunda femoris,
superficial femoral, or popliteal veins.
• There may be hypoplasia, aplasia, or aneurysmal dilatation of the deep
veins.
• The veins do not function normally. There is always superficial reflux that
is accompanied by deep vein reflux and perforator reflux in the majority of
affected legs.
17 Klippel-Trenaunay Syndrome 175
Fig. 17.2 Venous
malformation in KTS, a port
wine stain is just visible
• Such morphological and functional abnormalities result in the following:
– Superficial thrombophlebitis
– Deep venous thrombosis
– Cellulitis
– Chronic venous insufficiency with lipodermatosclerosis and frank ulceration.
• Large abnormalities may have an associated coagulopathy, which rarely has
resulted in significant hemorrhage.
Other Features
• 10% of patients also have a lymphatic vascular malformation.
• Associated nonvascular abnormalities have been described in most organ
systems.
• Up to 23% of patients have imaging evidence of involvement of the genito-
urinary tract, sometimes clinically evident as bleeding or problems with labor.
• Gastrointestinal involvement occasionally results in bleeding and anemia.
176 P. G a i n e s
Assessment
• Thorough history and clinical examination is the essential foundation of manage-
ment.
• Absence of clinically evident high-flow abnormality separates this from Parkes
Weber syndrome.
• Examination with a hand-held Doppler device will confirm the lack of high flow
in the vascular abnormality.
• Clinical photographs are very helpful to document clinical progression.
• If invasive treatment is considered, an MR examination (including T1 and T2 fat
saturated) will demonstrate the extent of the venous abnormality (Fig. 17.3).
• Ultrasound will identify functional venous abnormalities.
• Coagulopathy in large abnormalities can be diagnosed and assessed by measuring
platelet count, serum fibrinogen, and fibrin degradation products.
Fig. 17.3 T-2 weighted fat-saturated image showing extensive venous malformation extending
from the foot into the buttock
Management
• Patients should be educated regarding the syndrome. Emphasis includes a lack of
cure, lack of inheritance, and unlikely impact upon life expectancy.
• Orthopedic correction of functional bone abnormalities should be considered
when the patient is a child.
• Invasive management of the venous malformation is largely futile and likely to
be associated with recurrence and complications.
• Very occasionally a focal aspect of the venous malformation can be treated by
percutaneous embolisation techniques to manage local complications, e.g. pain,
bleeding, etc. (see Chapter 2.1.1).
17 Klippel-Trenaunay Syndrome 177
• Before performing embolotherapy/sclerotherapy, it is essential to establish the
condition of the deep veins. If the deep veins are abnormal, then treating the
superficial veins can lead to worsening edema.
• Recurrence rates following treatment of varicosities are high.
• Care should be directed towards preventing complications and treating disabling
symptoms.
• The cosmetic implications of the capillary malformation can be underestimated.
Care can include camouflage cosmetics and occasionally laser therapy.
• All patients with leg venous malformation should wear a compression stocking
to prevent the complications of venous hypertension.
• Patients with a venous malformation are at increased risk of DVT and PE and
therefore should be treated as high risk for this complication through hospital
admissions, pregnancy, and on long flights. Female patients may be advised to
avoid oral contraceptives.
• Pelvic venous abnormalities may obstruct and complicate labor. Imaging should
preferably precede labor and consideration given to elective caesarean section.
Keypoints
• Patients with Klippel-Trenaunay syndrome will seldom require
embolotherapy.
• Invasive therapy is indicated for local problems such as pain and bleeding.
• It is essential to remember that the deep veins are frequently abnormal and
that this will increase the risks of therapy.
• Patients requiring treatment should be referred for specialist opinion.
Chapter 18
Biologic Effects of Tumor Embolization
Erik Cressman
Introduction
The biological effects of tumor embolization are complex. Effects can be classified
as local which are a direct consequence of ischemia in the target organ and sys-
temic due to the release of chemical mediators by the target organ and the embolic
agent/chemotherapy. The biological effects will depend on many interrelated factors including the target tissue, the goal of the embolization, and the choice of the
embolic agent and technique used.
The Target Tissue
This depends on susceptibility of both the tumor and the associated organ to
embolotherapy. In particular
• Will organ dysfunction following embolization be clinically important?
• Will the tumor respond to treatment?
The Goal of the Embolization Procedure
• Temporary blockage to simplify surgery
• Local chemotherapy
• Infarction of the tumor.
The choice of agent and technique: this will depend on the following:
• The goal of the procedure
• The level of occlusion to be achieved
The following discussion is divided into issues related to the target organ, the
local effects, and complications, that are influenced by (and in turn will influence)
the biologic effects of embolotherapy.
Transcatheter Embolization and Therapy,
Techniques in Interventional Radiology, DOI 10.1007/978-1-84800-897-7_18,
C
Springer-Verlag London Limited 2010
179
180 E. Cressman
Biological Effects on the Embolized Tissue/Organ
Short Term
• Ischemia: blockage of the arterial supply will render the tumor and surrounding
tissue ischemic.
• Inflammation: the degree varies with embolic agent. Some agents cause an
arteritis.
• Post-embolization syndrome: This is dealt with in Chapter 13.
• Necrosis: cell death due to ischemia or the effects of adjunctive agents such as
chemotherapy.
Hypoxia Inducible Factor 1 (HIF-1)
The mechanism underlying many of the local effects is upregulation of HIF-1.
• It is one of the main regulatory substances and is present in every cell.
• Regulates many genes (Table 18.1).
• Allows a cell to rapidly respond to changes in the oxygen environment, although
the exact effects differ in each cell type.
Table 18.1 Examples of genes affected by Hypoxia Inducible Factor
Gene
ABC (ATP-binding cassette),
GLUT1 (glucose transporter 1),
LDHA (Lactate dehydrogenase
A), and PDK1 (Pyruvate
dehydrogenase kinase 1)
VEGF—vascular endothelial
growth factor
HGF—hepatocyte growth factor
TGF-a—transforming growth
factor alpha
TGF-b—transforming growth
factor beta
Ki-67
PCNA—proliferating cell nuclear
antigen
Up (↑)ordown
(↓) regulated Consequence
↑
↑
↑
↑
↑
↓
↓
Promote glycolysis
Promotes angiogenesis
Promotes hepatocyte proliferation
Promotes hepatocyte proliferation in
remnant liver following portal vein
embolization promoting hypertrophy
Promotes hepatocyte proliferation in
embolized liver
Reduces hepatocyte proliferation, Ki-67
is absent in G0 or quiescent cells
Reduces hepatocyte proliferation, nuclear
protein seen in late G1 and S phase
18 Biologic Effects of Tumor Embolization 181
Long-Term Effects of Embolization
• Fibrosis
• Neovascularization
• Recanalization
Tumor Lysis Syndrome (TLS)
This is seen most commonly with leukemias and lymphomas treated with IV
chemotherapy, in which large numbers of tumor cells die simultaneously following
exposure to cytotoxic drugs.
• TLS phenomenon occurs only rarely with embolization procedures.
• Tumors that are particularly susceptible undergo massive necrosis or apoptosis at
a rate faster than the body can dispose of the released intracellular contents.
• Elevated s erum levels of potassium, uric acid, and phosphorus and a compen-
satory lowering of serum of calcium can result.
• Uric acid precipitation in the kidneys may lead to renal failure. One possible
treatment strategy is neutralization or very mild alkalinization of the urine, which
will decrease the precipitation of uric acid in the kidneys. It must also be remembered that patients vary in their ability to respond to the embolization procedure,
with greater risk of renal failure and other complications in advancing age.
Target of Embolization
The Patient
The first question to be addressed is the overall fitness of the patient.
• If the patient is severely compromised already, then any adverse biological effects
may be amplified.
• The ability of the patient to tolerate or survive side effects must be taken into
account. This is particularly true with chemoembolization of liver cancer patients.
The Target Organ
The function of the target organ may be compromised as a result of the underlying disease process. This will modify the tolerance to and clinical sequelae of
embolization. This may limit the amount or degree of treatment that can be safely
performed.
182 E. Cressman
Liver
• A patient with a cirrhotic liver and advanced local disease will have less-
functional reserve and will not tolerate chemoembolization, as well as a patient
with good synthetic function.
• A patient with an occluded portal vein may not tolerate embolization at all.
• Staged and/or superselective procedures may be appropriate to avoid a systemic
effect or fulminant iatrogenic liver failure.
Kidney
• A patient with impaired renal function will have less ability to tolerate renal
embolization procedures or the sequelae of embolization of other targets.
The Disease Process
The prognosis of the target condition and other co-morbidity will also affect
the risk/benefit ratio of the procedure. This entails a thorough knowledge of the
prognosis of the patient and also the severity of the symptoms. In general terms:
• In patients with benign disease/good long-term prognosis/mild symptoms, avery
low-risk profile and excellent long-term outcome are required.
• In patients with malignant disease with a potential for a good prognosis, more
aggressive intervention with a greater degree of risk may be warranted.
• In patients with malignant disease with poor prognosis or undergoing palliative
procedures, the short-term outcome is most important.
• The nature of the treatment will depend on the severity of the symptoms and the
patient’s feelings regarding intervention. It is likely that therapy with less risk
involved will be appropriate.
Keypoints
The overall effect of embolization at the local level always involves some
degree of ischemia, but to assume factors such as VEGF and HIF1 are
upregulated in all cases is an oversimplification.
Most embolic agents also result in some degree of inflammation, more so
when chemotherapy is coadministered.
Few temporary agents are permanent, whereas there are many cases where
a presumably permanent agent was in fact temporary.
18 Biologic Effects of Tumor Embolization 183
Controversy persists over whether or not permanent occlusion is desirable in tumors, and whether ischemia without chemotherapy (as in uterine
fibroid embolization) is sufficient to cause tumor degradation. Further work
in relevant animal models would help shed light on these issues and is much
needed.
Recommended Reading
1. S Baum, MJ Pentecost (eds.) Abrams’ Angiography Interventional Radiology 2nd ed, Chapters
10 and 11 Lippincott, Williams, and Wilkins Philadelphia PA, 2006
2. S Stampfl, N Bellemann, U Stampfl et al. Inflammation and Recanalization of Four Different
Spherical Embolization Agents in the Porcine Kidney Model. JVIR 2008 19(4): 577–586
3. GP Siskin, A Beck, M Schuster et al. Leiomyoma Infarction After Uterin Artery Embolization:
A Prospective Randomized Study Comparing Tris-acryl Gelatin Microspheres Versus
Polyvinyl Alcohol Microspheres JVIR 2008 19(1): 58–65
4. BJ Moeller, Y Cao, Z Vujaskovic et al. The Relationship Between Hypoxia and Angiogenesis.
Sem Rad Onc 2004 14(3): 215–221
5. S Gupta, S Kobayashi, S Phongkitkarun et al. Effect of Transcatheter Hepatic Arterial
Embolization on Angiogenesis in an Animal Model. Invest Rad 2006 41(6):516–521
6. TY Patel, DM Hovsepian, JR Duncan Measurement of Blood Flow Before and After
Embolization with Use of Fluorescent Microspheres in an Animal Model. JVIR 2006
17:103–111
7. GL Semenza Hypoxia-inducible Factor 1 and Human Cancer. ASCO Educational Book 2008
548–551
Chapter 19
Liver Tumors (Hepatocellular Cancer)
Jai Patel
This section covers embolic therapy for the treatment of hepatocellular carcinoma
(HCC) only. Liver embolization for neuroendocrine tumors and other metastatic
tumors is covered elsewhere.
Epidemiology of HCC
• Fifth commonest malignancy world-wide, third commonest cause of cancerrelated death.
• Predisposing factors include cirrhosis, chronic hepatitis, aflatoxin.
• Incidence rising due to high prevalence of hepatitis B virus (HBV) in Asia/Africa
and hepatitis C virus (HCV) in Europe/United States.
• 90% occur in cirrhotics—common causes include alcohol and HCV
in Europe/United States and HBV in Asia/Africa. Other risk factors—
hemochromatosis, primary biliary cirrhosis (PBC).
Diagnosis
Based on the European Association for the Study of the Liver (EASL) criteria.
For tumors >2 cm in a patient with cirrhosis, diagnosis is confirmed on the basis
of one of the following:
• Two imaging modalities showing arterial hypervascularity in the liver mass.
• One imaging modality showing arterial hypervascularity with alpha-fetoprotein
(AFP) > 400 μg/mL.
• Biopsy confirmation of HCC.
Imaging
• CT—hypervascular liver mass enhancing in arterial phase, with washout in the
portal phase.
Transcatheter Embolization and Therapy,
Techniques in Interventional Radiology, DOI 10.1007/978-1-84800-897-7_19,
C
Springer-Verlag London Limited 2010
185